Pemetrexed Fresenius Kabi

1 

 

 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



 

2 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Pemetrexed Fresenius Kabi 100 mg powder for concentrate for solution for infusion 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each vial contains 100 mg of pemetrexed (as pemetrexed diacid). 

 

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. 

 

White to off-white lyophilised powder or solid. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Malignant pleural mesothelioma 

Pemetrexed Fresenius Kabi in combination with cisplatin is indicated for the treatment of 

chemotherapy naïve patients with unresectable malignant pleural mesothelioma. 

 

Non-small cell lung cancer 

Pemetrexed Fresenius Kabi 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 Fresenius Kabi is indicated as monotherapy for the maintenance treatment of locally 

advanced or metastatic non-small cell lung cancer other than predominantly squamous cell 

histology in patients whose disease has not progressed immediately following platinum-based 

chemotherapy (see section 5.1). 

 

Pemetrexed Fresenius Kabi 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 Fresenius Kabi must only be administered under the supervision of a physician 

qualified in the use of anti-cancer chemotherapy. 

 

Posology 

 

Pemetrexed Fresenius Kabi in combination with cisplatin 

The recommended dose of Pemetrexed Fresenius Kabi 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. 



 

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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 section 6.2 and cisplatin Summary of Product Characteristics for 

specific dosing advice). 

 

Pemetrexed Fresenius Kabi as single agent 

In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended 

dose of Pemetrexed Fresenius Kabi is 500 mg/m2 BSA administered as an intravenous infusion 

over 10 minutes on the first day of each 21-day cycle. 

 

Pre-medication regimen 

To reduce the incidence and severity of skin reactions, a corticosteroid should be given the day 

prior to, on the day of, and the day after pemetrexed administration. The corticosteroid should be 

equivalent to 4 mg of dexamethasone administered orally twice a day (see section 4.4). 

 

To reduce toxicity, patients treated with pemetrexed must also receive vitamin supplementation 

(see section 4.4). Patients must take oral folic acid or a multivitamin containing folic acid (350 

to 1000 micrograms) on a daily basis. At least five doses of folic acid must be taken during the 

seven days preceding the first dose of pemetrexed, and dosing must continue during the full 

course of therapy and for 21 days after the last dose of pemetrexed. Patients must also receive an 

intramuscular injection of vitamin B12 (1000 micrograms) in the week preceding the first dose of 

pemetrexed and once every three cycles thereafter. Subsequent vitamin B12 injections may be 

given on the same day as pemetrexed. 

 

Monitoring 

Patients receiving pemetrexed should be monitored before each dose with a complete blood 

count, including a differential white cell count (WCC) and platelet count. Prior to each 

chemotherapy administration blood chemistry tests should be collected to evaluate renal and 

hepatic function. Before the start of any cycle of chemotherapy, patients are required to have the 

following: absolute neutrophil count (ANC) should be ≥ 1500 cells/mm3 and platelets should be 

≥ 100,000 cells/mm3. 

Creatinine clearance should be ≥ 45 ml/min. 

The total bilirubin should be ≤ 1.5 times upper limit of normal. Alkaline phosphatase (AP), 

aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) 

should be ≤ 3 times upper limit of normal. Alkaline phosphatase, AST and ALT ≤ 5 times upper 

limit of normal is acceptable if liver has tumour involvement. 

 

Dose adjustments 

Dose adjustments at the start of a subsequent cycle should be based on nadir haematologic 

counts or maximum non-haematologic toxicity from the preceding cycle of therapy. Treatment 

may be delayed to allow sufficient time for recovery. Upon recovery patients should be retreated 

using the guidelines in Tables 1, 2 and 3, which are applicable for Pemetrexed Fresenius Kabi 

used as a single agent or in combination with cisplatin. 

 

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

cisplatin - Haematologic toxicities 

Nadir ANC < 500 /mm3 and nadir platelets 

≥ 50,000 /mm3 

75 % of previous dose (both pemetrexed and 

cisplatin) 

Nadir platelets < 50,000 /mm3 regardless of 

nadir ANC 

75 % of previous dose (both pemetrexed and 

cisplatin) 

Nadir platelets < 50,000 /mm3 with bleedinga, 

regardless of nadir ANC 

50 % of previous dose (both pemetrexed and 

cisplatin) 



 

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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 

Fresenius Kabi should be withheld until resolution to less than or equal to the patient’s 

pre-therapy value. Treatment should be resumed according to the guidelines in Table 2. 

 

Table 2 - Dose modification table for pemetrexed (as single agent or in combination) and 

cisplatin-Non-haematologic toxicities a, b 

 Dose of pemetrexed  

(mg/m2) 

Dose for cisplatin 

(mg/m2) 

Any Grade 3 or 4 toxicities except 

mucositis 

75 % of previous dose 75 % of previous dose 

Any diarrhoea requiring 

hospitalisation (irrespective of 

grade) or grade 3 or 4 diarrhoea. 

75 % of previous dose 75 % of previous dose 

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

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

 

In the event of neurotoxicity, the recommended dose adjustment for Pemetrexed Fresenius Kabi 

and cisplatin is documented in Table 3. Patients should discontinue therapy if Grade 3 or 4 

neurotoxicity is observed. 

 

Table 3 - Dose modification table for pemetrexed (as single agent or in combination) and 

cisplatin-Neurotoxicity 

CTC a Grade Dose of pemetrexed  

(mg/m2) 

Dose for cisplatin 

(mg/m2) 

0-1 100 % of previous dose 100 % of previous dose 

2 100 % of previous dose 50 % of previous dose 

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

 

Treatment with Pemetrexed Fresenius Kabi should be discontinued if a patient experiences any 

haematologic or non-haematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately 

if Grade 3 or 4 neurotoxicity is observed. 

 

Special populations 

 

Elderly 

In clinical studies, there has been no indication that patients 65 years of age or older are at 

increased risk of adverse reaction 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 Fresenius Kabi in the paediatric population in malignant 

pleural mesothelioma and non-small cell lung cancer. 

 

Patients with renal impairment (standard cockcroft and gault formula or glomerular filtration 



 

5 

 

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 

 

Pemetrexed Fresenius Kabi is for intravenous use. Pemetrexed Fresenius Kabi should be 

administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.  

 

For precautions to be taken before handling or administering Pemetrexed Fresenius Kabi and for 

instructions on reconstitution and dilution of Pemetrexed Fresenius Kabi 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 



 

6 

 

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). 

 

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. 



 

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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 medicinal product (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 medicinal product are combined with pemetrexed. If necessary, creatinine clearance 

should be closely monitored. 

 

In patients with normal renal function (creatinine clearance ≥ 80 ml/min), high doses of 

non-steroidal anti-inflammatory medicinal product (NSAIDs, such as ibuprofen > 1600 mg/day) 

and acetylsalicylic acid at higher dose (≥ 1.3 g daily) may decrease pemetrexed elimination and, 

consequently, increase the occurrence of pemetrexed adverse reactions. Therefore, caution 

should be made when administering higher doses of NSAIDs or acetylsalicylic acid, 

concurrently with pemetrexed to patients with normal function (creatinine clearance 

≥ 80 ml/min). 

 

In patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 

79 ml/min), the concomitant administration of pemetrexed with NSAIDs (e.g. ibuprofen) or 

acetylsalicylic acid at higher dose should be avoided for 2 days before, on the day of, and 2 days 

following pemetrexed administration (see section 4.4). 

 

In the absence of data regarding potential interaction with NSAIDs having longer half-lives such 

as piroxicam or rofecoxib, the concomitant administration with pemetrexed in patients with mild 

to moderate renal insufficiency should be interrupted for at least 5 days prior to, on the day of, 

and at least 2 days following pemetrexed administration (see section 4.4). If concomitant 

administration of NSAIDs is necessary, patients should be monitored closely for toxicity, 

especially myelosuppression and gastrointestinal toxicity. 

 

Pemetrexed undergoes limited hepatic metabolism. Results from in vitro studies with human 

liver microsomes indicated that pemetrexed would not be predicted to cause clinically 

significant inhibition of the metabolic clearance of medicinal product 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). 

 



 

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4.6 Fertility, pregnancy and lactation 

 

Women of childbearing potential/Contraception in males and females 

Women of childbearing potential must use effective contraception during treatment with 

pemetrexed. Pemetrexed can have genetically damaging effects. Sexually mature males are 

advised not to father a child during the treatment and up to 6 months thereafter. Contraceptive 

measures or abstinence are recommended. 

 

Pregnancy 

There are no data from the use of pemetrexed in pregnant women but pemetrexed, like other 

anti-metabolites, is suspected to cause serious birth defects when administered during 

pregnancy. Animal studies have shown reproductive toxicity (see section 5.3). Pemetrexed 

should not be used during pregnancy unless clearly necessary, after a careful consideration of 

the needs of the mother and the risk for the foetus (see section 4.4). 

 

Breast-feeding 

It is unknown whether pemetrexed is excreted in human milk and adverse reactions on the 

breast-feeding 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 4 lists the adverse drug events regardless of causality associated with pemetrexed used 

either as a monotherapy treatment or in combination with cisplatin from the pivotal registration 

studies (JMCH, JMEI, JMBD, JMEN and PARAMOUNT) and from the post marketing period. 

 

ADRs are listed by MedDRA body system organ class. The following convention has been used 

for classification of frequency:  

 very common (≥ 1/10): common (≥ 1/100 to < 1/10); uncommon: (≥ 1/1,000 to < 1/100); rare: 

(≥ 1/10,000 to < 1/1,000); very rare: (< 1/10,000) and not known (cannot be estimated from 

available data). 



 

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Table 4. Frequencies of all grades adverse drug events regardless of causality from the 

pivotal registration studies: JMEI (Pemetrexed vs Docetaxel), JMDB (Pemetrexed and 

Cisplatin versus Gemcitabine and Cisplatin, JMCH (Pemetrexed plus Cisplatin versus 

Cisplatin), JMEN and PARAMOUNT (Pemetrexed plus Best Supportive Care versus 

Placebo plus Best Supportive Care) and from post-marketing period. 

 

System 

Organ Class  

(MedDRA) 

 

Very common 

 

Common Uncommon Rare Very rare Not 

known 

Infections and 

infestations 

Infectiona 

Pharyngitis 

 

Sepsisb   Dermo-

hypodermitis 

 

 

Blood and 

lymphatic 

system 

disorders 

Neutropenia 

Leukopenia 

Haemoglobin 

decreased 

 

Febrile 

neutropenia 

Platelet count 

decreased 

Pancytopenia Autoimmune 

haemolytic 

anaemia 

  

Immune 

System 

disorders 

 Hypersensiti-

vity 

 Anaphylactic 

shock 

  

Metabolism 

and nutrition 

disorders 

 Dehydration     

Nervous 

system 

disorders 

 Taste disorder 

Peripheral 

motor 

neuropathy 

Peripheral 

sensory 

neuropathy 

Dizziness 

 

Cerebrovascul

ar accident 

Ischaemic 

stroke 

Haemorrhage 

intracranial  

   

Eye disorders  Conjunctivitis 

Dry eye 

Lacrimation 

increased 

Keratoconjunc

tivitis sicca 

Eyelid oedema 

Ocular surface 

disease 

    

Cardiac 

disorders  

 Cardiac failure 

Arrhythmia 

Angina 

Myocardial 

infarction 

Coronary 

artery disease 

Arrhythmia 

supraventricul

ar 

   



 

10 

 

System 

Organ Class  

(MedDRA) 

 

Very common 

 

Common Uncommon Rare Very rare Not 

known 

Vascular 

disorders 

  Peripheral 

ischaemiac 
   

Respiratory, 

thoracic and 

mediastinal 

disorders 

 

 

 Pulmonary 

embolism 

Interstitial 

pneumonitisbd 

   

Gastrointes-

tinal disorders 

Stomatitis 

Anorexia 

Vomiting 

Diarrhoea 

Nausea 

 

Dyspepsia 

Constipation 

Abdominal  

pain 

  

 

 

 

Rectal 

haemorrhage 

Gastrointestina

l haemorrhage 

Intestinal 

perforation 

Oesophagitis 

Colitis e 

   

Hepatobiliary 

disorders 

  Aalanine 

aminotransfera

se increased 

Aspartate 

aminotransfera

se increased 

 

 Hepatitis   

Skin and 

subcutaneous 

tissue 

disorders 

Rash 

Skin 

exfoliation  

 

Hyperpigment

ation 

Pruritus 

Erythema 

multiforme 

Alopecia 

Urticaria 

 

 Erythema 

 

 

 

 

 

 

 

 

 

 

 

 

Stevens-

Johnson 

syndromeb 

Toxic 

epidermal 

necrolysisb 

Pemphigoid 

Dermatitis 

bullous 

Acquired 

epidermolysi

s bullosa 

Erythema-

tous oedemaf  

Pseudocellu-

litis 

Dermatitis 

Eczema 

Prurigo 

 

 
 

Renal and 

urinary 

disorders 

Creatinine 

clearance 

decreased 

Blood 

creatinine 

Renal failure 

Glomerular 

filtration rate 

decreased 

   Nephrog

e-nic 

diabetes 

insipidus 

 

Renal 



 

11 

 

System 

Organ Class  

(MedDRA) 

 

Very common 

 

Common Uncommon Rare Very rare Not 

known 

increasede tubular 

necrosis 

General 

disorders and 

administration 

site conditions 

Fatigue 

 

Pyrexia 

Pain 

Oedema 

Chest pain 

Mucosal 

inflammation 

 

    

Investigations  Gamma-

glutamyltransf

erase increased 

    

Injury, 

poisoning and 

procedural 

complications 

  Radiation 

oesophagitis 

Radiation 

pneumonitis 

Recall pheno-

menon 

  

a with and without neutropenia  
b in some cases fatal  
c sometimes leading to extremity necrosis  
d with respiratory insufficiency 
eseen only in combination with cisplatin  
f mainly of the lower limbs 

 

Reporting of suspected adverse reactions  

Reporting suspected adverse reactions after authorisation of the medicinal product is important. 

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting 

system listed in Appendix V. 

 

4.9 Overdose 

 

Reported symptoms of overdose include neutropenia, anaemia, thrombocytopenia, mucositis, 

sensory polyneuropathy and rash. Anticipated complications of overdose include bone marrow 

suppression as manifested by neutropenia, thrombocytopenia and anaemia. In addition, infection 

with or without fever, diarrhoea, and/or mucositis may be seen. In the event of suspected 

overdose, patients should be monitored with blood counts and should receive supportive therapy 

as necessary. The use of calcium folinate / folinic acid in the management of pemetrexed 

overdose should be considered. 

 

 

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. 



 

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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. 

 

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: 

 

Table 5. Efficacy of pemetrexed plus cisplatin vs. cisplatin in malignant pleural 

mesothelioma 

 

  Randomized and treated 

patients 

Fully supplemented patients 

Efficacy parameter Pemetrexed/ 

Cisplatin 

(N = 226) 

Cisplatin 

(N = 222) 

Pemetrexed/ 

Cisplatin 

(N = 168) 

Cisplatin 

(N = 163) 

Median overall survival 

(months) 

(95% CI) 

12.1 

 

(10.0-14.4) 

9.3 

 

(7.8-10.7) 

13.3 

 

(11.4-14.9) 

10.0 

 

(8.4-11.9) 

Log Rank p-valuea 0.020 0.051 

Median time to tumour 

progression (months) 

(95% CI) 

5.7 

 

(4.9-6.5) 

3.9 

 

(2.8-4.4) 

6.1 

 

(5.3-7.0) 

3.9 

 

(2.8-4.5) 

Log Rank p-valuea 0.001 0.008 

Time to treatment failure 

(months) 

(95% CI) 

4.5 

 

(3.9-4.9) 

2.7 

 

(2.1-2.9) 

4.7 

 

(4.3-5.6) 

2.7 

 

(2.2-3.1) 

Log Rank p-valuea 0.001 0.001 

Overall response rateb 

(95% CI) 

41.3% 

(34.8-48.1) 

16.7% 

(12.0-22.2) 

45.5% 

(37.8-53.4) 

19.6% 

(13.8-26.6) 



 

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  Randomized and treated 

patients 

Fully supplemented patients 

Efficacy parameter Pemetrexed/ 

Cisplatin 

(N = 226) 

Cisplatin 

(N = 222) 

Pemetrexed/ 

Cisplatin 

(N = 168) 

Cisplatin 

(N = 163) 

Fisher's exact p-valuea <0.001 <0.001 

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

 supplemented (N = 167) 

 

A statistically significant improvement of the clinically relevant symptoms (pain and dyspnoea) 

associated with malignant pleural mesothelioma in the pemetrexed /cisplatin arm (212 patients) 

versus the cisplatin arm alone (218 patients) was demonstrated using the Lung Cancer Symptom 

Scale. Statistically significant differences in pulmonary function tests were also observed. The 

separation between the treatment arms was achieved by improvement in lung function in the 

pemetrexed /cisplatin arm and deterioration of lung function over time in the control arm. 

 

There are limited data in patients with malignant pleural mesothelioma treated with pemetrexed 

alone. Pemetrexed at a dose of 500 mg/m2 was studied as a single-agent in 64 chemonaive 

patients with malignant pleural mesothelioma. The overall response rate was 14.1 %. 

 

NSCLC, second-line treatment 

 

A multicentre, randomised, open label phase 3 study of pemetrexed versus docetaxel in patients 

with locally advanced or metastatic NSCLC after prior chemotherapy has shown median 

survival times of 8.3 months for patients treated with pemetrexed (Intent To Treat population 

n = 283) and 7.9 months for patients treated with docetaxel (ITT n = 288). Prior chemotherapy 

did not include pemetrexed. An analysis of the impact of NSCLC histology on the treatment 

effect on overall survival was in favour of pemetrexed versus docetaxel for other than 

predominantly squamous histologies (n = 399, 9.3 versus 8.0 months, adjusted HR = 0.78; 95% 

CI = 0 .61-1.00, p = 0.047) and was in favour of docetaxel for squamous cell carcinoma 

histology (n = 172, 6.2 versus 7.4 months, adjusted HR = 1.56; 95% CI = 1.08-2.26, p = 0.018). 

There were no clinically relevant differences observed for the safety profile of pemetrexed 

within the histology subgroups. 

 

Limited clinical data from a separate randomized, Phase 3, controlled trial, suggest that efficacy 

data (overall survival, progression free survival) for pemetrexed are similar between patients 

previously pre treated with docetaxel (n = 41) and patients who did not receive previous 

docetaxel treatment (n = 540). 

 

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

 

  Pemetrexed  Docetaxel 

Survival time (months) 

▪ Median (m) 
▪ 95% CI for median 
▪ HR 
▪ 95% CI for HR 
▪ Non-inferiority p-value (HR) 

(n = 283) 

8.3 

(7.0-9.4) 

(n = 288) 

7.9 

(6.3-9.2) 

0.99 

(0.82-1.20) 

0.226 

Progression-free survival (months) (n = 283) (n = 288) 



 

14 

 

  Pemetrexed  Docetaxel 

▪ Median 
▪ HR (95% CI) 

2.9 2.9 

0.97 (0.82-1.16) 

Time to treatment failure (TTTF - months) 

▪ Median 
▪ HR (95% CI) 

(n = 283) 

2.3 

(n = 288) 

2.1 

0.84 (0.71-0.997) 

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 PC 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. 

 

Table 7. Efficacy of pemetrexed + cisplatin vs. gemcitabine + cisplatin in first-line non-

small cell lung cancer – ITT population and histology subgroups. 

 

 

ITT population 

and histology 

subgroups 

Median overall survival in months 

(95% CI) 

Adjusted 

hazard ratio 

(HR) (95% 

CI) 

 

Superiority 

p-value 
Pemetrexed + cisplatin 

Gemcitabine + 

cisplatin 

ITT population 

(N = 1725) 

10.3 

(9.8 – 11.2) 

N=862 10.3 

(9.6 – 10.9) 

N=863 0.94a 

(0.84 – 1.05) 

0.259 

Adenocarcinoma 

(N=847) 

12.6  

(10.7 – 13.6) 

N=436 10.9  

(10.2 – 11.9) 

N=411 0.84 

(0.71–0.99) 

0.033 

Large cell 

(N=153) 

10.4 

(8.6 – 14.1) 

N=76 6.7 

(5.5 – 9.0) 

N=77 0.67 

(0.48–0.96) 

0.027 



 

15 

 

 

ITT population 

and histology 

subgroups 

Median overall survival in months 

(95% CI) 

Adjusted 

hazard ratio 

(HR) (95% 

CI) 

 

Superiority 

p-value 
Pemetrexed + cisplatin 

Gemcitabine + 

cisplatin 

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. 
aStatistically 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 

 

 

 
Abbreviations: PC=Pemetrexed+cisplatin; GC= Gemcitabine+cisplatin 

 

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) 



 

16 

 

therapy. Patients received a median of 5 cycles of maintenance treatment with pemetrexed and 

3.5 cycles of placebo. A total of 213 patients (48.3%) completed ≥ 6 cycles and a total of 103 

patients (23.4%) completed ≥ 10 cycles of treatment with pemetrexed. 

 

The study met its primary endpoint and showed a statistically significant improvement in PFS in 

the pemetrexed arm over the placebo arm (n = 581, independently reviewed population; median 

of 4.0 months and 2.0 months, respectively) (hazard ratio = 0.60, 95% CI = 0.49-0.73, p < 

0.00001). The independent review of patient scans confirmed the findings of the investigator 

assessment of PFS. The median OS for the overall population (n = 663) was 13.4 months for the 

pemetrexed arm and 10.6 months for the placebo arm, hazard ratio = 0.79 (95% CI = 0.65-0.95, p 

= 0.01192). 

 

Consistent with other pemetrexed studies, a difference in efficacy according to NSCLC 

histology was observed in JMEN. For patients with NSCLC other than predominantly 

squamous cell histology (n = 430, independently reviewed population) median PFS was 4.4 

months for the pemetrexed arm and 1.8 months for the placebo arm, hazard ratio = 0.47 

(95% CI = 0.37-0.60, p = 0.00001). The median OS for patients with NSCLC other than 

predominantly squamous cell histology (n = 481) was 15.5 months for the pemetrexed arm 

and 10.3 months for the placebo arm, hazard ratio = 0.70 (95% CI = 0.56-0.88, p = 0.002). 

Including the induction phase the median OS for patients with NSCLC other than 

predominantly squamous cell histology was 18.6 months for the pemetrexed arm and 13.6 

months for the placebo arm, hazard ratio = 0.71 (95% CI = 0.56-0.88, p = 0.002). 

 

The PFS and OS results in patients with squamous cell histology suggested no advantage for 

pemetrexed over placebo. 

 

There were no clinically relevant differences observed for the safety profile of pemetrexed 

within the histology subgroups. 

 

JMEN: Kaplan Meier plots of progression-free survival (PFS) and overall survival 

pemetrexed versus placebo in patients with NSCLC other than predominantly 

squamous cell histology: 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

PARAMOUNT 

A multi-centre, 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 



 

17 

 

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 were measured from the time of 

randomisation after completion of first-line (induction) therapy. Patients received a 

median of 4 cycles of maintenance treatment with pemetrexed and 4 cycles of placebo. A 

total of 169 patients (47.1%) completed ≥ 6 cycles maintenance treatment with 

pemetrexed, representing at least 10 total cycles of pemetrexed. 

 

The study met its primary endpoint and showed a statistically significant improvement in PFS in 

the pemetrexed arm over the placebo arm (n = 472, independently reviewed population; median 

of 3.9 months and 2.6 months, respectively) (hazard ratio = 0.64, 95% CI = 0.51-0.81, p = 

0.0002). The independent review of patient scans confirmed the findings of the investigator 

assessment of PFS. For randomised patients, as measured from the start of pemetrexed plus 

cisplatin first line induction treatment, the median investigator-assessed PFS was 6.9 months for 

the pemetrexed arm and 5.6 months for the placebo arm (hazard ratio = 0.59 95% CI = 

0.47-0.74). 

 

Following pemetrexed plus cisplatin induction (4 cycles), treatment with pemetrexed was 

statistically superior to placebo for OS (median 13.9 months versus 11.0 months, hazard 

ratio = 0.78, 95%CI=0.64-0.96, p=0.0195). At the time of this final survival analysis, 

28.7% of patients were alive or lost to follow up on the pemetrexed arm versus 21.7% on 

the placebo arm.  The relative treatment effect of pemetrexed was internally consistent 

across subgroups (including disease stage, induction response, ECOG PS, smoking status, 

gender, histology and age) and similar to that observed in the unadjusted OS and PFS 

analyses. The 1 year and 2 year survival rates for patients on pemetrexed were 58% and 

32% respectively, compared to 45% and 21% for patients on placebo.  From the start of 

pemetrexed plus cisplatin first line induction treatment, the median OS of patients was 16.9 

months for the pemetrexed arm and 14.0 months for the placebo arm (hazard ratio= 0.78, 

95% CI= 0.64-0.96). The percentage of patients that received post study treatment was 

64.3% for pemetrexed and 71.7% for placebo. 
 

PARAMOUNT: Kaplan Meier plot of progression-free survival (PFS) and Overall 

Survival (OS) for continuation pemetrexed maintenance versus placebo in patients with 

NSCLC other than predominantly squamous cell histology (measured from 

randomisation) 

 



 

18 

 

 
The pemetrexed maintenance safety profiles from the two studies JMEN and PARAMOUNT 

were similar. 

 

Paediatric population  

The European Medicines Agency has waived the obligation to submit the results of studies with 

the reference medicinal product containing pemetrexed in all subsets of the paediatric population 

in the granted indications (see section 4.2 for information on paediatric use). 

 

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 administered 

dose being recovered unchanged in urine within the first 24 hours following 

administration. In vitro studies indicate that pemetrexed is actively secreted by OAT3 

(organic anion transporter). Pemetrexed total systemic clearance is 91.8 ml/min and the 

elimination half-life from plasma is 3.5 hours in patients with normal renal function 

(creatinine clearance of 90 ml/min). 

Between patient variability in clearance is moderate at 19.3 %. Pemetrexed total systemic 

exposure (AUC) and maximum plasma concentration increase proportionally with dose. The 

pharmacokinetics of pemetrexed are consistent over multiple treatment cycles. 

 
The pharmacokinetic properties of pemetrexed are not influenced by concurrently 
administered cisplatin. Oral folic acid and intramuscular vitamin B12 supplementation 

do not affect the pharmacokinetics of pemetrexed. 

 

5.3 Preclinical safety data 

 

Administration of pemetrexed to pregnant mice resulted in decreased foetal viability, decreased 

foetal weight, incomplete ossification of some skeletal structures and cleft palate. 

 

Administration of pemetrexed to male mice resulted in reproductive toxicity characterised by 

reduced fertility rates and testicular atrophy. In a study conducted in beagle dog by intravenous 



 

19 

 

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) (pH adjustment) 

Trometamol (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. 

 

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

 

6.3 Shelf life 
 

Unopened vial 

2 years. 
 

Reconstituted and infusion solutions 

When prepared as directed, reconstituted and infusion solutions of Pemetrexed Fresenius Kabi 

contain no antimicrobial preservatives. Chemical and physical in-use stability of reconstituted 

solutions of pemetrexed was demonstrated for 24 hours at refrigerated temperature.   

 

For infusion solution of pemetrexed, chemical and physical in-use stability was demonstrated 

for 21 days  at refrigerated temperature and 7 days at room temperature. From a microbiological 

point of view, the product should be used immediately. If not used immediately, in-use storage 

times and conditions prior to use are the responsibility of the user and would not be longer than 

24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic 

conditions. 

 

6.4 Special precautions for storage 
 

This medicinal product does not require any special storage conditions. 

 

For storage conditions after reconstitution of the medicinal product, see section 6.3. 

 



 

20 

 

 

6.5 Nature and contents of container 

 

Type I, clear, colourless glass vial, with 20 mm chlorobutyl rubber stopper and sealed with 

green flip-off aluminium seal. 

 

Pack of 1 vial. 

 

6.6 Special precautions for disposal and other handling 
 

- Use aseptic technique during the reconstitution and further dilution of pemetrexed for 
intravenous infusion administration. 

 

- Calculate the dose and the number of Pemetrexed Fresenius Kabi vials needed. Each vial 
contains an excess of pemetrexed to facilitate delivery of label amount. 

 

- Reconstitute 100-mg vials with 4.2 ml of 5% glucose intravenous infusion 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. 

 

- The appropriate volume of reconstituted pemetrexed solution must be further diluted to 
100 ml with 5% glucose intravenous infusion and administered as an intravenous infusion 

over 10 minutes. 

 

- Pemetrexed infusion solutions prepared as directed above are compatible with polyvinyl 
chloride and polyolefin lined administration sets and infusion bags. 

 

- Parenteral medicinal products must be inspected visually for particulate matter and 
discolouration prior to administration. If particulate matter is observed, do not 

administer. 

- Pemetrexed solutions are for single use only. Any unused medicinal product or waste 
material must be disposed of in accordance with local requirements. 

 

Preparation and administration precautions 

As with other potentially toxic anticancer agents, care should be exercised in the handling and 

preparation of pemetrexed infusion solutions. The use of gloves is recommended. If a 

pemetrexed solution contacts the skin, wash the skin immediately and thoroughly with soap and 

water. If pemetrexed solutions contact the mucous membranes, flush thoroughly with water. 

Pregnant women must avoid contact with cytostatic medicinal product. 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 

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1, 

61352 Bad Homburg v.d.Höhe 

Germany 
 



 

21 

 

8. MARKETING AUTHORISATION NUMBER 
 
EU/1/16/1115/001 
 
 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 22 July 2016 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 

Detailed information on this product is available on the website of the European Medicines 

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



 

22 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Pemetrexed Fresenius Kabi 500 mg powder for concentrate for solution for infusion 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each vial contains 500 mg of pemetrexed (as pemetrexed diacid). 

 

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. 

 

White to off-white lyophilised powder or solid. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Malignant pleural mesothelioma 

Pemetrexed Fresenius Kabi in combination with cisplatin is indicated for the treatment of 

chemotherapy naïve patients with unresectable malignant pleural mesothelioma. 

 

Non-small cell lung cancer 

Pemetrexed Fresenius Kabi 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 Fresenius Kabi is indicated as monotherapy for the maintenance treatment of locally 

advanced or metastatic non-small cell lung cancer other than predominantly squamous cell 

histology in patients whose disease has not progressed immediately following platinum-based 

chemotherapy (see section 5.1). 

 

Pemetrexed Fresenius Kabi 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 Fresenius Kabi must only be administered under the supervision of a physician 

qualified in the use of anti-cancer chemotherapy. 

 

Posology 

 

Pemetrexed Fresenius Kabi in combination with cisplatin 

The recommended dose of Pemetrexed Fresenius Kabi 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. 



 

23 

 

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 section 6.2 and cisplatin Summary of Product Characteristics for 

specific dosing advice). 

 

Pemetrexed Fresenius Kabi as single agent 

In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended 

dose of Pemetrexed Fresenius Kabi is 500 mg/m2 BSA administered as an intravenous infusion 

over 10 minutes on the first day of each 21-day cycle. 

 

Pre-medication regimen 

To reduce the incidence and severity of skin reactions, a corticosteroid should be given the day 

prior to, on the day of, and the day after pemetrexed administration. The corticosteroid should be 

equivalent to 4 mg of dexamethasone administered orally twice a day (see section 4.4). 

 

To reduce toxicity, patients treated with pemetrexed must also receive vitamin supplementation 

(see section 4.4). Patients must take oral folic acid or a multivitamin containing folic acid (350 

to 1000 micrograms) on a daily basis. At least five doses of folic acid must be taken during the 

seven days preceding the first dose of pemetrexed, and dosing must continue during the full 

course of therapy and for 21 days after the last dose of pemetrexed. Patients must also receive an 

intramuscular injection of vitamin B12 (1000 micrograms) in the week preceding the first dose of 

pemetrexed and once every three cycles thereafter. Subsequent vitamin B12 injections may be 

given on the same day as pemetrexed. 

 

Monitoring 

Patients receiving pemetrexed should be monitored before each dose with a complete blood 

count, including a differential white cell count (WCC) and platelet count. Prior to each 

chemotherapy administration blood chemistry tests should be collected to evaluate renal and 

hepatic function. Before the start of any cycle of chemotherapy, patients are required to have the 

following: absolute neutrophil count (ANC) should be ≥ 1500 cells/mm3 and platelets should be 

≥ 100,000 cells/mm3. 

Creatinine clearance should be ≥ 45 ml/min. 

The total bilirubin should be ≤ 1.5 times upper limit of normal. Alkaline phosphatase (AP), 

aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) 

should be ≤ 3 times upper limit of normal. Alkaline phosphatase, AST and ALT ≤ 5 times upper 

limit of normal is acceptable if liver has tumour involvement. 

 

Dose adjustments 

Dose adjustments at the start of a subsequent cycle should be based on nadir haematologic 

counts or maximum non-haematologic toxicity from the preceding cycle of therapy. Treatment 

may be delayed to allow sufficient time for recovery. Upon recovery patients should be retreated 

using the guidelines in Tables 1, 2 and 3, which are applicable for Pemetrexed Fresenius Kabi 

used as a single agent or in combination with cisplatin. 

 

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

cisplatin - Haematologic toxicities 

Nadir ANC < 500 /mm3 and nadir platelets 

≥ 50,000 /mm3 

75 % of previous dose (both pemetrexed and 

cisplatin) 

Nadir platelets < 50,000 /mm3 regardless of 

nadir ANC 

75 % of previous dose (both pemetrexed and 

cisplatin) 

Nadir platelets < 50,000 /mm3 with bleedinga, 

regardless of nadir ANC 

50 % of previous dose (both pemetrexed and 

cisplatin) 



 

24 

 

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 

Fresenius Kabi should be withheld until resolution to less than or equal to the patient’s 

pre-therapy value. Treatment should be resumed according to the guidelines in Table 2. 

 

Table 2 - Dose modification table for pemetrexed (as single agent or in combination) and 

cisplatin-Non-haematologic toxicities a, b 

 Dose of pemetrexed  

(mg/m2) 

Dose for cisplatin 

(mg/m2) 

Any Grade 3 or 4 toxicities except 

mucositis 

75 % of previous dose 75 % of previous dose 

Any diarrhoea requiring 

hospitalisation (irrespective of 

grade) or grade 3 or 4 diarrhoea. 

75 % of previous dose 75 % of previous dose 

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

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

 

In the event of neurotoxicity, the recommended dose adjustment for Pemetrexed Fresenius Kabi 

and cisplatin is documented in Table 3. Patients should discontinue therapy if Grade 3 or 4 

neurotoxicity is observed. 

 

Table 3 - Dose modification table for pemetrexed (as single agent or in combination) and 

cisplatin-Neurotoxicity 

CTC a Grade Dose of pemetrexed  

(mg/m2) 

Dose for cisplatin 

(mg/m2) 

0-1 100 % of previous dose 100 % of previous dose 

2 100 % of previous dose 50 % of previous dose 

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

 

Treatment with Pemetrexed Fresenius Kabi should be discontinued if a patient experiences any 

haematologic or non-haematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately 

if Grade 3 or 4 neurotoxicity is observed. 

 

Special populations 

 

Elderly 

In clinical studies, there has been no indication that patients 65 years of age or older are at 

increased risk of adverse reactions compared to patients younger than 65 years old. No dose 

reductions other than those recommended for all patients are necessary. 

 

Paediatric population 

There is no relevant use of Pemetrexed Fresenius Kabi in the paediatric population in malignant 

pleural mesothelioma and non-small cell lung cancer. 

 

Patients with renal impairment (standard cockcroft and gault formula or glomerular filtration 



 

25 

 

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 

Pemetrexed Fresenius Kabi is for intravenous use. Pemetrexed Fresenius Kabi should be 

administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.  

 

For precautions to be taken before handling or administering Pemetrexed Fresenius Kabi, and 

for instructions on reconstitution and dilution of Pemetrexed Fresenius Kabi 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). 

 



 

26 

 

Patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min) 

should avoid taking non-steroidal anti-inflammatory medicinal product (NSAIDs) such as 

ibuprofen, and acetylsalicylic acid (> 1.3 g daily) for 2 days before, on the day of, and 2 days 

following pemetrexed administration (see section 4.5). 

 

In patients with mild to moderate renal insufficiency eligible for pemetrexed therapy NSAIDs 

with long elimination half-lives should be interrupted for at least 5 days prior to, on the day of, 

and at least 2 days following pemetrexed administration (see section 4.5). 

 

Serious renal events, including acute renal failure, have been reported with pemetrexed alone or 

in association with other chemotherapeutic agents. Many of the patients in whom these occurred 

had underlying risk factors for the development of renal events including dehydration or 

pre-existing hypertension or diabetes. Nephrogenic diabetes insipidus and renal tubular necrosis 

were also reported in post marketing setting with pemetrexed alone or with other 

chemotherapeutic agents. Most of these events resolved after pemetrexed withdrawal. Patients 

should be regularly monitored for acute tubular necrosis, decreased renal function and signs and 

symptoms of nephrogenic diabetes insipidus (e.g. hypernatraemia). 

 

The effect of third space fluid, such as pleural effusion or ascites, on pemetrexed is not fully 

defined. A phase 2 study of pemetrexed in 31 solid tumour patients with stable third space fluid 

demonstrated no difference in pemetrexed dose normalized plasma concentrations or clearance 

compared to patients without third space fluid collections. Thus, drainage of third space fluid 

collection prior to pemetrexed treatment should be considered, but may not be necessary. 

 

Due to the gastrointestinal toxicity of pemetrexed given in combination with cisplatin, severe 

dehydration has been observed. Therefore, patients should receive adequate antiemetic treatment 

and appropriate hydration prior to and/or after receiving treatment. 

 

Serious cardiovascular events, including myocardial infarction and cerebrovascular events have 

been uncommonly reported during clinical studies with pemetrexed, usually when given in 

combination with another cytotoxic agent. Most of the patients in whom these events have been 

observed had pre-existing cardiovascular risk factors (see section 4.8). 

 

Immunodepressed status is common in cancer patients. As a result, concomitant use of live 

attenuated vaccines is not recommended (see section 4.3 and 4.5). 

 

Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to 

father a child during the treatment and up to 6 months thereafter. Contraceptive measures or 

abstinence are recommended. Owing to the possibility of pemetrexed treatment causing 

irreversible infertility, men are advised to seek counselling on sperm storage before starting 

treatment. 

 

Women of childbearing potential must use effective contraception during treatment with 

pemetrexed (see section 4.6). 

 

Cases of radiation pneumonitis have been reported in patients treated with radiation either prior, 

during or subsequent to their pemetrexed therapy. Particular attention should be paid to these 

patients and caution exercised with use of other radiosensitising agents. 

 

Cases of radiation recall have been reported in patients who received radiotherapy weeks or 

years previously. 

 



 

27 

 

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 medicinal product (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 medicinal product are combined with pemetrexed. If necessary, creatinine clearance 

should be closely monitored. 

 

In patients with normal renal function (creatinine clearance ≥ 80 ml/min), high doses of 

non-steroidal anti-inflammatory medicinal product (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 reactions. Therefore, caution 

should be made when administering higher doses of NSAIDs or acetylsalicylic acid, 

concurrently with pemetrexed to patients with normal function (creatinine clearance 

≥ 80 ml/min). 

 

In patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 

79 ml/min), the concomitant administration of pemetrexed with NSAIDs (e.g. ibuprofen) or 

acetylsalicylic acidat 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 medicinal product 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). 



 

28 

 

4.6 Fertility, pregnancy and lactation 

 

Women of childbearing potential/Contraception in males and females 

Women of childbearing potential must use effective contraception during treatment with 

pemetrexed. Pemetrexed can have genetically damaging effects. Sexually mature males are 

advised not to father a child during the treatment and up to 6 months thereafter. Contraceptive 

measures or abstinence are recommended. 

 

Pregnancy 

There are no data from the use of pemetrexed in pregnant women but pemetrexed, like other 

anti-metabolites, is suspected to cause serious birth defects when administered during 

pregnancy. Animal studies have shown reproductive toxicity (see section 5.3). Pemetrexed 

should not be used during pregnancy unless clearly necessary, after a careful consideration of 

the needs of the mother and the risk for the foetus (see section 4.4). 

 

Breast-feeding 

It is unknown whether pemetrexed is excreted in human milk and adverse reactions on the 

breast-feeding 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 4 lists the adverse drug events regardless of causality associated with pemetrexed used 

either as a monotherapy treatment or in combination with cisplatin from the pivotal registration 

studies (JMCH, JMEI, JMBD, JMEN and PARAMOUNT) and from the post marketing period.. 

 

ADRs are listed by MedDRA body system organ class. The following convention has been used 

for classification of frequency::  

very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare 

(≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from 

available data). 



 

29 

 

Table 4. Frequencies of all grades adverse drug events regardless of causality from the 

pivotal registration studies: JMEI (Pemetrexed vs Docetaxel), JMDB (Pemetrexed and 

Cisplatin versus Gemcitabine and Cisplatin, JMCH (Pemetrexed plus Cisplatin versus 

Cisplatin), JMEN and PARAMOUNT (Pemetrexed plus Best Supportive Care versus 

Placebo plus Best Supportive Care) and from post-marketing period. 

 

System Organ 

Class  

(MedDRA) 

 

Very 

common 

 

Common Uncommon Rare Very rare Not 

known 

Infections and 

infestations 

Infectiona 

Pharyngitis 

 

Sepsisb   Dermo-

hypodermitis 

 

 

Blood and 

lymphatic 

system 

disorders 

Neutropenia 

Leukopenia 

Haemoglobin 

decreased 

 

Febrile 

neutropenia 

Platelet count 

decreased 

Pancytopenia Autoimmune 

haemolytic 

anaemia 

  

Immune System 

disorders 

 Hypersensiti-

vity 

 Anaphylac-tic 

shock 

  

Metabolism 

and nutrition 

disorders 

 Dehydration     

Nervous system 

disorders 

 Taste 

disorder 

Peripheral 

motor 

neuropathy 

Peripheral 

sensory 

neuropathy 

Dizziness 

 

Cerebrovascul

ar accident 

Ischaemic 

stroke 

Haemorrhage 

intracranial  

   



 

30 

 

System Organ 

Class  

(MedDRA) 

 

Very 

common 

 

Common Uncommon Rare Very rare Not 

known 

Eye disorders  Conjunctiviti

s 

Dry eye 

Lacrimation 

increased 

Keratoconjun

ctivitis sicca 

Eyelid 

oedema 

Ocular 

surface 

disease 

    

Cardiac 

disorders  

 Cardiac 

failure 

Arrhythmia 

Angina 

Myocardial 

infarction 

   

Coronary 

artery disease 

Arrhythmia 

supraventricul

ar 

   

Vascular 

disorders 

  Peripheral 

ischaemiac 
   

Respiratory, 

thoracic and 

mediastinal 

disorders 

 

 

 Pulmonary 

embolism 

Interstitial 

pneumonitisbd 

   

Gastrointes-

tinal disorders 

Stomatitis 

Anorexia 

Vomiting 

Diarrhoea 

Nausea 

 

Dyspepsia 

Constipation 

Abdominal  

pain 

  

 

 

 

Rectal 

haemorrhage 

Gastrointestin

al 

haemorrhage 

Intestinal 

perforation 

Oesophagitis 

Colitis e 

   

Hepatobiliary 

disorders 

  Aalanine 

aminotransfe

rase 

increased 

Aspartate 

aminotransfe

rase 

increased 

 Hepatitis   



 

31 

 

System Organ 

Class  

(MedDRA) 

 

Very 

common 

 

Common Uncommon Rare Very rare Not 

known 

 

Skin and 

subcutaneous 

tissue disorders 

Rash 

Skin 

exfoliation  

 

Hyperpigmen

tation 

Pruritus 

Erythema 

multiforme 

Alopecia 

Urticaria 

 

 Erythema 

 

 

 

 

 

 

 

 

 

 

 

 

Stevens-

Johnson 

syndromeb 

Toxic 

epidermal 

necrolysisb 

Pemphigoid 

Dermatitis 

bullous 

Acquired 

epidermolysi

s bullosa 

Erythema-

tous oedemaf  

Pseudocellu-

litis 

Dermatitis 

Eczema 

Prurigo 

 

 
 

Renal and 

urinary 

disorders 

Creatinine 

clearance 

decreased 

Blood 

creatinine 

increasede 

Renal failure 

Glomerular 

filtration rate 

decreased 

   Nephro

ge-nic 

diabete

s 

insipid

us 

 

Renal 

tubular 

necrosi

s 



 

32 

 

System Organ 

Class  

(MedDRA) 

 

Very 

common 

 

Common Uncommon Rare Very rare Not 

known 

General 

disorders and 

administration 

site conditions 

Fatigue 

 

Pyrexia 

Pain 

Oedema 

Chest pain 

Mucosal 

inflammation 

 

    

Investigations  Gamma-

glutamyltrans

ferase 

increased 

    

Injury, 

poisoning and 

procedural 

complications 

  Radiation 

oesophagitis 

Radiation 

pneumonitis 

Recall pheno-

menon 

  

a with and without neutropenia  
b in some cases fatal  
c sometimes leading to extremity necrosis  
d with respiratory insufficiency 
eseen only in combination with cisplatin  
f mainly of the lower limbs 

 

Reporting of suspected adverse reactions  

Reporting suspected adverse reactions after authorisation of the medicinal product is important. 

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting 

system listed in Appendix V. 

 

4.9 Overdose 

 

Reported symptoms of overdose include neutropenia, anaemia, thrombocytopenia, mucositis, 

sensory polyneuropathy and rash. Anticipated complications of overdose include bone marrow 

suppression as manifested by neutropenia, thrombocytopenia and anaemia. In addition, infection 

with or without fever, diarrhoea, and/or mucositis may be seen. In the event of suspected 

overdose, patients should be monitored with blood counts and should receive supportive therapy 

as necessary. The use of calcium folinate / folinic acid in the management of pemetrexed 

overdose should be considered. 

 

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. 

 



 

33 

 

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. 

 

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: 

 

Table 5. Efficacy of pemetrexed plus cisplatin vs. cisplatin in malignant pleural 

mesothelioma 

  Randomized and treated 

patients 

Fully supplemented patients 

Efficacy parameter Pemetrexed / 

Cisplatin 

(N = 226) 

Cisplatin 

(N = 222) 

Pemetrexed / 

Cisplatin 

(N = 168) 

Cisplatin 

(N = 163) 

Median overall survival 

(months) 

(95% CI) 

12.1 

 

(10.0-14.4) 

9.3 

 

(7.8-10.7) 

13.3 

 

(11.4-14.9) 

10.0 

 

(8.4-11.9) 

Log Rank p-valuea 0.020 0.051 

Median time to tumour 

progression (months) 

(95% CI) 

5.7 

 

(4.9-6.5) 

3.9 

 

(2.8-4.4) 

6.1 

 

(5.3-7.0) 

3.9 

 

(2.8-4.5) 

Log Rank p-valuea 0.001 0.008 

Time to treatment failure 

(months) 

(95% CI) 

4.5 

 

(3.9-4.9) 

2.7 

 

(2.1-2.9) 

4.7 

 

(4.3-5.6) 

2.7 

 

(2.2-3.1) 

Log Rank p-valuea 0.001 0.001 

Overall response rateb 

(95% CI) 

41.3% 

(34.8-48.1) 

16.7% 

(12.0-22.2) 

45.5% 

(37.8-53.4) 

19.6% 

(13.8-26.6) 

Fisher's exact p-valuea <0.001 <0.001 



 

34 

 

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

(N = 167) 

 

A statistically significant improvement of the clinically relevant symptoms (pain and dyspnoea) 

associated with malignant pleural mesothelioma in the pemetrexed /cisplatin arm (212 patients) 

versus the cisplatin arm alone (218 patients) was demonstrated using the Lung Cancer Symptom 

Scale. Statistically significant differences in pulmonary function tests were also observed. The 

separation between the treatment arms was achieved by improvement in lung function in the 

pemetrexed /cisplatin arm and deterioration of lung function over time in the control arm. 

 

There are limited data in patients with malignant pleural mesothelioma treated with pemetrexed 

alone. Pemetrexed at a dose of 500 mg/m2 was studied as a single-agent in 64 chemonaive 

patients with malignant pleural mesothelioma. The overall response rate was 14.1 %. 

 

NSCLC, second-line treatment 

 

A multicentre, randomised, open label phase 3 study of pemetrexed versus docetaxel in patients 

with locally advanced or metastatic NSCLC after prior chemotherapy has shown median 

survival times of 8.3 months for patients treated with pemetrexed (Intent To Treat population 

n = 283) and 7.9 months for patients treated with docetaxel (ITT n = 288). Prior chemotherapy 

did not include pemetrexed. An analysis of the impact of NSCLC histology on the treatment 

effect on overall survival was in favour of pemetrexed versus docetaxel for other than 

predominantly squamous histologies (n = 399, 9.3 versus 8.0 months, adjusted HR = 0.78; 95% 

CI = 0 .61-1.00, p = 0.047) and was in favour of docetaxel for squamous cell carcinoma 

histology (n = 172, 6.2 versus 7.4 months, adjusted HR = 1.56; 95% CI = 1.08-2.26, p = 0.018). 

There were no clinically relevant differences observed for the safety profile of pemetrexed 

within the histology subgroups. 

 

Limited clinical data from a separate randomized, Phase 3, controlled trial, suggest that efficacy 

data (overall survival, progression free survival) for pemetrexed are similar between patients 

previously pre treated with docetaxel (n = 41) and patients who did not receive previous 

docetaxel treatment (n = 540). 

 

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

 

  Pemetrexed  Docetaxel 

Survival time (months) 

▪ Median (m) 
▪ 95% CI for median 
▪ HR 
▪ 95% CI for HR 
▪ Non-inferiority p-value (HR) 

(n = 283) 

8.3 

(7.0-9.4) 

(n = 288) 

7.9 

(6.3-9.2) 

0.99 

(0.82-1.20) 

0.226 

Progression-free survival (months) 

▪ Median 
▪ HR (95% CI) 

(n = 283) 

2.9 

(n = 288) 

2.9 

0.97 (0.82-1.16) 

Time to treatment failure (TTTF - months) 

▪ Median 
▪ HR (95% CI) 

(n = 283) 

2.3 

(n = 288) 

2.1 

0.84 (0.71-0.997) 

Response (n: qualified for response) (n = 264) (n = 274) 



 

35 

 

▪ Response rate (%) (95% CI) 
▪ Stable disease (%) 

9.1 (5.9-13.2) 

45.8 

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 PC 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. 

 

Table 7. Efficacy of pemetrexed + cisplatin vs. gemcitabine + cisplatin in first-line non-

small cell lung cancer – ITT population and histology subgroups. 

 

 

ITT population 

and histology 

subgroups 

Median overall survival in months 

(95% CI) 

Adjusted 

hazard ratio 

(HR) (95% 

CI) 

 

Superiority 

p-value 
Pemetrexed + cisplatin 

Gemcitabine + 

cisplatin 

ITT population 

(N = 1725) 

10.3 

(9.8 – 11.2) 

N=862 10.3 

(9.6 – 10.9) 

N=863 0.94a 

(0.84 – 1.05) 

0.259 

Adenocarcinoma 

(N=847) 

12.6  

(10.7 – 13.6) 

N=436 10.9  

(10.2 – 11.9) 

N=411 0.84 

(0.71–0.99) 

0.033 

Large cell 

(N=153) 

10.4 

(8.6 – 14.1) 

N=76 6.7 

(5.5 – 9.0) 

N=77 0.67 

(0.48–0.96) 

0.027 

Other 

(N=252) 

8.6 

(6.8 – 10.2) 

N=106 9.2 

(8.1 – 10.6) 

N=146 1.08 

(0.81–1.45) 

0.586 

Squamous cell 

(N=473) 

9.4 

(8.4 – 10.2) 

N=244 10.8 

(9.5 – 12.1) 

N=229 1.23 

(1.00–1.51) 

0.050 

Abbreviations: CI = confidence interval; ITT = intent-to-treat; N = total population size. 
aStatistically 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 



 

36 

 

 

 

 
 

Abbreviations: PC=Pemetrexed+cisplatin; GC= Gemcitabine+cisplatin 

 

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 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). 

 



 

37 

 

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 multi-centre, 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 were measured from the time of 

randomisation after completion of first-line (induction) therapy. Patients received a 

median of 4 cycles of maintenance treatment with pemetrexed and 4 cycles of placebo. A 

total of 169 patients (47.1%) completed ≥ 6 cycles maintenance treatment with 



 

38 

 

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. 

 

Paediatric population  

The European Medicines Agency has waived the obligation to submit the results of studies with 

the reference medicinal product containing pemetrexed in all subsets of the paediatric population 

in the granted indications (see section 4.2 for information on paediatric use). 



 

39 

 

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 administered 

dose being recovered unchanged in urine within the first 24 hours following 

administration. In vitro studies indicate that pemetrexed is actively secreted by OAT3 

(organic anion transporter). Pemetrexed total systemic clearance is 91.8 ml/min and the 

elimination half-life from plasma is 3.5 hours in patients with normal renal function 

(creatinine clearance of 90 ml/min). 

Between patient variability in clearance is moderate at 19.3 %. Pemetrexed total systemic 

exposure (AUC) and maximum plasma concentration increase proportionally with dose. The 

pharmacokinetics of pemetrexed are consistent over multiple treatment cycles. 

 
The pharmacokinetic properties of pemetrexed are not influenced by concurrently 
administered cisplatin. Oral folic acid and intramuscular vitamin B12 supplementation 

do not affect the pharmacokinetics of pemetrexed. 

 

5.3 Preclinical safety data 

 

Administration of pemetrexed to pregnant mice resulted in decreased foetal viability, decreased 

foetal weight, incomplete ossification of some skeletal structures and cleft palate. 

 

Administration of pemetrexed to male mice resulted in reproductive toxicity characterised by 

reduced fertility rates and testicular atrophy. In a study conducted in beagle dog by intravenous 

bolus injection for 9 months, testicular findings (degeneration/necrosis of the seminiferous 

epithelium) have been observed. This suggests that pemetrexed may impair male fertility. 

Female fertility was not investigated. 

 

Pemetrexed was not mutagenic in either the in vitro chromosome aberration test in Chinese 

hamster ovary cells, or the Ames test. Pemetrexed has been shown to be clastogenic in the in 

vivo micronucleus test in the mouse. 

 

Studies to assess the carcinogenic potential of pemetrexed have not been conducted. 
 
 
6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 
 

Mannitol (E421) 

Hydrochloric acid (E507) (pH adjustment) 

Trometamol (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. 

 



 

40 

 

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

 

6.3 Shelf life 
 

Unopened vial 

2 years. 
 

Reconstituted and infusion solutions 

When prepared as directed, reconstituted and infusion solutions of Pemetrexed Fresenius Kabi 

contain no antimicrobial preservatives. Chemical and physical in-use stability of reconstituted 

solutions of pemetrexed was demonstrated for 24 hours at refrigerated temperature.  

 

For infusion solution of pemetrexed, chemical and physical in-use stability was demonstrated 

for 21 days at refrigerated temperature and 7 days at room temperature. From a microbiological 

point of view, the product should be used immediately. If not used immediately, in-use storage 

times and conditions prior to use are the responsibility of the user and would not be longer than 

24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic 

conditions 

 

6.4 Special precautions for storage 
 

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 

 

Type I, clear, colourless glass vial, with 20 mm chlorobutyl rubber stopper and sealed with 

blue flip-off aluminium seal. 

 

Pack of 1 vial. 

 

6.6 Special precautions for disposal and other handling 
 

- Use aseptic technique during the reconstitution and further dilution of pemetrexed for 
intravenous infusion administration. 

 

- Calculate the dose and the number of Pemetrexed Fresenius Kabi vials needed. Each vial 
contains an excess of pemetrexed to facilitate delivery of label amount. 

 

- Reconstitute 500-mg vials with 20 ml of 5% glucose intravenous infusion 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. 

 

- The appropriate volume of reconstituted pemetrexed solution must be further diluted to 
100 ml with 5% glucose intravenous infusion and administered as an intravenous infusion 

over 10 minutes. 

 



 

41 

 

- Pemetrexed infusion solutions prepared as directed above are compatible with polyvinyl 
chloride and polyolefin lined administration sets and infusion bags. 

 

- Parenteral medicinal products must be inspected visually for particulate matter and 
discolouration prior to administration. If particulate matter is observed, do not 

administer. 

- Pemetrexed solutions are for single use only. Any unused medicinal product or waste 
material must be disposed of in accordance with local requirements. 

 

Preparation and administration precautions 

 As with other potentially toxic anticancer agents, care should be exercised in the handling and 

preparation of pemetrexed infusion solutions. The use of gloves is recommended. If a 

pemetrexed solution contacts the skin, wash the skin immediately and thoroughly with soap and 

water. If pemetrexed solutions contact the mucous membranes, flush thoroughly with water. 

Pregnant women must avoid contact with cytostatic medicinal product. 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 

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1, 

61352 Bad Homburg v.d.Höhe 

Germany 
 
 
8. MARKETING AUTHORISATION NUMBER 
 
EU/1/16/1115/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 22 July 2016 
 
 
10. DATE OF REVISION OF THE TEXT 
 

Detailed information on this product is available on the website of the European Medicines 

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



 

42 

 

1. NAME OF THE MEDICINAL PRODUCT 
 

Pemetrexed Fresenius Kabi 25 mg/ml concentrate for solution for infusion 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

 

One ml of concentrate contains 25 mg pemetrexed (as pemetrexed diacid). 

 

One vial of 4 ml concentrate contains 100 mg pemetrexed (as pemetrexed diacid). 

One vial of 20 ml concentrate contains 500 mg pemetrexed (as pemetrexed diacid) . 

One vial of 40 ml concentrate contains 1,000 mg pemetrexed (as pemetrexed diacid). 

 

Excipient(s) with known effect 

One vial of 4 ml concentrate contains 964 mg hydroxypropylbetadex. 

One vial of 20 ml concentrate contains 4820 mg hydroxypropylbetadex. 

One vial of 40 ml concentrate contains 9640 mg hydroxypropylbetadex. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Concentrate for solution for infusion (sterile concentrate). 

 

The concentrate is colourless to slightly yellowish or yellow-greenish solution. 

 

The pH is between 6.8 and 7.8. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Malignant pleural mesothelioma 

Pemetrexed Fresenius Kabi in combination with cisplatin is indicated for the treatment of 

chemotherapy naïve patients with unresectable malignant pleural mesothelioma. 

 

Non-small cell lung cancer 

Pemetrexed Fresenius Kabi 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 Fresenius Kabi is indicated as monotherapy for the maintenance treatment of locally 

advanced or metastatic non-small cell lung cancer other than predominantly squamous cell 

histology in patients whose disease has not progressed immediately following platinum-based 

chemotherapy (see section 5.1). 

 

Pemetrexed Fresenius Kabi 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). 

 



 

43 

 

4.2 Posology and method of administration 

 

Pemetrexed Fresenius Kabi must only be administered under the supervision of a physician 

qualified in the use of anti-cancer chemotherapy. 

 

Posology 

 

Pemetrexed Fresenius Kabi in combination with cisplatin 

The recommended dose of Pemetrexed Fresenius Kabi 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 section 6.2 and cisplatin Summary of Product Characteristics for 

specific dosing advice).  

 

Pemetrexed Fresenius Kabi as single agent 

In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended 

dose of Pemetrexed Fresenius Kabi is 500 mg/m2 BSA administered as an intravenous infusion 

over 10 minutes on the first day of each 21-day cycle. 

 

Pre-medication regimen 

To reduce the incidence and severity of skin reactions, a corticosteroid should be given the day 

prior to, on the day of, and the day after pemetrexed administration. The corticosteroid should be 

equivalent to 4 mg of dexamethasone administered orally twice a day (see section 4.4). 

 

To reduce toxicity, patients treated with pemetrexed must also receive vitamin supplementation 

(see section 4.4). Patients must take oral folic acid or a multivitamin containing folic acid (350 

to 1000 micrograms) on a daily basis. At least five doses of folic acid must be taken during the 

seven days preceding the first dose of pemetrexed, and dosing must continue during the full 

course of therapy and for 21 days after the last dose of pemetrexed. Patients must also receive an 

intramuscular injection of vitamin B12 (1000 micrograms) in the week preceding the first dose of 

pemetrexed and once every three cycles thereafter. Subsequent vitamin B12 injections may be 

given on the same day as pemetrexed. 

 

Monitoring 

Patients receiving pemetrexed should be monitored before each dose with a complete blood 

count, including a differential white cell count (WCC) and platelet count. Prior to each 

chemotherapy administration blood chemistry tests should be collected to evaluate renal and 

hepatic function. Before the start of any cycle of chemotherapy, patients are required to have the 

following: absolute neutrophil count (ANC) should be ≥ 1500 cells/mm3 and platelets should be 

≥ 100,000 cells/mm3. 

 Creatinine clearance should be ≥ 45 ml/min. 

 

The total bilirubin should be ≤ 1.5 times upper limit of normal. Alkaline phosphatase (AP), 

aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) 

should be ≤ 3 times upper limit of normal. Alkaline phosphatase, AST and ALT ≤ 5 times upper 

limit of normal is acceptable if liver has tumour involvement. 

 

Dose adjustments 

Dose adjustments at the start of a subsequent cycle should be based on nadir haematologic 

counts or maximum non-haematologic toxicity from the preceding cycle of therapy. Treatment 

may be delayed to allow sufficient time for recovery. Upon recovery patients should be retreated 



 

44 

 

using the guidelines in Tables 1, 2 and 3, which are applicable for Pemetrexed Fresenius Kabi 

used as a single agent or in combination with cisplatin. 

 

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

cisplatin - Haematologic toxicities 

Nadir ANC < 500 /mm3 and nadir platelets 

≥ 50,000/mm3 

75 % of previous dose (both pemetrexed and 

cisplatin) 

Nadir platelets < 50,000 /mm3 regardless of nadir 

ANC 

75 % of previous dose (both pemetrexed and 

cisplatin) 

Nadir platelets < 50,000 /mm3 with bleedinga, 

regardless of nadir ANC 

50 % of previous dose (both pemetrexed and 

cisplatin) 

a These criteria meet the National Cancer Institute Common Toxicity Criteria (CTC v2.0; 

NCI 1998) definition of ≥ CTC Grade 2 bleeding. 

 

If patients develop non-haematologic toxicities ≥ Grade 3 (excluding neurotoxicity), Pemetrexed 

Fresenius Kabi should be withheld until resolution to less than or equal to the patient’s 

pre-therapy value. Treatment should be resumed according to the guidelines in Table 2. 

 

Table 2 - Dose modification table for pemetrexed (as single agent or in combination) and 

cisplatin-Non-haematologic toxicities a, b 

 Dose of pemetrexed 

(mg/m2) 

Dose for cisplatin 

(mg/m2) 

Any Grade 3 or 4 toxicities except 

mucositis 

75 % of previous dose 75 % of previous dose 

Any diarrhoea requiring 

hospitalisation (irrespective of grade) 

or grade 3 or 4 diarrhoea. 

75 % of previous dose 75 % of previous dose 

Grade 3 or 4 mucositis 50 % of previous dose 100 % of previous dose 
a National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998) b Excluding 

neurotoxicity 

 

In the event of neurotoxicity, the recommended dose adjustment for Pemetrexed Fresenius Kabi 

and cisplatin is documented in Table 3. Patients should discontinue therapy if Grade 3 or 4 

neurotoxicity is observed. 

 

Table 3 - Dose modification table for pemetrexed (as single agent or in combination) and 

cisplatin-Neurotoxicity 

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

(mg/m2) 

0-1 100 % of previous dose 100 % of previous dose 

2 100 % of previous dose 50 % of previous dose 
a National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998) 

 

Treatment with Pemetrexed Fresenius Kabi 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. 

 



 

45 

 

Special populations 

 

Elderly 

In clinical studies, there has been no indication that patients 65 years of age or older are at 

increased risk of adverse reaction 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 Fresenius Kabi in the paediatric population in malignant 

pleural mesothelioma and non-small cell lung cancer. 

 

Patients with renal impairment (standard cockcroft and gault formula or glomerular filtration 

rate measured Tc99m-DPTA serum clearance method) 

 

Pemetrexed is primarily eliminated unchanged by renal excretion. In clinical studies, patients 

with creatinine clearance of ≥ 45 ml/min required no dose adjustments other than those 

recommended for all patients. There are insufficient data on the use of pemetrexed in patients 

with creatinine clearance below 45 ml/min; therefore the use of pemetrexed is not recommended 

(see section 4.4). 

 

Patients with hepatic impairment 

No relationships between AST (SGOT), ALT (SGPT), or total bilirubin and pemetrexed 

pharmacokinetics were identified. However patients with hepatic impairment such as bilirubin 

> 1.5 times the upper limit of normal and/or aminotransferase > 3.0 times the upper limit of 

normal (hepatic metastases absent) or > 5.0 times the upper limit of normal (hepatic metastases 

present) have not been specifically studied. 

 

Method of administration 

 

Pemetrexed Fresenius Kabi is for intravenous use. Pemetrexed Fresenius Kabi should be 

administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.  

 

For precautions to be taken before handling or administering Pemetrexed Fresenius Kabi, and 

for instructions on dilution of Pemetrexed Fresenius Kabi 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). 



 

46 

 

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). 

 

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 



 

47 

 

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. 

 

In patients with moderate to severe renal dysfunction accumulation of cyclodextrins may occur. 

 

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 medicinal product are combined with pemetrexed. If necessary, creatinine clearance 

should be closely monitored. 

 

In patients with normal renal function (creatinine clearance ≥80 ml/min), high doses of 

non-steroidal anti-inflammatory medicinal product (NSAIDs, such as ibuprofen > 1600 mg/day) 

and acetylsalicylic acid at higher dose (≥1.3 g daily) may decrease pemetrexed elimination and, 

consequently, increase the occurrence of pemetrexed adverse reactions. Therefore, caution 

should be made when administering higher doses of NSAIDs or acetylsalicylic acid, 

concurrently with pemetrexed to patients with normal function (creatinine clearance 

≥ 80 ml/min). 

 

In patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 

79 ml/min), the concomitant administration of pemetrexed with NSAIDs (e.g. ibuprofen) or 

acetylsalicylic acid at higher dose should be avoided for 2 days before, on the day of, and 2 days 

following pemetrexed administration (see section 4.4). 

 

In the absence of data regarding potential interaction with NSAIDs having longer half-lives such 

as piroxicam or rofecoxib, the concomitant administration with pemetrexed in patients with mild 

to moderate renal insufficiency should be interrupted for at least 5 days prior to, on the day of, 

and at least 2 days following pemetrexed administration (see section 4.4). If concomitant 

administration of NSAIDs is necessary, patients should be monitored closely for toxicity, 

especially myelosuppression and gastrointestinal toxicity. 

 

Pemetrexed undergoes limited hepatic metabolism. Results from in vitro studies with human 

liver microsomes indicated that pemetrexed would not be predicted to cause clinically significant 

inhibition of the metabolic clearance of medicinal product metabolised by CYP3A, CYP2D6, 

CYP2C9, and CYP1A2. 

 

Interactions common to all cytotoxics 



 

48 

 

Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation treatment 

is frequent. The high intra-individual variability of the coagulation status during diseases and the 

possibility of interaction between oral anticoagulants and anticancer chemotherapy require 

increased frequency of INR (International Normalised Ratio) monitoring, if it is decided to treat 

the patient with oral anticoagulants. 

 

Concomitant use contraindicated: Yellow fever vaccine: risk of fatal generalised vaccinale 

disease (see section 4.3). 

 

Concomitant use not recommended: Live attenuated vaccines (except yellow fever, for which 

concomitant use is contraindicated): risk of systemic, possibly fatal, disease. The risk is 

increased in subjects who are already immunosuppressed by their underlying disease. Use an 

inactivated vaccine where it exists (poliomyelitis) (see section 4.4). 

 

4.6 Fertility, pregnancy and lactation 

 

Women of childbearing potential/Contraception in males and females 

Women of childbearing potential must use effective contraception during treatment with 

pemetrexed. Pemetrexed can have genetically damaging effects. Sexually mature males are 

advised not to father a child during the treatment and up to 6 months thereafter. Contraceptive 

measures or abstinence are recommended. 

 

Pregnancy 

There are no data from the use of pemetrexed in pregnant women but pemetrexed, like other 

anti-metabolites, is suspected to cause serious birth defects when administered during 

pregnancy. Animal studies have shown reproductive toxicity (see section 5.3). Pemetrexed 

should not be used during pregnancy unless clearly necessary, after a careful consideration of 

the needs of the mother and the risk for the foetus (see section 4.4). 

 

Breast-feeding 

It is unknown whether pemetrexed is excreted in human milk and adverse reactions on the 

breast-feeding 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, 



 

49 

 

dehydration, rash, infection/sepsis and neuropathy. Rarely seen events include Stevens-Johnson 

syndrome and toxic epidermal necrolysis. 

 

Tabulated list of adverse reactions 

 

The table 4 lists the adverse drug events regardless of causality associated with pemetrexed used 

either as a monotherapy treatment or in combination with cisplatin from the pivotal registration 

studies (JMCH, JMEI, JMBD, JMEN and PARAMOUNT) and from the post marketing period. 

 

ADRs are listed by MedDRA body system organ class. The following convention has been used 

for classification of frequency:  

very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare 

(≥ 1/10,000 to < 1/1000); very rare (< 1/10,000) and not known (cannot be estimated from 

available data). 

 

Table 4. Frequencies of all grades adverse drug events regardless of causality from the 

pivotal registration studies: JMEI (Pemetrexed vs Docetaxel), JMDB (Pemetrexed and 

Cisplatin versus Gemcitabine and Cisplatin, JMCH (Pemetrexed plus Cisplatin versus 

Cisplatin), JMEN and PARAMOUNT (Pemetrexed plus Best Supportive Care versus 

Placebo plus Best Supportive Care) and from post-marketing period. 

 

System 

Organ Class  

(MedDRA) 

 

Very common 

 

Common Uncommon Rare Very rare Not 

known 

Infections and 

infestations 

Infectiona 

Pharyngitis 

 

Sepsisb   Dermo-

hypodermit

is 

 

 

Blood and 

lymphatic 

system 

disorders 

Neutropenia 

Leukopenia 

Haemoglobin 

decreased 

 

Febrile 

neutropenia 

Platelet count 

decreased 

Pancytopenia Autoimmune 

haemolytic 

anaemia 

  

Immune 

System 

disorders 

 Hypersensiti-

vity 

 Anaphylac-tic 

shock 

  

Metabolism 

and nutrition 

disorders 

 Dehydration     

Nervous 

system 

disorders 

 Taste disorder 

Peripheral 

motor 

neuropathy 

Peripheral 

sensory 

neuropathy 

Dizziness 

 

Cerebrovascul

ar accident 

Ischaemic 

stroke 

Haemorrhage 

intracranial  

   

Eye disorders  Conjunctivitis 

Dry eye 

Lacrimation 

    



 

50 

 

System 

Organ Class  

(MedDRA) 

 

Very common 

 

Common Uncommon Rare Very rare Not 

known 

increased 

Keratoconjunc

tivitis sicca 

Eyelid oedema 

Ocular surface 

disease 

Cardiac 

disorders  

 Cardiac failure 

Arrhythmia 

Angina 

Myocardial 

infarction 

   

Coronary 

artery disease 

Arrhythmia 

supraventricul

ar 

   

Vascular 

disorders 

  Peripheral 

ischaemiac 
   

Respiratory, 

thoracic and 

mediastinal 

disorders 

 

 

 Pulmonary 

embolism 

Interstitial 

pneumonitisbd 

   

Gastrointes-

tinal disorders 

Stomatitis 

Anorexia 

Vomiting 

Diarrhoea 

Nausea 

 

Dyspepsia 

Constipation 

Abdominal  

pain 

  

 

 

 

Rectal 

haemorrhage 

Gastrointestina

l haemorrhage 

Intestinal 

perforation 

Oesophagitis 

Colitis e 

   

Hepatobiliary 

disorders 

  Aalanine 

aminotransfera

se increased 

Aspartate 

aminotransfera

se increased 

 

 Hepatitis   

Skin and 

subcutaneous 

tissue 

disorders 

Rash 

Skin 

exfoliation  

 

Hyperpigment

ation 

Pruritus 

Erythema 

multiforme 

Alopecia 

Urticaria 

 

 Erythema 

 

 

 

 

 

 

 

 

 

 

Stevens-

Johnson 

syndromeb 

Toxic 

epidermal 

necrolysisb 

Pemphigoi

d 

Dermatitis 

bullous 

 

 
 



 

51 

 

System 

Organ Class  

(MedDRA) 

 

Very common 

 

Common Uncommon Rare Very rare Not 

known 

 

 

Acquired 

epidermoly

sis bullosa 

Erythema-

tous 

oedemaf  

Pseudocell

u-litis 

Dermatitis 

Eczema 

Prurigo 

Renal and 

urinary 

disorders 

Creatinine 

clearance 

decreased 

Blood 

creatinine 

increasede 

Renal failure 

Glomerular 

filtration rate 

decreased 

   Nephroge-

nic 

diabetes 

insipidus 

 

Renal 

tubular 

necrosis 

General 

disorders and 

administration 

site conditions 

Fatigue 

 

Pyrexia 

Pain 

Oedema 

Chest pain 

Mucosal 

inflammation 

 

    

Investigations  Gamma-

glutamyltransf

erase increased 

    

Injury, 

poisoning and 

procedural 

complications 

  Radiation 

oesophagitis 

Radiation 

pneumonitis 

Recall pheno-

menon 

  

a with and without neutropenia  
b in some cases fatal  
c sometimes leading to extremity necrosis  
d with respiratory insufficiency 
eseen only in combination with cisplatin  
f mainly of the lower limbs 

 

Reporting of suspected adverse reactions 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. 

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting 

system listed in Appendix V. 

 

 



 

52 

 

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. 

 

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: 

 

Table 5. Efficacy of pemetrexed plus cisplatin vs. cisplatin in malignant pleural 

mesothelioma 

 

 



 

53 

 

 Randomized and treated 

patients 

Fully supplemented patients 

Efficacy parameter Pemetrexed/ 

cisplatin 

(N = 226) 

Cisplatin 

 

(N = 222) 

Pemetrexed/ 

cisplatin 

(N = 168) 

Cisplatin 

 

(N = 163) 

Median overall survival (months) 

(95 % CI) 

12.1 

(10.0-14.4) 

9.3 

(7.8-10.7) 

13.3 

(11.4-14.9) 

10.0 

(8.4-11.9) 

Log Rank p-valuea 0.020 0.051 

Median time to tumour progression 

(months) 

(95 % CI) 

5.7 

 

(4.9-6.5) 

3.9 

 

(2.8-4.4) 

6.1 

 

(5.3-7.0) 

3.9 

 

(2.8-4.5) 

Log Rank p-value a 0.001 0.008 

Time to treatment failure (months) 

(95 % CI) 

4.5 

(3.9-4.9) 

2.7 

(2.1-2.9) 

4.7 

(4.3-5.6) 

2.7 

(2.2-3.1) 

Log Rank p-value a 0.001 0.001 

Overall response rateb (95 % CI) 41.3% 

(34.8-48.1) 

16.7% 

(12.0-22.2) 

45.5% 

(37.8-53.4) 

19.6% 

(13.8-26.6) 

Fisher’s exact p-valuea < 0.001 < 0.001 

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

(N=167) 

 

A statistically significant improvement of the clinically relevant symptoms (pain and dyspnoea) 

associated with malignant pleural mesothelioma in the pemetrexed /cisplatin arm (212 patients) 

versus the cisplatin arm alone (218 patients) was demonstrated using the Lung Cancer Symptom 

Scale. Statistically significant differences in pulmonary function tests were also observed. The 

separation between the treatment arms was achieved by improvement in lung function in the 

pemetrexed /cisplatin arm and deterioration of lung function over time in the control arm. 

 

There are limited data in patients with malignant pleural mesothelioma treated with pemetrexed 

alone. Pemetrexed at a dose of 500 mg/m2 was studied as a single-agent in 64 chemonaive 

patients with malignant pleural mesothelioma. The overall response rate was 14.1 %. 

 

NSCLC, second-line treatment 

 

A multicentre, randomised, open label phase 3 study of pemetrexed versus docetaxel in patients 

with locally advanced or metastatic NSCLC after prior chemotherapy has shown median 

survival times of 8.3 months for patients treated with pemetrexed (Intent To Treat population 

n = 283) and 7.9 months for patients treated with docetaxel (ITT n=  288). Prior chemotherapy 

did not include pemetrexed. An analysis of the impact of NSCLC histology on the treatment 

effect on overall survival was in favour of pemetrexed versus docetaxel for other than 

predominantly squamous histologies (n = 399, 9.3 versus 8.0 months, adjusted HR=0.78; 

95% CI=0.61-1.00, p=0.047) and was in favour of docetaxel for squamous cell carcinoma 

histology (n = 172, 6.2 versus 7.4 months, adjusted HR=1.56; 95% CI=1.08-2.26, p=0.018). 

There were no clinically relevant differences observed for the safety profile of pemetrexed 

within the histology subgroups. 

 

Limited clinical data from a separate randomized, Phase 3, controlled trial, suggest that efficacy 

data (overall survival, progression free survival) for pemetrexed are similar between patients 



 

54 

 

previously pre treated with docetaxel (n = 41) and patients who did not receive previous 

docetaxel treatment (n=540). 

 

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

Survival time (months) 

▪ Median (m) 
▪ 95% CI for median 
▪ HR 
▪ 95% CI for HR 
▪ • Non-inferiority p-value (HR) 

(N = 283) 

8.3 

(7.0-9.4) 

(N = 288) 

7.9 

(6.3-9.2) 

0.99 

(0.82-1.20) 

0.226 

Progression-free survival (months) 

▪ Median 
▪ HR (95% CI) 

(N = 283) 

2.9 

(N = 288) 

2.9 

0.97 (0.82-1.16) 

Time to treatment failure (TTTF-months) 

▪ Median 
▪ HR (95% CI) 

(N = 283) 

2.3 

(N = 288) 

2.1 

0.84 (0.71-0.997) 

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 PC 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. 

 

Table 7. Efficacy of pemetrexed + cisplatin vs. gemcitabine + cisplatin in first-line 

non-small cell lung cancer – ITT population and histology subgroups. 



 

55 

 

 

 

ITT population 

and histology 

subgroups 

Median overall survival in months 

(95% CI) 

Adjusted 

hazard ratio 

(HR) (95% 

CI) 

 

Superiority 

p-value 
Pemetrexed + cisplatin 

Gemcitabine + 

cisplatin 

ITT population 

(N = 1725) 

10.3 

(9.8 – 11.2) 

N=862 10.3 

(9.6 – 10.9) 

N=863 0.94a 

(0.84 – 1.05) 

0.259 

Adenocarcinoma 

(N=847) 

12.6  

(10.7 – 13.6) 

N=436 10.9  

(10.2 – 11.9) 

N=411 0.84 

(0.71–0.99) 

0.033 

Large cell 

(N=153) 

10.4 

(8.6 – 14.1) 

N=76 6.7 

(5.5 – 9.0) 

N=77 0.67 

(0.48–0.96) 

0.027 

Other 

(N=252) 

8.6 

(6.8 – 10.2) 

N=106 9.2 

(8.1 – 10.6) 

N=146 1.08 

(0.81–1.45) 

0.586 

Squamous cell 

(N=473) 

9.4 

(8.4 – 10.2) 

N=244 10.8 

(9.5 – 12.1) 

N=229 1.23 

(1.00–1.51) 

0.050 

 
Abbreviations: CI = confidence interval; ITT = intent-to-treat; N = total population size. 
aStatistically 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 

 
Abbreviations: PC=Pemetrexed+cisplatin; GC= Gemcitabine+cisplatin 

 

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 



 

56 

 

(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 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: 

 



 

57 

 

 
 

 

 

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 were measured from the time of randomisation after completion 

of first-line (induction) therapy. Patients received a median of 4 cycles of maintenance treatment 

with pemetrexed and 4 cycles of placebo. A total of 169 patients (47.1%) completed ≥ 6 cycles 

maintenance treatment with pemetrexed, representing at least 10 total cycles of pemetrexed. 

 

The study met its primary endpoint and showed a statistically significant improvement in PFS in 

the pemetrexed arm over the placebo arm (n = 472, independently reviewed population; median 

of 3.9 months and 2.6 months, respectively) (hazard ratio= 0.64, 95% CI= 0.51-0.81, p= 0.0002). 

The independent review of patient scans confirmed the findings of the investigator assessment of 

PFS. For randomised patients, as measured from the start of pemetrexed plus cisplatin first line 

induction treatment, the median investigator-assessed PFS was 6.9 months for the pemetrexed 

arm and 5.6 months for the placebo arm (hazard ratio=0.59 95% CI= 0.47-0.74). 

 

Following pemetrexed plus cisplatin induction (4 cycles), treatment with pemetrexed was 

statistically superior to placebo for OS (median 13.9 months versus 11.0 months, hazard 

ratio= 0.78, 95% CI= 0.64-0.96, p= 0.0195). At the time of this final survival analysis, 28.7% of 

patients were alive or lost to follow up on the pemetrexed arm versus 21.7% on the placebo arm. 

The relative treatment effect of pemetrexed was internally consistent across subgroups 

(including disease stage, induction response, ECOG PS, smoking status, gender, histology and 

age) and similar to that observed in the unadjusted OS and PFS analyses. The 1 year and 2 year 

survival rates for patients on pemetrexed were 58% and 32% respectively, compared to 45% and 

21% for patients on placebo. From the start of pemetrexed plus cisplatin first line induction 

treatment, the median OS of patients was 16.9 months for the pemetrexed arm and 14.0 months 



 

58 

 

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. 

 

Paediatric population  

The European Medicines Agency has waived the obligation to submit the results of studies with 

the reference medicinal product containing pemetrexed in all subsets of the paediatric population 

in the granted indications (see section 4.2 for information on paediatric use). 

  

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 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. 

 

 



 

59 

 

5.3 Preclinical safety data 

 

Administration of pemetrexed to pregnant mice resulted in decreased foetal viability, decreased 

foetal weight, incomplete ossification of some skeletal structures and cleft palate. 

 

Administration of pemetrexed to male mice resulted in reproductive toxicity characterised by 

reduced fertility rates and testicular atrophy. In a study conducted in beagle dog by intravenous 

bolus injection for 9 months, testicular findings (degeneration/necrosis of the seminiferous 

epithelium) have been observed. This suggests that pemetrexed may impair male fertility. 

Female fertility was not investigated. 

 

Pemetrexed was not mutagenic in either the in vitro chromosome aberration test in Chinese 

hamster ovary cells, or the Ames test. Pemetrexed has been shown to be clastogenic in the in 

vivo micronucleus test in the mouse. 

 

Studies to assess the carcinogenic potential of pemetrexed have not been conducted. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Hydroxypropylbetadex 

Hydrochloric acid (E507) (pH adjustment) 

Trometamol (pH adjustment) 

Water for injections 

 

6.2 Incompatibilities 

 

Pemetrexed is physically incompatible with diluents containing calcium, including lactated 

Ringer’s injection and Ringer’s injection. In the absence of other compatibility studies this 

medicinal product must not be mixed with other medicinal products. 

 

Pemetrexed Fresenius Kabi contains trometamol as an excipient. Trometamol is incompatible 

with cisplatin resulting in degradation of cisplatin. This medicinal product must not be mixed 

with other medicinal products. Intravenous lines should be flushed after administration of 

Pemetrexed Fresenius Kabi. 

 

6.3 Shelf life 

 

Unopened vial 

18 months 

 

Infusion solution 

Chemical and physical in-use stability of diluted solution was demonstrated for 21 days at 

refrigerated temperature and 7 days at room temperature. When prepared as directed, infusion 

solutions of Pemetrexed Fresenius Kabi contain no antimicrobial preservatives. From a 

microbiological point of view, the product should be used immediately. If not used immediately, 

in-use storage times and conditions prior to use are the responsibility of the user and would not 

be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated 

aseptic conditions. 

 

 



 

60 

 

6.4 Special precautions for storage 

 

Unopened vial 

Store below 25°C. 

 

Keep the vial in the outer carton in order to protect from light. 

 

For storage conditions after dilution of the medicinal product, see section 6.3. 

 

6.5 Nature and contents of container 

 

Pemetrexed Fresenius Kabi 100 mg/4 ml concentrate for solution for infusion 

Type I, clear, colourless glass vial, with 20 mm chlorobutyl rubber stopper and sealed with 

green flip-off aluminium seal, containing 4 ml concentrate. Each pack contains one vial. 

 

Pemetrexed Fresenius Kabi 500 mg/20 ml concentrate for solution for infusion 

Type I, clear, colourless glass vial, with 20 mm chlorobutyl rubber stopper and sealed with blue 

flip-off aluminium seal, containing 20 ml concentrate. Each pack contains one vial. 

 

Pemetrexed Fresenius Kabi 1,000 mg/40 ml concentrate for solution for infusion 

Type I, clear, colourless glass vial, with 20 mm chlorobutyl rubber stopper and sealed with red 

flip-off aluminium seal, containing 40 ml concentrate. Each pack contains one vial. 

 

Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal and other handling 

 

- Use aseptic technique during the dilution of pemetrexed for intravenous infusion 
administration. 

 

- Calculate the dose and the number of Pemetrexed Fresenius Kabi vials needed.  
 

- The appropriate volume of Pemetrexed Fresenius Kabi must be diluted to 100 ml with 
sodium chloride 9 mg/ml (0.9 %) solution for injection or 5% glucose intravenous 

infusion and administered as an intravenous infusion over 10 minutes. 

 

- Pemetrexed infusion solutions prepared as directed above are compatible with polyvinyl 
chloride and polyolefin lined administration sets and infusion bags. 

 

- Parenteral medicinal products must be inspected visually for particulate matter and 
discolouration prior to administration. If particulate matter is observed, do not 

administer. 

 

- Pemetrexed solutions are for single use only. Any unused medicinal product or waste 
material must be disposed of in accordance with local requirements. 

 

Preparation and administration precautions 

As with other potentially toxic anticancer agents, care should be exercised in the handling and 

preparation of pemetrexed infusion solutions. The use of gloves is recommended. If a 

pemetrexed solution contacts the skin, wash the skin immediately and thoroughly with soap and 

water. If pemetrexed solutions contact the mucous membranes, flush thoroughly with water. 

Pregnant women must avoid contact with cytostatic medicinal product. Pemetrexed is not a 

vesicant. There is not a specific antidote for extravasation of pemetrexed. There have been few 



 

61 

 

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 

 
Fresenius Kabi Deutschland GmbH 
Else-Kröner-Straße 1, 
61352 Bad Homburg v.d.Höhe 

Germany 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/16/1115/003 

EU/1/16/1115/004 

EU/1/16/1115/005 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 
Date of first authorisation: 22 July 2016 
 

 

10. DATE OF REVISION OF THE TEXT 

 

 

Detailed information on this product is available on the website of the European Medicines 

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



 

62 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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 



 

63 

 

A.  MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer(s) responsible for batch release 

 

Fresenius Kabi Deutschland GmbH 

Pfingstweide 53 

61169 Friedberg 

Germany  

 

Or  

Fresenius Kabi Polska Sp. z o.o. 

ul. Sienkiewicza 25, Kutno, 99-300, Poland 

 

Or 

Fresenius Kabi France- Louviers 

6 rue du Rempart 

Louviers, 27400 

France 

 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of 

Product Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  

 

• Periodic safety update reports (PSURs)  
 

The requirements for submission of  (PSURs)for this medicinal product are set out in the list 

of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

• Risk management plan (RMP) 
 

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 

activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 

marketing authorisation and any agreed subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

 

• At the request of the European Medicines Agency; 



 

64 

 

• 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.  



 

65 

 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 



 

66 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 

67 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON 
 
 

1. NAME OF THE MEDICINAL PRODUCT 

 
Pemetrexed Fresenius Kabi 100 mg powder for concentrate for solution for infusion  
pemetrexed 
 
 

2. STATEMENT OF ACTIVE SUBSTANCE 

 
Each vial contains 100 mg of pemetrexed (as pemetrexed diacid). 
 
After reconstitution, each vial contains 25 mg/ml of pemetrexed. 
 
 

3. LIST OF EXCIPIENTS 

 
Mannitol, hydrochloric acid, trometamol.  

See package leaflet for further information. 
 
 

4. PHARMACEUTICAL FORM AND CONTENTS 

 
Powder for concentrate for solution for infusion. 
1 vial 
 
 

5. METHOD AND ROUTE OF ADMINISTRATION 

 
Intravenous use after reconstitution and dilution. 
For single use only. 
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 IF NECESSARY 

 
Cytotoxic 
 
 

8. EXPIRY DATE 

 

EXP: 

 

 



 

68 

 

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 

 

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1, 

61352 Bad Homburg v.d.Höhe 

Germany 
 

12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/16/1115/001 
 
 

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: 



 

69 

 

 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

VIAL LABEL 
 
 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Pemetrexed Fresenius Kabi 100 mg powder for concentrate for solution for infusion  

pemetrexed 

Intravenous 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 

 

For single use only. 

 

Cytotoxic 
 



 

70 

 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON 
 
 

1. NAME OF THE MEDICINAL PRODUCT 

 
Pemetrexed Fresenius Kabi 500 mg powder for concentrate for solution for infusion  
pemetrexed 
 
 

2. STATEMENT OF ACTIVE SUBSTANCE 

 
Each vial contains 500 mg of pemetrexed (as pemetrexed diacid). 
 
After reconstitution, each vial contains 25 mg/ml of pemetrexed. 
 
 

3. LIST OF EXCIPIENTS 

 
Mannitol, hydrochloric acid, trometamol 

See package leaflet for further information. 
 
 

4. PHARMACEUTICAL FORM AND CONTENTS 

 
Powder for concentrate for solution for infusion. 
1 vial 
 
 

5. METHOD AND ROUTE OF ADMINISTRATION 

 
Intravenous use after reconstitution and dilution. 
For single use only. 
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 IF NECESSARY 

 
Cytotoxic 
 
 

8. EXPIRY DATE 

 

EXP: 

 

 



 

71 

 

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 

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1, 

61352 Bad Homburg v.d.Höhe 

Germany 
 

12. MARKETING AUTHORISATION NUMBER(S) 

 
EU/1/16/1115/002 
 
 

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: 

 

 



 

72 

 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

VIAL LABEL 
 
 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Pemetrexed Fresenius Kabi 500 mg powder for concentrate for solution for infusion  

pemetrexed 

Intravenous use 
 

2. METHOD OF ADMINISTRATION 
 
 
 

3. EXPIRY DATE 

 

EXP 
 

4. BATCH NUMBER 

 

Lot 
 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

500 mg 
 

6. OTHER 

 

For single use only. 

 

Cytotoxic 



 

73 

 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 OUTER CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Pemetrexed Fresenius Kabi 25 mg/ml concentrate for solution for infusion  

 

 

2. STATEMENT OF ACTIVE SUBSTANCE 

 

One ml of concentrate contains 25 mg pemetrexed (as pemetrexed diacid). 

 

One vial of 4 ml concentrate contains 100 mg pemetrexed (as pemetrexed diacid). 

One vial of 20 ml concentrate contains 500 mg pemetrexed (as pemetrexed diacid). 

One vial of 40 ml concentrate contains 1,000 mg pemetrexed (as pemetrexed diacid). 

 

 

3. LIST OF EXCIPIENTS 

 

Hydroxypropylbetadex, hydrochloric acid, trometamol and water for injections.  

See package leaflet for further information. 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Concentrate for solution for infusion 

 

1 vial 

100 mg / 4 mL 

1 vial 

500 mg / 20 mL 

1 vial 

1000 mg / 40 mL 

 

 

5. METHOD AND ROUTE OF ADMINISTRATION 

 

Intravenous use after dilution. 

For single use only. 

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 

 



 

74 

 

Cytotoxic 

 

Must only be diluted in 0.9 % NaCl or 5% glucose solution 

 

 

8. EXPIRY DATE 

 

EXP: 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

Store below 25°C. 

Keep the vial in the outer carton in order to protect from light. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1, 

61352 Bad Homburg v.d.Höhe 

Germany 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/16/1115/003 

EU/1/16/1115/004 

EU/1/16/1115/005 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 



 

75 

 

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: 



 

76 

 

 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

VIAL LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Pemetrexed Fresenius Kabi 25 mg/ml concentrate for solution for infusion 

 

pemetrexed 

IV after dilution 

 

 

2. METHOD OF ADMINISTRATION 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

100 mg / 4 mL 

500 mg / 20 mL 

1,000 mg / 40 mL 

 

 

6. OTHER 

 

For single use only. 

 

Cytotoxic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



 

77 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 

 

 

 

B. PACKAGE LEAFLET 



 

78 

 

Package leaflet: Information for the user 

 

Pemetrexed Fresenius Kabi 100 mg powder for concentrate for solution for infusion 

Pemetrexed Fresenius Kabi 500 mg powder for concentrate for solution for infusion 

pemetrexed 

 

 

Read all of this leaflet carefully before you start receiving this medicine because it contains 

important information for you. 

- Keep this leaflet. You may need to read it again. 

- If you have any further questions, ask your doctor or pharmacist. 

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

 effects not listed in this leaflet. See section 4. 

 

 

What is in this leaflet 

 

1. What Pemetrexed Fresenius Kabi is and what it is used for 

2. What you need to know before you use Pemetrexed Fresenius Kabi 

3. How to use Pemetrexed Fresenius Kabi 

4. Possible side effects 

5. How to store Pemetrexed Fresenius Kabi 

6. Contents of the pack and other information 

 

 

1. What Pemetrexed Fresenius Kabi is and what it is used for 

 

Pemetrexed Fresenius Kabi is a medicine used in the treatment of cancer. 

 

Pemetrexed Fresenius Kabi 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 Fresenius Kabi is also given in combination with cisplatin for the initial treatment of 

patients with advanced stage of lung cancer. 

 

Pemetrexed Fresenius Kabi 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 Fresenius Kabi 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 Fresenius Kabi 

 

Do not use Pemetrexed Fresenius Kabi 

- 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 Fresenius Kabi. 

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

 

 



 

79 

 

Warnings and precautions 

 

Talk to your doctor or hospital pharmacist before receiving Pemetrexed Fresenius Kabi. 

 

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 Fresenius Kabi. 

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 

Fresenius Kabi. 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 Fresenius Kabi. 

 

If you have been recently vaccinated, please tell your doctor, as this can possibly cause bad effects 

with Pemetrexed Fresenius Kabi. 

 

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 Fresenius Kabi. 

 

Children and adolescents 

This medicine should not be used in children or adolescents, since there is no experience with this 

medicine in children and adolescents under 18 years of age. 

 

Other medicines and Pemetrexed Fresenius Kabi 

Tell your doctor if you are taking, have recently taken or might take any medicine 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 Fresenius Kabi 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, think you may be pregnant or are planning to have a baby, tell your doctor. The 

use of Pemetrexed Fresenius Kabi should be avoided during pregnancy. Your doctor will discuss 

with you the potential risk of taking Pemetrexed Fresenius Kabi during pregnancy. Women must use 

effective contraception during treatment with Pemetrexed Fresenius Kabi. 

 

Breast-feeding 

If you are breast-feeding, tell your doctor. 

Breast-feeding must be discontinued during treatment with Pemetrexed Fresenius Kabi. 

 

Fertility 

Men are advised not to father a child during and up to 6 months following treatment with Pemetrexed 

Fresenius Kabi and should therefore use effective contraception during treatment with Pemetrexed 



 

80 

 

Fresenius Kabi and for up to 6 months afterwards. If you would like to father a child during the 

treatment or in the 6 months following receipt of treatment, seek advice from your doctor or 

pharmacist. You may want to seek counselling on sperm storage before starting your therapy. 

 

Driving and using machines 

Pemetrexed Fresenius Kabi may make you feel tired. Be careful when driving a car or using 

machines. 

 

 

3. How to use Pemetrexed Fresenius Kabi 

 

The dose of Pemetrexed Fresenius Kabi 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 Fresenius Kabi powder with 5% 

glucose intravenous infusion before it is given to you. 

 

You will always receive Pemetrexed Fresenius Kabi by infusion into one of your veins. The infusion 

will last approximately 10 minutes. 

 

When using Pemetrexed Fresenius Kabi 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 Fresenius Kabi has finished. The infusion of cisplatin will last 

approximately 2 hours. 

 

You should usually receive your infusion once every 3 weeks. 

 

Additional medicines: 

Corticosteroids: 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 Fresenius Kabi 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 Fresenius Kabi. You must take at least 5 doses during the seven days before the first 

dose of Pemetrexed Fresenius Kabi. You must continue taking the folic acid for 21 days after the last 

dose of Pemetrexed Fresenius Kabi. You will also receive an injection of vitamin B12 

(1000 micrograms) in the week before administration of Pemetrexed Fresenius Kabi and then 

approximately every 9 weeks (corresponding to 3 courses of Pemetrexed Fresenius Kabi 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 

 

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: 



 

81 

 

▪ 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 may include: 

 

Very common (may affect more than 1 in 10 people) 

Infection 

Pharyngitis (a sore throat) 

Low number of neutrophil granulocytes (a type of white blood cell) 

Low white blood cells 

Low haemoglobin level  

Pain, redness, swelling or sores in your mouth 

Loss of appetite 

Vomiting 

Diarrhoea  

Nausea 

Skin rash 

Flaking skin 

Abnormal blood tests showing reduced functionality of kidneys  

Fatigue (tiredness) 

 

Common (may affect up to 1 in 10 people) 

Blood infection 

Fever with low number of neutrophil granulocytes (a type of white blood cell) 

Low platelet count 

Allergic reaction 

Loss of body fluids 

Taste change 

Damage to the motor nerves which may cause muscle weakness and atrophy (wasting) primary in the 

arms and legs) 

Damage to the sensory nerves that may cause lost of sensation, burning pain and unsteady gait 

Dizziness 

Inflammation or swelling of the conjunctiva (the membrane that lines the eyelids and covers the 

white of the eye 

Dry eye 

Watery eyes 

Dryness of the conjunctiva (the membrane that lines the eyelids and covers the white of the eye) and 

cornea (the clear layer in front of the iris and pupil. 

Swelling of the eyelids 



 

82 

 

Eye disorder with dryness, tearing, irritation, and/or pain 

Cardiac Failure (Condition that affects the pumping power of your heart muscles) 

Irregular heart rhythm 

Indigestion 

Constipation 

Abdominal pain 

Liver: increases in the chemicals in the blood made by the liver  

Increased skin pigmentation 

Itchy skin 

Rash on the body where each mark resembles a bullseye 

Hair loss 

Hives 

Kidney stop working 

Reduced functionality of kidney  

Fever 

Pain 

Excess fluid in body tissue, causing swelling 

Chest pain 

Inflammation and ulceration of the mucous membranes lining the digestive tract 

 

Uncommon (may affect up to 1 in 100 people) 

Reduction in the number of red,white blood cells and platelets 

Stroke 

Type of stroke when an artery to the brain is blocked 

Bleeding inside the skull 

Angina (Chest pain caused by reduced blood flow to the heart) 

Heart attack 

Narrowing or blockage of the coronary arteries 

Abnormal heart rythm)  

Deficient blood distribution to the limbs 

Blockage in one of the pulmonary arteries in your lungs 

Inflammation and scarring of the lining of the lungs with breathing problems 

Passage of bright red blood from the anus 

Bleeding in the gastrointestinal tract 

Ruptured bowel 

Inflammation of the lining of the oesophagus 

Inflammation of the lining of the large bowel, which may be accompanied by intestinal or rectal 

bleeding (seen only in combination with cisplatin) 

Inflammation, edema, erythema, and erosion of the mucosal surface of the esophagus caused by 

radiation therapy 

Inflammation of the lung caused by radiation therapy 

 

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

Destruction of red blood cells 

Anaphylactic shock (severe allergic reaction) 

Inflammatory condition of the liver 

Redness of the skin 

Skin rash that develops throughout a previously irradiated area 

 

Very rare (affect up to 1 of 10 000 people) 

Infections of skin and soft tissues 

Stevens-Johnson syndrome (a type of severe skin and mucous membranes reaction that may be life 

threatening) 



 

83 

 

Toxic epidermal necrolysis (a type of severe skin reaction that may be life threatening) 

Autoimmune disorder that results in skin rashes and blistering on the legs, arms, and abdomen 

Inflammation of the skin characterized by the presence of bullae which are filled with fluid 

Skin fragility, blisters and erosions and skin scarring 

Redness, pain and swelling mainly of the lower limbs 

Inflammation of the skin and fat beneath the skin (pseudocellulitis) 

Inflammation of the skin (dermatitis) 

Skin to become inflamed, itchy, red, cracked, and rough 

Intensely itchy spots  

 

Not known: frequency cannot be estimated from the available data 

Form of diabetes primarily due to pathology of the kidney 

Disorder of the kidneys involving the death of tubular epithelial cells that form the renal tubules 

 

You might have any of these symptoms and/or conditions. You must tell your doctor as soon as 

possible when you start experiencing any of these side effects. 

 

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. 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 Fresenius Kabi 

 

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 vial label and carton after ‘EXP’. 

The expiry date refers to the last day of that month. 

 

This medicine does not require any special storage conditions. 

 

Reconstituted and infusion solutions: The product should be used immediately. When prepared as 

directed, chemical and physical in-use stability of reconstituted solution of pemetrexed was 

demonstrated for 24 hours at refrigerated temperature. For infusion solution of pemetrexed, chemical 

and physical in-use stability was demonstrated for 21 days at refrigerated temperature and 7 days at 

room temperature. 

 

This medicine should not been used if there are any signs of particles. 

 

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 Fresenius Kabi contains 

 



 

84 

 

The active substance is pemetrexed. 

 

Pemetrexed Fresenius Kabi 100 mg: Each vial contains 100 milligrams of pemetrexed (as 

pemetrexed diacid). 

. 

Pemetrexed Fresenius Kabi 500 mg: Each vial contains 500 milligrams of pemetrexed (as 

pemetrexed diacid). 

 

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 trometamol. 

 

What Pemetrexed Fresenius Kabi looks like and contents of the pack 

Pemetrexed Fresenius Kabi is a powder for concentrate for solution for infusion in a glass vial. It is a 

white to off-white lyophilised powder or solid. 

 

It is available in packs of 1 vial. 
 
Marketing Authorisation Holder  

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1, 

61352 Bad Homburg v.d.Höhe 

Germany 

 

Manufacturer 

Fresenius Kabi Deutschland GmbH 

Pfingstweide 53 

61169 Friedberg 

Germany  

 

Or  

Fresenius Kabi Polska Sp. z o.o. 

ul. Sienkiewicza 25, Kutno, 99-300, Poland 

 

 

Or 

Fresenius Kabi France- Louviers 

6 rue du Rempart 

Louviers, 27400 

France 

 

 

For any information about this medicine, please contact the Marketing Authorisation Holder. 
 
 

This leaflet was last revised in 

 

Other sources of information 

Detailed information on this medicine is available on the website of European Medicines 

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



 

85 

 

<--------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for medical or healthcare professionals only: 

 

Instructions for use, handling and disposal. 

 

- Use aseptic techniques during the reconstitution and further dilution of pemetrexed 
for intravenous infusion administration. 

 

- Calculate the dose and the number of Pemetrexed Fresenius Kabi vials needed. Each vial 
contains an excess of pemetrexed to facilitate delivery of the label amount. 

 

- Pemetrexed Fresenius Kabi 100 mg: 
- Reconstitute each 100 mg vial with 4.2 ml of 5% glucose intravenous infusion 

resulting in a solution containing 25 mg/ml pemetrexed. 

 

- Pemetrexed Fresenius Kabi 500 mg: 
- Reconstitute each 500 mg vial with 20 ml of 5% glucose intravenous infusion 

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. 

 

- The appropriate volume of reconstituted pemetrexed solution must be further diluted to 
100 ml with 5% glucose intravenous infusion and administered as an intravenous infusion 

over 10 minutes. 

 

- 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. 

 

Pemetrexed Fresenius Kabi contains trometamol as an excipient. Trometamol is 

incompatible with cisplatin resulting in degradation of cisplatin. This medicinal product 

must not be mixed with other medicinal products. Intravenous lines should be flushed after 

administration of Pemetrexed Fresenius Kabi 

 

- Parenteral medicinal products should be inspected visually for particulate matter and 
discolouration prior to administration. If particulate matter is observed, do not 

administer. 

 

- Pemetrexed solutions are for single use only. Any unused product or waste material should 
be disposed of in accordance with local requirements. 

 

Preparation and administration precautions: As with other potentially toxic anticancer agents, 

care should be exercised in the handling and preparation of pemetrexed infusion solutions. The use 

of gloves is recommended. If a pemetrexed solution contacts the skin, wash the skin immediately 

and thoroughly with soap and water. If pemetrexed solutions contact the mucous membranes, flush 

thoroughly with water. Pregnant women must avoid contact with cytostatic medicinal product. 

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 



 

86 

 

serious by the investigator. Extravasation should be managed by local standard practice as with 

other non-vesicants. 



 

87 

 

 

Package leaflet: Information for the user 

Pemetrexed Fresenius Kabi 25 mg/ml concentrate for solution for infusion 

pemetrexed 

 

 

Read all of this leaflet carefully before you start receiving this medicine because it contains 

important information for you. 

- Keep this leaflet. You may need to read it again. 

- If you have any further questions, ask your doctor or pharmacist. 

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

 effects not listed in this leaflet. See section 4. 

 

 

What is in this leaflet 

 

1. What Pemetrexed Fresenius Kabi is and what it is used for 

2. What you need to know before you use Pemetrexed Fresenius Kabi 

3. How to use Pemetrexed Fresenius Kabi 

4. Possible side effects 

5. How to store Pemetrexed Fresenius Kabi 

6. Contents of the pack and other information 

 

 

1. What Pemetrexed Fresenius Kabi is and what it is used for 

 

Pemetrexed Fresenius Kabi is a medicine used in the treatment of cancer. 

 

Pemetrexed Fresenius Kabi 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 Fresenius Kabi is also given in combination with cisplatin for the initial treatment of 

patients with advanced stage of lung cancer. 

 

Pemetrexed Fresenius Kabi 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 Fresenius Kabi 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 Fresenius Kabi 

 

Do not use Pemetrexed Fresenius Kabi 

- 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 Fresenius Kabi. 

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

 

 

 



 

88 

 

Warnings and precautions 

 

Talk to your doctor or hospital pharmacist before receiving Pemetrexed Fresenius Kabi. 

 

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 Fresenius Kabi. 

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 

Fresenius Kabi. 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 Fresenius Kabi. 

 

If you have been recently vaccinated, please tell your doctor, as this can possibly cause bad effects 

with Pemetrexed Fresenius Kabi. 

 

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 Fresenius Kabi. 

 

Children and adolescents 

This medicine should not be used in children or adolescents, since there is no experience with this 

medicine in children and adolescents under 18 years of age. 

Other medicines and Pemetrexed Fresenius Kabi 

Tell your doctor if you are taking, have recently taken or might take any medicine 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 Fresenius Kabi 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, think you may be pregnant or are planning to have a baby, tell your doctor. The 

use of Pemetrexed Fresenius Kabi should be avoided during pregnancy. Your doctor will discuss 

with you the potential risk of taking Pemetrexed Fresenius Kabi during pregnancy. Women must use 

effective contraception during treatment with Pemetrexed Fresenius Kabi. 

 

Breast-feeding 

If you are breast-feeding, tell your doctor. 

Breast-feeding must be discontinued during treatment with Pemetrexed Fresenius Kabi. 

 

Fertility 

Men are advised not to father a child during and up to 6 months following treatment with Pemetrexed 

Fresenius Kabi and should therefore use effective contraception during treatment with Pemetrexed 

Fresenius Kabi and for up to 6 months afterwards. If you would like to father a child during the 



 

89 

 

treatment or in the 6 months following receipt of treatment, seek advice from your doctor or 

pharmacist. You may want to seek counselling on sperm storage before starting your therapy. 

 

Driving and using machines 

Pemetrexed Fresenius Kabi may make you feel tired. Be careful when driving a car or using 

machines. 

 

Pemetrexed Fresenius Kabi contains 964 mg of hydroxypropylbetadex per 100 mg pemetrexed. 

 

If you have a kidney disease, talk to your doctor before you receive this medicine. 

 

 

3. How to use Pemetrexed Fresenius Kabi 

 

The dose of Pemetrexed Fresenius Kabi 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 Fresenius Kabi with sodium 

chloride 9 mg/ml (0.9 %) solution for injection or 5% glucose intravenous infusion before it is given 

to you. 

 

You will always receive Pemetrexed Fresenius Kabi by infusion into one of your veins. The infusion 

will last approximately 10 minutes. 

 

When using Pemetrexed Fresenius Kabi 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 Fresenius Kabi has finished. The infusion of cisplatin will last 

approximately 2 hours. 

 

You should usually receive your infusion once every 3 weeks. 

 

Additional medicines: 

Corticosteroids: 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 Fresenius Kabi 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 Fresenius Kabi. You must take at least 5 doses during the seven days before the first 

dose of Pemetrexed Fresenius Kabi. You must continue taking the folic acid for 21 days after the last 

dose of Pemetrexed Fresenius Kabi. You will also receive an injection of vitamin B12 

(1000 micrograms) in the week before administration of Pemetrexed Fresenius Kabi and then 

approximately every 9 weeks (corresponding to 3 courses of Pemetrexed Fresenius Kabi 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. 

 

 

 



 

90 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

You must contact your doctor immediately if you notice any of the following: 

▪ Fever or infection (common): if you have a temperature of 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 may include: 

 

Very common (may affect more than 1 in 10 people) 

Infection 

Pharyngitis (a sore throat) 

Low number of neutrophil granulocytes (a type of white blood cell) 

Low white blood cells 

Low haemoglobin level  

Pain, redness, swelling or sores in your mouth 

Loss of appetite 

Vomiting 

Diarrhoea  

Nausea 

Skin rash 

Flaking skin 

Abnormal blood tests showing reduced functionality of kidneys  

Fatigue (tiredness) 

 

Common (may affect up to 1 in 10 people) 

Blood infection 

Fever with low number of neutrophil granulocytes (a type of white blood cell) 

Low platelet count 

Allergic reaction 

Loss of body fluids 

Taste change 

Damage to the motor nerves which may cause muscle weakness and atrophy (wasting) primary in the 

arms and legs) 

Damage to the sensory nerves that may cause lost of sensation, burning pain and unsteady gait 

Dizziness 

Inflammation or swelling of the conjunctiva (the membrane that lines the eyelids and covers the 

white of the eye 



 

91 

 

Dry eye 

Watery eyes 

Dryness of the conjunctiva (the membrane that lines the eyelids and covers the white of the eye) and 

cornea (the clear layer in front of the iris and pupil. 

Swelling of the eyelids 

Eye disorder with dryness, tearing, irritation, and/or pain 

Cardiac Failure (Condition that affects the pumping power of your heart muscles) 

Irregular heart rhythm 

Indigestion 

Constipation 

Abdominal pain 

Liver: increases in the chemicals in the blood made by the liver  

Increased skin pigmentation 

Itchy skin 

Rash on the body where each mark resembles a bullseye 

Hair loss 

Hives 

Kidney stop working 

Reduced functionality of kidney  

Fever 

Pain 

Excess fluid in body tissue, causing swelling 

Chest pain 

Inflammation and ulceration of the mucous membranes lining the digestive tract 

 

Uncommon (may affect up to 1 in 100 people) 

Reduction in the number of red,white blood cells and platelets 

Stroke 

Type of stroke when an artery to the brain is blocked 

Bleeding inside the skull 

Angina (Chest pain caused by reduced blood flow to the heart) 

Heart attack 

Narrowing or blockage of the coronary arteries 

Abnormal heart rythm)  

Deficient blood distribution to the limbs 

Blockage in one of the pulmonary arteries in your lungs 

Inflammation and scarring of the lining of the lungs with breathing problems 

Passage of bright red blood from the anus 

Bleeding in the gastrointestinal tract 

Ruptured bowel 

Inflammation of the lining of the oesophagus 

Inflammation of the lining of the large bowel, which may be accompanied by intestinal or rectal 

bleeding (seen only in combination with cisplatin) 

Inflammation, edema, erythema, and erosion of the mucosal surface of the esophagus caused by 

radiation therapy 

Inflammation of the lung caused by radiation therapy 

 

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

Destruction of red blood cells 

Anaphylactic shock (severe allergic reaction) 

Inflammatory condition of the liver 

Redness of the skin 

Skin rash that develops throughout a previously irradiated area 



 

92 

 

 

Very rare (affect up to 1 of 10 000 people) 

Infections of skin and soft tissues 

Stevens-Johnson syndrome (a type of severe skin and mucous membranes reaction that may be life 

threatening) 

Toxic epidermal necrolysis (a type of severe skin reaction that may be life threatening) 

Autoimmune disorder that results in skin rashes and blistering on the legs, arms, and abdomen 

Inflammation of the skin characterized by the presence of bullae which are filled with fluid 

Skin fragility, blisters and erosions and skin scarring 

Redness, pain and swelling mainly of the lower limbs 

Inflammation of the skin and fat beneath the skin (pseudocellulitis) 

Inflammation of the skin (dermatitis) 

Skin to become inflamed, itchy, red, cracked, and rough 

Intensely itchy spots  

 

Not known: frequency cannot be estimated from the available data 

Form of diabetes primarily due to pathology of the kidney 

Disorder of the kidneys involving the death of tubular epithelial cells that form the renal tubules 

 

 

You might have any of these symptoms and/or conditions. You must tell your doctor as soon as 

possible when you start experiencing any of these side effects. 

 

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. 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 Fresenius Kabi 

 

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the label and carton after ‘EXP’. The 

expiry date refers to the last day of that month. 

 

Store below 25°C. 

Keep the vial in the outer carton in order to protect from light. 

 

Infusion Solution: The product should be used immediately. When prepared as directed, chemical 

and physical in-use stability of diluted solutions of pemetrexed was demonstrated for 21 days at 

refrigerated temperature and 7 days at room temperature. 

 

This medicine should not been used if there are any signs of particles. 

 

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. 

 

 



 

93 

 

6. Contents of the pack and other information  

 

What Pemetrexed Fresenius Kabi contains 

 

The active substance is pemetrexed. 

One ml of concentrate contains 25 mg pemetrexed. 

After dilution, one vial of 4 ml concentrate contains 100 mg pemetrexed (as pemetrexed diacid). 

One vial of 20 ml concentrate contains 500 mg pemetrexed (as pemetrexed diacid). 

One vial of 40 ml concentrate contains 1,000 mg pemetrexed (as pemetrexed diacid).  

 

The other ingredients are hydroxypropylbetadex, hydrochloric acid, trometamol and water for 

injections. 

 

What Pemetrexed Fresenius Kabi looks like and contents of the pack 

Pemetrexed Fresenius Kabi is a concentrate for solution for infusion (sterile concentrate) in a glass 

vial. It is a colourless to slightly yellowish or yellow-greenish solution. 

It is available in packs of 1 vial. 

 
 
Marketing Authorisation Holder  

 

Fresenius Kabi Deutschland GmbH 

Else-Kröner-Straße 1, 

61352 Bad Homburg v.d.Höhe 

Germany 

 

Manufacturer 

Fresenius Kabi Deutschland GmbH 

Pfingstweide 53 

61169 Friedberg 

Germany  

 

 

For any information about this medicine, please contact the Marketing Authorisation Holder. 
 
 

This leaflet was last revised in 

 

Other sources of information 

Detailed information on this medicine is available on the website of European Medicines 

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



 

105 

<--------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for medical or healthcare professionals only: 

 

Instructions for use, handling and disposal. 

 

- Use aseptic techniques during the dilution of pemetrexed  for intravenous infusion 
administration. 

 

- Calculate the dose and the number of Pemetrexed Fresenius Kabi vials needed.  
 

- The appropriate volume of pemetrexed Fresenius Kabi must be diluted to 100 ml with 
sodium chloride 9 mg/ml (0.9 %) solution for injection or 5% glucose intravenous infusion 

and administered as an intravenous infusion over 10 minutes. 

 

- 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. 

 

Pemetrexed Fresenius Kabi contains trometamol as an excipient. Trometamol is incompatible 

with cisplatin resulting in degradation of cisplatin. This medicinal product must not be mixed 

with other medicinal products. Intravenous lines should be flushed after administration of 

Pemetrexed Fresenius Kabi 

 

- Parenteral medicinal products should be inspected visually for particulate matter and 
discolouration prior to administration. If particulate matter is observed, do not 

administer. 

 

- Pemetrexed solutions are for single use only. Any unused product or waste material should 
be disposed of in accordance with local requirements. 

 

Preparation and administration precautions: As with other potentially toxic anticancer agents, 

care should be exercised in the handling and preparation of pemetrexed infusion solutions. The use 

of gloves is recommended. If a pemetrexed solution contacts the skin, wash the skin immediately 

and thoroughly with soap and water. If pemetrexed solutions contact the mucous membranes, flush 

thoroughly with water. Pregnant women must avoid contact with cytostatic medicinal product. 

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. 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
	A. LABELLING
	B. PACKAGE LEAFLET