Pemetrexed Sandoz

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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



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Pemetrexed Sandoz 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 Sandoz must only be administered under the supervision of a physician qualified in the 
use of anti-cancer chemotherapy.  
 
Posology 
 
Pemetrexed Sandoz in combination with cisplatin 
The recommended dose of pemetrexed is 500 mg/m2 of body surface area (BSA) administered as an 
intravenous infusion over 10 minutes on the first day of each 21-day cycle. The recommended dose of 
cisplatin is 75 mg/m2 BSA infused over two hours approximately 30 minutes after completion of the 
pemetrexed infusion on the first day of each 21-day cycle. Patients must receive adequate antiemetic 
treatment and appropriate hydration prior to and/or after receiving cisplatin (see also cisplatin 
Summary of Product Characteristics for specific dosing advice).  
 
Pemetrexed Sandoz as single agent 
In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended dose of 
pemetrexed is 500 mg/m2 BSA administered as an intravenous infusion over 10 minutes on the first 
day of each 21-day cycle.  
 
Pre-medication regimen 
To reduce the incidence and severity of skin reactions, a corticosteroid should be given the day prior 
to, on the day of, and the day after pemetrexed administration. The corticosteroid should be equivalent 
to 4 mg of dexamethasone administered orally twice a day (see section 4.4).  
 
To reduce toxicity, patients treated with pemetrexed must also receive vitamin supplementation (see 
section 4.4). Patients must take oral folic acid or a multivitamin containing folic acid (350 to 
1,000 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 (1,000 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 ≥ 1,500 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 re-treated using the guidelines 
in Tables 1, 2, and 3, which are applicable for Pemetrexed Sandoz used as a single agent or in 
combination with cisplatin.  
 



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Table 1. Dose modification table for Pemetrexed Sandoz (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 
Sandoz 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 Sandoz (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 Sandoz 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 Sandoz (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 Sandoz 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.  
 



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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 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 Sandoz is for intravenous use. Pemetrexed Sandoz 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 Sandoz,  
and for instructions on reconstitution and dilution of the medicinal product 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 ≥ 1,500 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).  



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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 < 45ml/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 normalised 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 anti-emetic 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.  
 



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Cases of radiation recall have been reported in patients who received radiotherapy weeks or years 
previously. 
 
Excipients 
 
Pemetrexed Sandoz 100 mg powder for concentrate for solution for infusion 
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 
‘sodium- free’. 
 
Pemetrexed Sandoz 500 mg powder for concentrate for solution for infusion 
This medicinal product contains 54 mg sodium per vial, equivalent to 2.7% of the WHO recommended 
maximum daily intake of 2 g sodium for an adult.  
 
Pemetrexed Sandoz 1000 mg powder for concentrate for solution for infusion 
This medicinal product contains 108 mg sodium per vial, equivalent to 5.4% of the WHO 
recommended maximum daily intake of 2 g sodium for an adult. 
 
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 products (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 products are combined with pemetrexed. If necessary, creatinine clearance should be closely 
monitored.  
 
In patients with normal renal function (creatinine clearance ≥  80 ml/min), high doses of non-steroidal 
anti-inflammatory drugs (NSAIDs, such as ibuprofen > 1600 mg/day) and acetylsalicylic acid at 
higher dose (≥  1.3 g daily) may decrease pemetrexed elimination and, consequently, increase the 
occurrence of pemetrexed adverse rections. 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 products 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 



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possibility of interaction between oral anticoagulants and anti-cancer 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, leucopenia, 
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.  
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: 



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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).  
Table 4. Frequencies of all grades adverse drug events regardless of causality from the pivotal 
registration studies: JMEI (ALIMTA vs Docetaxel), JMDB (ALIMTA and Cisplatin versus GEMZAR 
and Cisplatin, JMCH (ALIMTA 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 
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,   Pulmonary    



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thoracic and 
mediastinal 
disorders 

 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 
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 

    



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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: 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 multi-targeted 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 medicinal product action in malignant cells.  
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Pemetrexed in all subsets of the paediatric population in the granted indications (see Section 4.2). 
 
Clinical efficacy 
 
Mesothelioma 
EMPHACIS, a multi-centre, randomised, single-blind Phase 3 study of pemetrexed plus cisplatin 
versus cisplatin in chemonaive patients with malignant pleural mesothelioma, has shown that patients 

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


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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 substance (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 
 Randomised 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)  

12.1  9.3  13.3  10.0  

(95% CI)  (10.0-14.4)  (7.8-10.7)  (11.4-14.9)  (8.4-11.9)  
Log rank p-value*  0.020  0.051  
Median time to tumour 
progression (months)  

5.7  3.9  6.1  3.9  

(95% CI)  (4.9-6.5)  (2.8-4.4)  (5.3-7.0)  (2.8-4.5)  
Log rank p-value*  0.001  0.008  
Time to treatment failure 
(months)  

4.5  2.7  4.7  2.7  

(95% CI)  (3.9-4.9)  (2.1-2.9)  (4.3-5.6)  (2.2-3.1)  
Log rank p-value*  0.001  0.001  
Overall response rate**  41.3%  16.7%  45.5%  19.6%  
(95% CI)  (34.8-48.1)  (12.0-22.2)  (37.8-53.4)  (13.8-26.6)  
Fisher's exact p-value*  < 0.001  < 0.001  
Abbreviation: CI = confidence interval.  
*p-value refers to comparison between arms.  
**In the pemetrexed/cisplatin arm, randomised 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 multi-centre, 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 [ITT] 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 = 



13 

399, 9.3 versus 8.0 months, adjusted hazard ratio (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 randomised, 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)  
• 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 multi-centre, 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 (HR) 0.94; 95% CI= 0.84-1.05). All 
patients included in this study had an ECOG performance status 0 or 1.  
The primary efficacy analysis was based on the ITT population. Sensitivity analyses of main efficacy 
endpoints were also assessed on the Protocol Qualified (PQ) population. The efficacy analyses using 
PQ population are consistent with the analyses for the ITT population and support the non-inferiority 
of AC versus GC.  
Progression-free survival (PFS) and overall response rate were similar between treatment arms: 
median PFS was 4.8 months for pemetrexed plus cisplatin versus 5.1 months for gemcitabine plus 
cisplatin (adjusted hazard ratio (HR) 1.04; 95% CI= 0.94-1.15), and overall response rate was 30.6% 
(95% CI= 27.3- 33.9) for pemetrexed plus cisplatin versus 28.2% (95% CI= 25.0-31.4) for 
gemcitabine plus cisplatin. PFS data were partially confirmed by an independent review (400/1725 
patients were randomly selected for review).  
The analysis of the impact of NSCLC histology on overall survival demonstrated clinically relevant 
differences in survival according to histology, see table below.  
 



14 

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

Median overall survival in months  
(95% CI)  

Adjusted 
hazard ratio 
(HR)  
(95% CI)  

Superiority 
p-value 

Pemetrexed + Cisplatin Gemcitabine + Cisplatin 

ITT population  
(N = 1725)  

10.3  
(9.8 – 11.2)  

N = 862  10.3  
(9.6 – 10.9)  

N = 863  0.94a  
(0.84 – 1.05)  

0.259  

Adenocarcinoma  
(N = 847)  

12.6  
(10.7 – 13.6)  

N = 436  10.9  
(10.2 –11.9)  

N = 411  0.84  
(0.71–0.99)  

0.033  

Large cell  
(N = 153)  

10.4  
(8.6 – 14.1)  

N = 76  6.7  
(5.5 – 9.0)  

N = 77  0.67  
(0.48–0.96)  

0.027  

Other  
(N = 252)  

8.6  
(6.8 – 10.2)  

N = 106  9.2  
(8.1 – 10.6)  

N = 146  1.08  
(0.81–1.45)  

0.586  

Squamous cell  
(N = 473)  

9.4  
(8.4 – 10.2)  

N = 244  10.8  
(9.5 – 12.1)  

N = 229  1.23  
(1.00–1.51)  

0.050  

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

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



15 

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

 
PARAMOUNT 
A 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 



16 

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

 
The pemetrexed maintenance safety profiles from the two studies JMEN and PARAMOUNT were 
similar. 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetic properties of pemetrexed following single-agent administration have been 
evaluated in 426 cancer patients with a variety of solid tumours at doses ranging from 0.2 to 
838 mg/m2 infused over a 10-minute period. Pemetrexed has a steady-state volume of distribution of 9 
l/m2. In vitro studies indicate that pemetrexed is approximately 81% bound to plasma proteins. 



17 

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 90ml/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 (for pH adjustment) 
Sodium hydroxide (for pH adjustment) 
 
6.2 Incompatibilities 
 
Pemetrexed is physically incompatible with diluents containing calcium, including lactated Ringer's 
injection and Ringer's injection.  
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
Unopened vial 
2 years 
 
Reconstituted and infusion solution 
Chemical and physical in-use stability of reconstituted solutions of Pemetrexed Sandoz has been 
demonstrated for 4 days at 2°C to 8°C and for 4 days below 25°C.  
 



18 

Chemical and physical in-use stability of infusion solutions of Pemetrexed Sandoz has been 
demonstrated for 4 days at 2°C to 8°C and for 2 days below 25°C.  
 
From a microbiological point of view, the product should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution / dilution has taken 
place in controlled and validated aseptic conditions. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Pemetrexed Sandoz 100 mg powder for concentrate for solution for infusion 
Clear, colorless 10 ml type I glass vial with chlorobutyl rubber stopper and aluminium crimp cap with 
a flip-off cap, containing 100 mg of pemetrexed. 
Pack of 1 vial with protective plastic overwrap. 
 
Pemetrexed Sandoz 500 mg powder for concentrate for solution for infusion 
Clear, colorless 50 ml type I glass vial with chlorobutyl rubber stopper and aluminium crimp cap with 
a flip-off cap, containing 500 mg of pemetrexed. 
Pack of 1 vial with protective plastic overwrap. 
 
Pemetrexed Sandoz 1000 mg powder for concentrate for solution for infusion 
Clear, colorless 100 ml type I glass vial with chlorobutyl rubber stopper and aluminium crimp cap 
with a flip-off cap, containing 1000 mg of pemetrexed. 
Pack of 1 vial with protective plastic overwrap. 
 
6.6 Special precautions for disposal and other handling 
 
1. Use aseptic technique during the reconstitution and further dilution of pemetrexed for 

intravenous infusion administration. 
 
2. Calculate the dose and the number of Pemetrexed Sandoz vials needed. Each vial contains an 

excess of pemetrexed to facilitate delivery of label amount. 
 
3. Pemetrexed Sandoz 100 mg  

Reconstitute 100-mg vials with 4.2 ml of sodium chloride 9 mg/ml (0.9%) solution for injection 
(without preservative), resulting in a solution containing 25 mg/ml pemetrexed.  

 
 Pemetrexed Sandoz 500 mg 

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

 
 Pemetrexed Sandoz 1000 mg 

Reconstitute 1000-mg vials with 40 ml of sodium chloride 9 mg/ml (0.9%) solution for injection 
(without preservative), resulting in a solution containing 25 mg/ml pemetrexed. 

 
Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear 
and ranges in colour from colourless to pale yellow without adversely affecting product quality. 
The pH of the reconstituted solution is between 6.6 and 7.8. Further dilution is required. 

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

with sodium chloride 9 mg/ml (0.9%) solution for injection (without preservative) or with 



19 

glucose 50 mg/ml (5%) solution for injection (without preservative) and administered as an 
intravenous infusion over 10 minutes. 

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

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

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

should be disposed of in accordance with local requirements. 
 
Preparation and administration precautions 
As with other potentially toxic anticancer agents, care should be exercised in the handling and 
preparation of pemetrexed infusion solutions. The use of gloves is recommended. If a pemetrexed 
solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If 
pemetrexed solutions contact the mucous membranes, flush thoroughly with water. Pemetrexed is not 
a vesicant. There is not a specific antidote for extravasation of pemetrexed. There have been 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 
 
Sandoz GmbH 
Biochemiestrasse 10 
A-6250 Kundl 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1037/001 
EU/1/15/1037/002 
EU/1/15/1037/003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 18 September 2015 
Data of latest renewal:  
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

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


20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE 
AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 



21 

 
A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Ebewe Pharma GmbH Nfg. KG 
Mondseestrasse 11  
A-4866 Unterach 
Austria 
 
Lek Pharmaceuticals d.d. 
Verovskova 57  
SI-1526 Ljubljana  
Slovenia 
 
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 periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

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

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

 
 



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



24 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pemetrexed Sandoz 100 mg powder for concentrate for solution for infusion  
pemetrexed 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One vial contains 100 mg of pemetrexed (as disodium). 
 
After reconstitution each vial contains 25 mg/ml of pemetrexed. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains mannitol (E421), hydrochloric acid and sodium hydroxide (for pH adjustment). 
 
See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion. 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only. 
For intravenous use after reconstitution and dilution. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
 



25 

8. EXPIRY DATE 
 
EXP 
Read the leaflet for the shelf life of the reconstituted product. 
 
 
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 
 
Sandoz GmbH 
Biochemiestrasse 10 
6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1037/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
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. 
 
 



26 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



27 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Pemetrexed Sandoz 100 mg powder for concentrate for solution for infusion  
pemetrexed 
Intravenous use after reconstitution and dilution 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
Read the leaflet for the shelf life of the reconstituted product. 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
100 mg 
 
 
6. OTHER 
 
 



28 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pemetrexed Sandoz 500 mg powder for concentrate for solution for infusion  
pemetrexed 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 500 mg of pemetrexed (as disodium). 
 
After reconstitution each vial contains 25 mg/ml of pemetrexed. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains mannitol (E421), hydrochloric acid and sodium hydroxide (for pH adjustment). 
 
See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion. 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only. 
For intravenous use after reconstitution and dilution. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
 



29 

8. EXPIRY DATE 
 
EXP 
Read the leaflet for the shelf life of the reconstituted product. 
 
 
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 
 
Sandoz GmbH 
Biochemiestrasse 10 
6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1037/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
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. 
 
 



30 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN  
 



31 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Pemetrexed Sandoz 500 mg powder for concentrate for solution for infusion  
pemetrexed 
Intravenous use after reconstitution and dilution 
 
 
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 
 
 



32 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pemetrexed Sandoz 1000 mg powder for concentrate for solution for infusion  
pemetrexed 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One vial contains 1000 mg of pemetrexed (as disodium). 
 
After reconstitution each vial contains 25 mg/ml of pemetrexed. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains mannitol (E421), hydrochloric acid and sodium hydroxide (for pH adjustment). 
 
See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion. 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only. 
For intravenous use after reconstitution and dilution. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic 
 
 



33 

8. EXPIRY DATE 
 
EXP 
Read the leaflet for the shelf life of the reconstituted product. 
 
 
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 
 
Sandoz GmbH 
Biochemiestrasse 10 
6250 Kundl 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1037/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
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. 
 
 



34 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN  
 



35 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Pemetrexed Sandoz 1000 mg powder for concentrate for solution for infusion  
pemetrexed 
Intravenous use after reconstitution and dilution 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1000 mg 
 
 
6. OTHER 
 
 



36 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



37 

Package leaflet: Information for the user 
 

Pemetrexed Sandoz 100 mg powder for concentrate for solution for infusion 
Pemetrexed Sandoz 500 mg powder for concentrate for solution for infusion 
Pemetrexed Sandoz 1000 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, please 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 Sandoz is and what it is used for 
2. What you need to know before you use Pemetrexed Sandoz 
3. How to use Pemetrexed Sandoz 
4. Possible side effects 
5. How to store Pemetrexed Sandoz 
6. Contents of the pack and other information 
 
 
1. What Pemetrexed Sandoz  is and what it is used for 
 
Pemetrexed Sandoz is a medicine used in the treatment of cancer. 
Pemetrexed Sandoz 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 Sandoz is also given in combination with cisplatin for the initial treatment of patients with 
advanced stage of lung cancer. 
 
Pemetrexed Sandoz 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 Sandoz 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 Sandoz  
 
Do not use Pemetrexed Sandoz: 
- if you are allergic (hypersensitive) 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 Sandoz. 
- if you have recently received or are about to receive a vaccine against yellow fever. 
 
Warnings and precautions  
Talk to your doctor or hospital pharmacist before receiving Pemetrexed Sandoz. 
 
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 Sandoz. 
Before each infusion you will have samples of your blood taken to evaluate if you have sufficient 



38 

kidney and liver function and to check that you have enough blood cells to receive Pemetrexed 
Sandoz. 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 Sandoz. 
 
If you have been recently vaccinated, please tell your doctor, as this can possibly cause bad effects 
with Pemetrexed Sandoz. 
 
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 Sandoz. 
 
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 Sandoz 
Please tell your doctor if you are taking 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 Sandoz 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 Sandoz should be avoided during pregnancy. Your doctor will discuss with you the 
potential risk of taking Pemetrexed Sandoz during pregnancy. 
Women must use effective contraception during treatment with Pemetrexed Sandoz. 
 
Breast-feeding 
If you are breast-feeding, tell your doctor. 
Breast-feeding must be discontinued during Pemetrexed Sandoz treatment. 
 
Fertility 
Men are advised not to father a child during and up to 6 months following treatment with Pemetrexed 
Sandoz and should therefore use effective contraception during treatment with Pemetrexed Sandoz 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 Sandoz may make you feel tired. Be careful when driving a car or using machines. 
 
Pemetrexed Sandoz contains sodium 
Pemetrexed Sandoz 100 mg powder for concentrate for solution for infusion 
This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium- 
free’. 



39 

 
Pemetrexed Sandoz 500 mg powder for concentrate for solution for infusion 
This medicine contains 54 mg sodium (main component of cooking/table salt) in each vial. This is 
equivalent to 2.7% of the recommended maximum daily dietary intake of sodium for an adult.  
 
Pemetrexed Sandoz 1000 mg powder for concentrate for solution for infusion 
This medicine contains 108 mg sodium (main component of cooking/table salt) in each vial. This is 
equivalent to 5.4% of the recommended maximum daily dietary intake of sodium for an adult.  
 
 
3. How to use Pemetrexed Sandoz 
 
The dose of Pemetrexed Sandoz is 500 mg 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 Sandoz powder with 9 mg/ml (0.9 %) sodium 
chloride solution for injection before it is given to you. 
 
You will always receive Pemetrexed Sandoz by infusion into one of your veins. The infusion will last 
approximately 10 minutes. 
 
When using Pemetrexed Sandoz 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 Sandoz has finished. The infusion of cisplatin will last approximately 2 
hours. 
 
You should usually receive your infusion once every 3 weeks. 
 
Additional medicines 
Corticosteriods: your doctor will prescribe you steroid tablets (equivalent to 4 milligram of 
dexamethasone twice a day) that you will need to take on the day before, on the day of, and the day 
after Pemetrexed Sandoz 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 Sandoz. You must take at least 5 doses during the seven days before the first dose of 
Pemetrexed Sandoz. You must continue taking the folic acid for 21 days after the last dose of 
Pemetrexed Sandoz. You will also receive an injection of vitamin B12 (1000 micrograms) in the week 
before administration of Pemetrexed Sandoz and then approximately every 9 weeks (corresponding to 
3 courses of Pemetrexed Sandoz 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: 
 
• 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. 



40 

• 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 Sandoz 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  
• Diarrhoea 
• Vomiting 
• Pain, redness, swelling or sores in your mouth 
• Nausea 
• Loss of appetite 
• Fatigue (tiredness) 
• Skin rash 
• Flaking skin 
• Abnormal blood tests showing reduced functionality of kidneys 
 
Common (may affect up to 1 in 10 people) 
• Blood infection 
• Fever with low number of neutrophil granulocytes (a type of white blood cell) 
• Low platelet count 
• Allergic reaction 
• Loss of body fluids 
• Taste change 
• Damage to the motor nerves which may cause muscle weakness and atrophy (wasting) primary 

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

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

and cornea (the clear layer in front of the iris and pupil. 
• Swelling of the eyelids 
• Eye disorder with dryness, tearing, irritation, and/or pain 
• Cardiac Failure (Condition that affects the pumping power of your heart muscles) 
• Irregular heart rhythm 
• Indigestion 
• Constipation 



41 

• 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) 
• 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) 



42 

• 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 Sandoz 
 
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 carton and label after EXP.  
 
This medicine does not require any special storage conditions. 
 
After reconstitution and infusion: 
Chemical and physical in-use stability of reconstituted solutions of Pemetrexed Sandoz has been 
demonstrated for 4 days at 2°C to 8°C and for 4 days below 25°C.  
 
Chemical and physical in-use stability of infusion solutions of Pemetrexed Sandoz has been 
demonstrated for 4 days at 2°C to 8°C and for 2 days below 25°C. 
 
From a microbiological point of view, the product should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution / dilution has taken 
place in controlled and validated aseptic conditions. 
 
Do not use this medicine if you notice particles or a discolouration.  
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measurements will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Pemetrexed Sandoz contains 
 
The active substance is pemetrexed. 
 
Pemetrexed Sandoz 100 mg: Each vial contains 100 milligrams of pemetrexed (as disodium). 
Pemetrexed Sandoz 500 mg: Each vial contains 500 milligrams of pemetrexed (as disodium). 
Pemetrexed Sandoz 1000 mg: Each vial contains 1000 milligrams of pemetrexed (as disodium). 
 
After reconstitution, the solution contains 25 mg/ml of pemetrexed. 

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


43 

 
The other ingredients are mannitol (E421), hydrochloric acid (for pH adjustment) and sodium 
hydroxide (for pH adjustment) (see section 2 “Pemetrexed Sandoz contains sodium”). 
 
What Pemetrexed Sandoz looks like and contents of the pack 
 
Pemetrexed Sandoz is a powder for concentrate for solution for infusion in a glass vial. It is a white to 
pale yellow lyophilised powder. 
 
Each pack of Pemetrexed Sandoz consists of one vial with protective plastic overwrap, containing 
100 mg, 500 mg or 1000 mg of pemetrexed. 
 
Marketing Authorisation Holder 
Sandoz GmbH 
Biochemiestrasse 10 
A-6250 Kundl 
Austria 
 
Manufacturer 
Ebewe Pharma Ges.m.b.H 
Nfg.KG 
Mondseestrasse 11, 
Unterach 
4866 Austria 
 
Lek Pharmaceuticals d.d. 
Verovškova 57 
1526 Ljubljana 
Slovenia 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Sandoz nv/sa 
Tél/Tel.: +32 2 722 97 97 
 

Lietuva 
Sandoz Pharmaceuticals d.d. filialas 
Šeimyniškių 3A, 
LT 09312 Vilnius 
Tel: +370 5 26 36 037 
Info.lithuania@sandoz.com 
 

България 
Сандоз България КЧТ 
Бул.“Никола Вапцаров“ No. 55 
сгр. 4, ет. 4 
1407 София 
Teл.: + 359 2 970 47 47 
regaffairs.bg@sandoz.com 

Luxembourg/Luxemburg 
Sandoz nv/sa 
Tél/Tel.: +32 2 722 97 97 
 

Česká republika 
Sandoz s.r.o. 
Na Pankráci 1724/129 
CZ-140 00 Praha 4 - Nusle  
Tel: +420 225 775 111office.cz@sandoz.com 
 

Magyarország 
Sandoz Hungária Kft. 
Tel.: +36 1 430 2890 



44 

Danmark 
Sandoz A/S 
Edvard Thomsens Vej 14 
DK-2300 København S 
Danmark 
Tlf: + 45 6395 1000 
info.danmark@sandoz.com 

Malta 
Medical Logistics Ltd. 
ADC Building, Triq L-Esportaturi 
Mriehel, BKR 3000 
Malta 
Tel: +356 2277 8000 
mgatt@medicallogisticsltd.com 
 

Deutschland 
Hexal AG 
Industriestrasse  25 
D-83607 Holzkirchen 
Tel: +49 8024 908 0  
E-mail: service@hexal.com 
 

Nederland 
Sandoz B.V. 
Veluwezoom 22  
NL-1327 AH Almere 
Tel: +31 36 5241600 
info.sandoz-nl@sandoz.com 

Eesti 
Sandoz d.d. Eesti filiaal 
Pärnu mnt105 
EE-11312 Tallinn 
Tel.: +372 665 2400 
Info.ee@sandoz.com 
 

Norge 
Sandoz A/S 
Edvard Thomsens Vej 14 
DK-2300 København S 
Danmark 
Tlf: + 45 6395 1000 
info.danmark@sandoz.com 
 

Ελλάδα 
Novartis (Hellas) A.E.B.E. 
Τηλ: +30 210 281 17 12 

Österreich 
Sandoz GmbH 
Biochemiestr. 10 
A-6250 Kundl 
Tel: +43 5338 2000 
 

España 
Sandoz Farmacéutica, S.A.  
Centro Empresarial Parque Norte  
C/ Serrano Galvache, 56 
Edificio Roble 
28033, Madrid 
EspañaTel: +34 900 456 856 
registros.spain@sandoz.com 
 

Polska 
Sandoz Polska Sp. z o.o. 
ul. Domaniewska 50C  
02-672 Warszawa 
Tel.: + 48 22 209 70 00 
biuro.pl@sandoz.com 
 

France 
Sandoz SAS 
49 avenue Georges Pompidou 
F-92593 Levallois-Perret Cedex 
Tél: + 33 1 4964 4800 
 

Portugal 
Sandoz Farmacêutica Lda. 
Tel: +351 21 196 40 00 
 

Hrvatska 
Sandoz d.o.o. 
Maksimirska 120 
10000 Zagreb 
Tel: + 385 1 2353111 
e-mail: upit.croatia@sandoz.com 
 

România 
Sandoz S.R.L, 
Tel: +40 265 208 120 

mailto:info.danmark@sandoz.com


45 

Ireland 
Rowex Ltd., 
Bantry, Co. Cork, 
Ireland. 
P75 V009 
Tel: + 353 27 50077 
e-mail: reg@rowa-pharma.ie 
 

Slovenija 
Lek farmacevtska družba d.d. 
Tel: +386 1 580 21 11 

Ísland 
Sandoz A/S 
Edvard Thomsens Vej 14 
DK-2300 København S 
Danmörk 
Tlf: + 45 6395 1000 
info.danmark@sandoz.com 
 

Slovenská republika 
Sandoz d.d. organizačná zložka 
Žižkova 22B 
SK-811 02 Bratislava 
Tel: + 421 2 48 200 600 

Italia 
Sandoz  S.p.A  
Largo Umberto Boccioni 1 
I - 21040 Origgio/VA 
Tel: + 39 02 96541 
 

Suomi/Finland 
Sandoz A/S 
Edvard Thomsens Vej 14 
DK-2300 Kööpenhamina S 
Tanska 
Tlf: + 358 010 6133 400 
info.suomi@sandoz.com 
 

Κύπρος 
Panayiotis Hadjigeorgiou  
31 Yildiz Street,  3042  
CY-000 00 Town: Limassol 
Τηλ: 00357 25372425 
hapanicos@cytanet.com.cy  
 

Sverige 
Sandoz A/S 
Edvard Thomsens Vej 14 
DK-2300 Köpenhamn S  
Danmark 
Tlf: + 45 6395 1000 
info.sverige@sandoz.com 
 

Latvija 
Sandoz d.d. Latvia filiale 
K.Valdemāra iela 33-29 
Rīga, LV1010 
Tel: + 371 67892006 
 

United Kingdom 
Sandoz Limited 
Tel: + 44 1276 698020 
 
 

 
This leaflet was last revised in 
 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  
 
 
--------------------------------------------------------------------------------------------------------------------------- 
 
 
The following information is intended for healthcare professionals only: 
 
Special precautions for disposal and other handling 
 
1. Use aseptic technique during the reconstitution and further dilution of pemetrexed for 

intravenous infusion administration. 
 

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


46 

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

 
3. Pemetrexed Sandoz 100 mg:  

Reconstitute 100-mg vials with 4.2 ml of sodium chloride 9 mg/ml (0.9%) solution for injection 
(without preservative), resulting in a solution containing 25 mg/ml pemetrexed.  

 
 Pemetrexed Sandoz 500 mg: 

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

 
 Pemetrexed Sandoz 1000 mg: 

Reconstitute 1000-mg vials with 40 ml of sodium chloride 9 mg/ml (0.9%) solution for injection 
(without preservative), resulting in a solution containing 25 mg/ml pemetrexed.  

 
Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear 
and ranges in colour from colourless to pale yellow without adversely affecting product quality. 
The pH of the reconstituted solution is between 6.6 and 7.8. Further dilution is required. 

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

with sodium chloride 9 mg/ml (0.9%) solution for injection (without preservative) or with 
glucose 50 mg/ml (5%) solution for injection (without preservative) and administered as an 
intravenous infusion over 10 minutes. 

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

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

 
6. Parenteral medicinal products must be inspected visually for particulate matter and 

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

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


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