Ciambra

1 
 

                                                            
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
  



2 
 

 
1. NAME OF THE MEDICINAL PRODUCT 
 
CIAMBRA 100 mg powder for concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One vial of powder contains 100 mg of pemetrexed (as pemetrexed disodium hemipentahydrate). 
 
After reconstitution (see section 6.6), each vial contains 25 mg/ml of pemetrexed.  
 
Excipient with known effect 
Each vial contains approximately 11 mg sodium. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion. 
 
White to almost white lyophilised powder.  
The pH of the reconstituted solution is between 6.6 and 7.8. 
The Osmolality of the reconstituted solution is 230-270 mOsmol/kg. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Malignant pleural mesothelioma 
CIAMBRA in combination with cisplatin is indicated for the treatment of chemotherapy naive patients 
with unresectable malignant pleural mesothelioma. 
 
Non-small cell lung cancer 
CIAMBRA 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). 
 
CIAMBRA 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). 
 
CIAMBRA 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 
 
CIAMBRA must only be administered under the supervision of a physician qualified in the use of  
anti-cancer chemotherapy. 
 
 
 
 



3 
 

Posology 
 
CIAMBRA in combination with cisplatin 
The recommended dose of CIAMBRA is 500 mg/m2 of body surface area (BSA) administered as an 
intravenous infusion over 10 minutes on the first day of each 21-day cycle. The recommended dose of 
cisplatin is 75 mg/m2 BSA infused over two hours approximately 30 minutes after completion of the 
pemetrexed infusion on the first day of each 21-day cycle. Patients must receive adequate anti-emetic 
treatment and appropriate hydration prior to and/or after receiving cisplatin (see also cisplatin 
Summary of Product Characteristics for specific dosing advice). 
 
CIAMBRA as single agent 
In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended dose of 
CIAMBRA 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. AP, 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 CIAMBRA used as a single agent or in combination with 
cisplatin. 
 
 
 
 
 
 
 
 



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Table 1 - Dose modification table for CIAMBRA (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 CIAMBRA 
and cisplatin) 

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

75 % of previous dose (both CIAMBRA 
and cisplatin) 

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

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

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

CTC a Grade Dose of CIAMBRA (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 CIAMBRA 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 Population 
 
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 CIAMBRA 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  
CIAMBRA is for intravenous use. CIAMBRA 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 CIAMBRA, see section 6.6. 
 
For instructions on reconstitution and dilution of CIAMBRA 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 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). 
 



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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 < 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 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 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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This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 
‘sodium-free’. 
 
 
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 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 medicines 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 International Normalised Ratio (INR) 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 not known 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 
 
Pemetrexed may have a minor influence on the ability to drive and use machines.  Fatigue may occur 
following administration of Pemetrexed (see section 4.8).  
 
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 (≥1/1000 to 
<1/100), rare (≥1/10,000 to <1/1000), 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 
GEMZAR 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 
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 

 
 

 Pulmonary 
embolism 

   



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mediastinal 
disorders 

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: Antineoplastic agents, folic acid analogues, ATC code: L01BA04 
 
CIAMBRA (pemetrexed) is a multi-targeted anti-cancer antifolate agent that exerts its action by 
disrupting crucial folate-dependent metabolic processes essential for cell replication. 
 
In vitro studies have shown that pemetrexed behaves as a multitargeted antifolate by inhibiting 
thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide 
formyltransferase (GARFT), which are key folate-dependent enzymes for the de novo biosynthesis of 
thymidine and purine nucleotides. Pemetrexed is transported into cells by both the reduced folate 
carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is rapidly 
and efficiently converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The 
polyglutamate forms are retained in cells and are even more potent inhibitors of TS and GARFT. 
Polyglutamation is a time- and concentration-dependent process that occurs in tumour cells and, to a 
lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life 
resulting in prolonged active substance action in malignant cells. 
 
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 the medicinal product (randomised and 

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


12 
 

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: 
 

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) 
(95 % CI) 

12.1 
(10.0 - 14.4) 

9.3 
(7.8 - 10.7) 

13.3 
(11.4 - 14.9) 

10.0 
(8.4 - 11.9) 

Log Rank p-value* 0.020 0.051 
Median  time  to  tumour  progression 
(months)  
(95 % CI) 

5.7 
 

(4.9 - 6.5) 

3.9 
 

(2.8 - 4.4) 

6.1 
 

(5.3 - 7.0) 

3.9 
 

(2.8 - 4.5) 
Log Rank p-value* 0.001 0.008 
Time to treatment failure (months) 
(95 % CI) 

4.5 
(3.9 - 4.9) 

2.7 
(2.1 - 2.9) 

4.7 
(4.3 - 5.6) 

2.7 
(2.2 - 3.1) 

Log Rank p-value* 0.001 0.001 
Overall response rate** 
(95 % CI) 

41.3 % 
(34.8 - 48.1) 

16.7 % 
(12.0 - 22.2) 

45.5 % 
(37.8 - 53.4) 

19.6 % 
(13.8 - 26.6) 

Fisher’s exact p-value* < 0.001 < 0.001 
Abbreviation: CI = confidence interval 
* p-value refers to comparison between arms. 
** In  the  pemetrexed /cisplatin  arm,  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 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 (ITT) 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 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  



13 
 

(n = 540). 
 
 

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) (n = 288) 
8.3 7.9       

(7.0 - 9.4) (6.3 - 9.2) 
0.99        

(0.82 - 1.20) 
  0.226 

Progression free survival (months) 
  Median 
  HR (95 % CI) 

(n = 283) (n = 288) 
2.9  2.9 

0.97 (0.82 – 1.16) 
Time to treatment failure (TTTF – months) 

  Median 
  HR (95 % CI) 

(n = 283) (n = 288) 
2.3 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) NSCLC 
showed that pemetrexed plus cisplatin (ITT population 
n = 862) met its primary endpoint and showed similar clinical efficacy as gemcitabine plus cisplatin 
(ITT n = 863) in overall survival (adjusted hazard ratio 0.94; 95% CI = 0.84-1.05). All patients 
included in this study had an ECOG performance status 0 or 1. 
The primary efficacy analysis was based on the ITT population. Sensitivity analyses of main efficacy 
endpoints were also assessed on the Protocol Qualified (PQ) population. The efficacy analyses using 
PQ population are consistent with the analyses for the ITT population and support the non-inferiority of 
AC versus GC. 
Progression free survival (PFS) and overall response rate were similar between treatment arms: 
median PFS was 4.8 months for pemetrexed plus cisplatin versus 5.1 months for gemcitabine plus 
cisplatin (adjusted hazard ratio 1.04; 95% CI = 0.94-1.15), and overall response rate was 30.6% 
(95% CI = 27.3-33.9) for pemetrexed plus cisplatin versus 28.2% (95% CI = 25.0-31.4) for 
gemcitabine plus cisplatin. PFS data were partially confirmed by an independent review (400/1725 
patients were randomly selected for review). 
The analysis of the impact of NSCLC histology on overall survival demonstrated clinically relevant 
differences in survival according to histology, see table below. 

 
 
 

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

 
 
ITT population 
and histology 
subgroups 

Median overall survival in months 
(95% CI) 

Adjusted 
hazard 

ratio (HR) 
(95% CI) 

 
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 



14 
 

Large cell 
(N=153) 

10.4 
(8.6 – 14.1) 

N=76 6.7 
(5.5 – 9.0) 

N=77 0.67 
(0.48–0.96) 

0.027 

Other 
(N=252) 

8.6 
(6.8 – 10.2) 

N=106 9.2 
(8.1 – 10.6) 

N=146 1.08 
(0.81–1.45) 

0.586 

Squamous cell 
(N=473) 

9.4 
(8.4 – 10.2) 

N=244 10.8 
(9.5 – 12.1) 

N=229 1.23 
(1.00–1.51) 

0.050 

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

 
 
There were no clinically relevant differences observed for the safety profile of pemetrexed plus 
cisplatin within the histology subgroups. 
Patients treated with pemetrexed and cisplatin required fewer transfusions (16.4% versus 28.9%, 
p<0.001), red blood cell transfusions (16.1% versus 27.3%, p<0.001) and platelet transfusions (1.8% 
versus 4.5%, p=0.002). Patients also required lower administration of erythropoietin/darbopoietin 
(10.4% versus 18.1%, p<0.001), G-CSF/GM-CSF (3.1% versus 6.1%, p=0.004), and iron preparations 
(4.3% versus 7.0%, p=0.021). 
 
NSCLC, maintenance treatment: 
JMEN 
A multicentre, randomised, double-blind, placebo-controlled Phase 3 study (JMEN), compared the 
efficacy and safety of maintenance treatment with pemetrexed plus best supportive care (BSC) (n = 
441) with that of placebo plus BSC (n = 222) in patients with locally advanced (Stage IIIB) or 
metastatic (Stage IV) (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 



15 
 

4.0 months and 2.0 months, respectively) (hazard ratio = 0.60, 95% CI = 0.49-0.73, p < 0.00001). The 
independent review of patient scans confirmed the findings of the investigator assessment of PFS. The 
median OS for the overall population (n = 663) was 13.4 months for the pemetrexed arm and 10.6 
months for the placebo arm, hazard ratio = 0.79 (95% CI = 0.65-0.95, p = 0.01192). 
 
Consistent with other pemetrexed studies, a difference in efficacy according to NSCLC histology was 
observed in JMEN. For patients with NSCLC other than predominantly squamous cell histology 
(n = 430, independently reviewed population) median PFS was 4.4 months for the pemetrexed arm and 
1.8 months for the placebo arm, hazard ratio = 0.47 (95% CI = 0.37-0.60, p = 0.00001). The median 
OS for patients with NSCLC other than predominantly squamous cell histology (n = 481) was 
15.5 months for the pemetrexed arm and 10.3 months for the placebo arm, hazard ratio = 0.70 (95% CI 
= 0.56-0.88, p = 0.002). Including the induction phase the median OS for patients with NSCLC other 
than predominantly squamous cell histology was 18.6 months for the pemetrexed arm and 
13.6 months for the placebo arm, hazard ratio = 0.71 (95% CI = 0.56-0.88, p = 0.002). 
 
The PFS and OS results in patients with squamous cell histology suggested no advantage for 
pemetrexed over placebo. 
 
There were no clinically relevant differences observed for the safety profile of pemetrexed within the 
histology subgroups. 
 
JMEN: Kaplan Meier plots of progression-free survival (PFS) and overall survival pemetrexed  
versus placebo in patients with NSCLC other than predominantly squamous cell histology: 
 

 
 
PARAMOUNT 
A multicentre, randomised, double-blind, placebo-controlled Phase 3 study (PARAMOUNT), 
compared the efficacy and safety of continuation maintenance treatment with pemetrexed plus BSC (n 
= 359) with that of placebo plus BSC (n = 180) in patients with locally advanced (Stage IIIB) or 
metastatic (Stage IV) NSCLC other than predominantly squamous cell histology who did not progress 
after 4 cycles of first line doublet therapy of pemetrexed in combination with cisplatin. Of the 939 
patients treated with pemetrexed plus cisplatin induction, 539 patients were randomised to maintenance 
treatment with pemetrexed or placebo. Of the randomised patients, 44.9% had a complete/partial 
response and 51.9% had a response of stable disease to pemetrexed plus cisplatin induction. Patients 
randomised to maintenance treatment were required to have an ECOG performance status 0 or 1. The 
median time from the start of pemetrexed plus cisplatin induction therapy to the start of maintenance 
treatment was 2.96 months on both the pemetrexed arm and the placebo arm. Randomised patients 
received maintenance treatment until disease progression. Efficacy and safety 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 



16 
 

(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. 
 
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 



17 
 

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 (E 421) 
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 solutions 
Chemical and physical in-use stability of the infusion solution of pemetrexed was demonstrated for 24 
hours at  2°C-8°C or 15-25°C. The reconstituted solution should be used immediately to prepare the 
infusion solution. From a microbiological point of view, the infusion solution should be used 
immediately. If not used immediately, in-use storage times and conditions prior to use are the 
responsibility of the user and should not be longer than 24 hours at 2°C to 8°C or 15°C to 25°C.  



18 
 

 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
For storage conditions after reconstitution/dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container  
 
Type I glass vial with chlorobutyl rubber stopper and an aluminium seal with flip off cap. The vial is  
covered with a shrink-wrapped plastic sleeve. Each 10 ml vial contains 100 mg of pemetrexed (as 
pemetrexed disodium hemipentahydrate).   
 
Pack of 1 vial. 
 
6.6 Special precautions for disposal and other handling 
 
1. Use aseptic technique during the reconstitution and further dilution of pemetrexed for 

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

pemetrexed to facilitate delivery of label amount. 
 
3. Reconstitute 100 mg vials with 4.2 ml of sodium chloride 9 mg/ml (0.9 %) solution for 

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

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

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

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

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

discolouration prior to administration. If particulate matter or discolouration is observed, do not 
administer. 

 
7. Pemetrexed solutions are for single use only. Any unused medicinal product or waste material 

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



19 
 

7. MARKETING AUTHORISATION HOLDER 
 
Menarini International Operations Luxembourg S.A. 
1, Avenue de la Gare 
L-1611, Luxembourg 
Luxembourg 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1055/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 2 December 2015 
Date of latest renewal: 
 
 
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. 
 
  

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


20 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
CIAMBRA 500 mg powder for concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One vial of powder contains 500 mg of pemetrexed (as pemetrexed disodium hemipentahydrate). 
 
After reconstitution (see section 6.6), each vial contains 25 mg/ml of pemetrexed.  
 
Excipient with known effect 
Each vial contains approximately 54 mg sodium. 
 
For the full list of excipients, see section 6.1 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for concentrate for solution for infusion. 
 
White to almost white lyophilised powder.  
The pH of the reconstituted solution is between 6.6 and 7.8. 
The osmolality of the reconstituted solution is 230-270 mOsmol/kg. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Malignant pleural mesothelioma 
CIAMBRA in combination with cisplatin is indicated for the treatment of chemotherapy naïve patients 
with unresectable malignant pleural mesothelioma. 
 
Non-small cell lung cancer 
CIAMBRA 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). 
 
CIAMBRA 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). 
 
CIAMBRA 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 
 
CIAMBRA must only be administered under the supervision of a physician qualified in the use of  
anti-cancer chemotherapy. 
 
 
 
 
 



21 
 

Posology 
 
CIAMBRA in combination with cisplatin 
The recommended dose of CIAMBRA is 500 mg/m2 of body surface area (BSA) administered as an 
intravenous infusion over 10 minutes on the first day of each 21-day cycle. The recommended dose of 
cisplatin is 75 mg/m2 BSA infused over two hours approximately 30 minutes after completion of the 
pemetrexed infusion on the first day of each 21-day cycle. Patients must receive adequate anti-emetic 
treatment and appropriate hydration prior to and/or after receiving cisplatin (see also cisplatin 
Summary of Product Characteristics for specific dosing advice). 
 
CIAMBRA as single agent 
In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended dose of 
CIAMBRA 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. AP, 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 CIAMBRA used as a single agent or in combination 
with cisplatin. 
 
 
 
 
 
 
 
 
 
 



22 
 

Table 1 - Dose modification table for CIAMBRA (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 CIAMBRA 
and cisplatin) 

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

75 % of previous dose (both CIAMBRA 
and cisplatin) 

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

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

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

CTC a Grade Dose of CIAMBRA (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 CIAMBRA 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. 
 
 
 
 
 
 
 



23 
 

Special Population 
 
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 CIAMBRA 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  
 
CIAMBRA is for intravenous use. CIAMBRA 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 CIAMBRA, see section 6.6. 
 
For instructions on reconstitution and dilution of CIAMBRA 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 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). 
 



24 
 

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 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 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. 
 



25 
 

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. 
 
 
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 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 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 
possibility of interaction between oral anticoagulants and anticancer chemotherapy require increased 
frequency of International Normalised Ratio (INR) 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). 
 
 
 
 
 



26 
 

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 not known 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 
 
Pemetrexed may have a minor influence on the ability to drive and use machines.  Fatigue may occur 
following administration of Pemetrexed (see section 4.8).  
 
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 (≥1/1000 to<1/100), rare (≥1/10,000 
to<1/1000), very rare (<1/10,000) and not known (cannot be estimated from available data). 
 



27 
 

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 
GEMZAR 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 
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 

 
 

 Pulmonary 
embolism 

   



28 
 

mediastinal 
disorders 

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 

    



29 
 

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 agent, folic acid analogues, ATC code: L01BA04 
 
CIAMBRA (pemetrexed) is a multi-targeted anti-cancer antifolate agent that exerts its action by 
disrupting crucial folate-dependent metabolic processes essential for cell replication. 
 
In vitro studies have shown that pemetrexed behaves as a multitargeted antifolate by inhibiting 
thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide 
formyltransferase (GARFT), which are key folate-dependent enzymes for the de novo biosynthesis of 
thymidine and purine nucleotides. Pemetrexed is transported into cells by both the reduced folate 
carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is rapidly 
and efficiently converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The 
polyglutamate forms are retained in cells and are even more potent inhibitors of TS and GARFT. 
Polyglutamation is a time- and concentration-dependent process that occurs in tumour cells and, to a 
lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life 
resulting in prolonged active substance action in malignant cells. 
 
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 

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


30 
 

patients randomly assigned to a treatment arm who received the medicinal products (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: 
 

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) 
(95 % CI) 

12.1 
(10.0 - 14.4) 

9.3 
(7.8 - 10.7) 

13.3 
(11.4 - 14.9) 

10.0 
(8.4 - 11.9) 

Log Rank p-value* 0.020 0.051 
Median  time  to  tumour  progression 
(months)  
(95 % CI) 

5.7 
 

(4.9 - 6.5) 

3.9 
 

(2.8 - 4.4) 

6.1 
 

(5.3 - 7.0) 

3.9 
 

(2.8 - 4.5) 
Log Rank p-value* 0.001 0.008 
Time to treatment failure (months) 
(95 % CI) 

4.5 
(3.9 - 4.9) 

2.7 
(2.1 - 2.9) 

4.7 
(4.3 - 5.6) 

2.7 
(2.2 - 3.1) 

Log Rank p-value* 0.001 0.001 
Overall response rate** 
(95 % CI) 

41.3 % 
(34.8 - 48.1) 

16.7 % 
(12.0 - 22.2) 

45.5 % 
(37.8 - 53.4) 

19.6 % 
(13.8 - 26.6) 

Fisher’s exact p-value* < 0.001 < 0.001 
Abbreviation: CI = confidence interval 
* p-value refers to comparison between arms. 
** In  the  pemetrexed /cisplatin  arm,  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 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 (ITT) 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. 
 



31 
 

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). 
 
 

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) (n = 288) 
8.3 7.9       

(7.0 - 9.4) (6.3 - 9.2) 
0.99        

(0.82 - 1.20) 
0.226 

Progression free survival (months) 
  Median 
  HR (95 % CI) 

(n = 283) (n = 288) 
2.9 2.9 

0.97 (0.82 – 1.16) 
Time to treatment failure (TTTF – months) 

  Median 
  HR (95 % CI) 

(n = 283) (n = 288) 
2.3 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) NSCLC 
showed that pemetrexed plus cisplatin (ITT population 
n = 862) met its primary endpoint and showed similar clinical efficacy as gemcitabine plus cisplatin 
(ITT n = 863) in overall survival (adjusted hazard ratio 0.94; 95% CI = 0.84-1.05). All patients 
included in this study had an ECOG performance status 0 or 1. 
The primary efficacy analysis was based on the ITT population. Sensitivity analyses of main efficacy 
endpoints were also assessed on the Protocol Qualified (PQ) population. The efficacy analyses using 
PQ population are consistent with the analyses for the ITT population and support the non-inferiority of 
AC versus GC. 
Progression free survival (PFS) and overall response rate were similar between treatment arms: 
median PFS was 4.8 months for pemetrexed plus cisplatin versus 5.1 months for gemcitabine plus 
cisplatin (adjusted hazard ratio 1.04; 95% CI = 0.94-1.15), and overall response rate was 30.6% 
(95% CI = 27.3-33.9) for pemetrexed plus cisplatin versus 28.2% (95% CI = 25.0-31.4) for 
gemcitabine plus cisplatin. PFS data were partially confirmed by an independent review (400/1725 
patients were randomly selected for review). 
The analysis of the impact of NSCLC histology on overall survival demonstrated clinically relevant 
differences in survival according to histology, see table below. 
 

 
Efficacy of pemetrexed + cisplatin vs. gemcitabine + cisplatin in first-line non-small cell lung 

cancer – ITT population and histology subgroups. 
 
ITT population 
and histology 
subgroups 

Median overall survival in months 
(95% CI) 

Adjusted 
hazard 

ratio (HR) 
(95% CI) 

 
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 



32 
 

Adenocarcinoma 
(N=847) 

12.6 
(10.7 – 13.6) 

N=436 10.9 
(10.2 – 11.9) 

N=411 0.84 
(0.71–0.99) 

0.033 

Large cell 
(N=153) 

10.4 
(8.6 – 14.1) 

N=76 6.7 
(5.5 – 9.0) 

N=77 0.67 
(0.48–0.96) 

0.027 

Other 
(N=252) 

8.6 
(6.8 – 10.2) 

N=106 9.2 
(8.1 – 10.6) 

N=146 1.08 
(0.81–1.45) 

0.586 

Squamous cell 
(N=473) 

9.4 
(8.4 – 10.2) 

N=244 10.8 
(9.5 – 12.1) 

N=229 1.23 
(1.00–1.51) 

0.050 

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

 
 
There were no clinically relevant differences observed for the safety profile of pemetrexed plus 
cisplatin within the histology subgroups. 
Patients treated with pemetrexed and cisplatin required fewer transfusions (16.4% versus 28.9%, 
p<0.001), red blood cell transfusions (16.1% versus 27.3%, p<0.001) and platelet transfusions (1.8% 
versus 4.5%, p=0.002). Patients also required lower administration of erythropoietin/darbopoietin 
(10.4% versus 18.1%, p<0.001), G-CSF/GM-CSF (3.1% versus 6.1%, p=0.004), and iron preparations 
(4.3% versus 7.0%, p=0.021). 
 
NSCLC, maintenance treatment: 
JMEN 
A multicentre, randomised, double-blind, placebo-controlled Phase 3 study (JMEN), compared the 
efficacy and safety of maintenance treatment with pemetrexed plus best supportive care (BSC) (n = 
441) with that of placebo plus BSC (n = 222) in patients with locally advanced (Stage IIIB) or 
metastatic (Stage IV) (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). 



33 
 

 
Consistent with other pemetrexed studies, a difference in efficacy according to NSCLC histology was 
observed in JMEN. For patients with NSCLC other than predominantly squamous cell histology 
(n = 430, independently reviewed population) median PFS was 4.4 months for the pemetrexed arm and 
1.8 months for the placebo arm, hazard ratio = 0.47 (95% CI = 0.37-0.60, p = 0.00001). The median 
OS for patients with NSCLC other than predominantly squamous cell histology (n = 481) was 
15.5 months for the pemetrexed arm and 10.3 months for the placebo arm, hazard ratio = 0.70 (95% CI 
= 0.56-0.88, p = 0.002). Including the induction phase the median OS for patients with NSCLC other 
than predominantly squamous cell histology was 18.6 months for the pemetrexed arm and 
13.6 months for the placebo arm, hazard ratio = 0.71 (95% CI = 0.56-0.88, p = 0.002). 
 
The PFS and OS results in patients with squamous cell histology suggested no advantage for 
pemetrexed over placebo. 
 
There were no clinically relevant differences observed for the safety profile of pemetrexed within the 
histology subgroups. 
 
JMEN: Kaplan Meier plots of progression-free survival (PFS) and overall survival pemetrexed 
versus placebo in patients with NSCLC other than predominantly squamous cell histology: 
 

 
 
PARAMOUNT 
A multicentre, randomised, double-blind, placebo-controlled Phase 3 study (PARAMOUNT), 
compared the efficacy and safety of continuation maintenance treatment with pemetrexed plus BSC (n 
= 359) with that of placebo plus BSC (n = 180) in patients with locally advanced (Stage IIIB) or 
metastatic (Stage IV) NSCLC other than predominantly squamous cell histology who did not progress 
after 4 cycles of first line doublet therapy of pemetrexed in combination with cisplatin. Of the 939 
patients treated with pemetrexed plus cisplatin induction, 539 patients were randomised to maintenance 
treatment with pemetrexed or placebo. Of the randomised patients, 44.9% had a complete/partial 
response and 51.9% had a response of stable disease to pemetrexed plus cisplatin induction. Patients 
randomised to maintenance treatment were required to have an ECOG performance status 0 or 1. The 
median time from the start of pemetrexed plus cisplatin induction therapy to the start of maintenance 
treatment was 2.96 months on both the pemetrexed arm and the placebo arm. Randomised patients 
received maintenance treatment until disease progression. Efficacy and safety 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 



34 
 

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. 
 
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 of9 
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 



35 
 

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 (E 421) 
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 
3 years 
 
Reconstituted and infusion solutions 
Chemical and physical in-use stability of the infusion solution of pemetrexed was demonstrated for 24 
hours at 2°C-8°C or at 15°C-25°C. The reconstituted solution should be used immediately to prepare 
the infusion solution.  
From a microbiological point of view, the infusion solution should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
should not be longer than 24 hours at 2°C to 8°C or at 15°C to 25°C.  
 
 
 



36 
 

6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
For storage conditions after reconstitution/dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container  
 
Type I glass vial with chlorobutyl rubber stopper and an aluminium seal with flip off cap. The vial is 
covered with a shrink-wrapped plastic sleeve . Each 50 ml vial contains 500 mg of pemetrexed (as 
pemetrexed disodium hemipentahydrate). 
 
Pack of 1 vial. 
 
6.6 Special precautions for disposal and other handling 
 
1. Use aseptic technique during the reconstitution and further dilution of pemetrexed for 

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

pemetrexed to facilitate delivery of label amount. 
 
3. 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. Gently swirl each 
vial until the powder is completely dissolved. The resulting solution is clear and ranges in colour 
from colourless to yellow or green-yellow without adversely affecting product quality. The pH 
of the reconstituted solution is between 6.6 and 7.8. Further dilution is required. 

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

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

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

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

discolouration prior to administration. If particulate matter or discolouration is observed, do not 
administer. 

 
7. Pemetrexed solutions are for single use only. Any unused medicinal product or waste material 

must be disposed of in accordance with local requirements. 
 
Preparation and administration precautions  
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 
 
Menarini International Operations Luxembourg S.A. 
1, Avenue de la Gare 
L-1611, Luxembourg 



37 
 

Luxembourg 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1055/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 2 December 2015 
Date of latest renewal: 
 
 
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 
  

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


38 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 
 
 



39 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 

 
Name and address of the manufacturer responsible for batch release 
 
Oncotec Pharma Produktion GmbH 
Am Pharmapark 
06861 Dessau-Rosslau 
Germany 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

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

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 
authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

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

  



40 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



41 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 



42 
 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
CIAMBRA 100 mg powder for concentrate for solution for infusion 
pemetrexed 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One vial contains 100 mg of pemetrexed (as pemetrexed disodium hemipentahydrate). 
 
After reconstitution, each vial contains 25 mg/ml of pemetrexed. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Mannitol (E 421), hydrochloric acid, sodium hydroxide  (see package leaflet for further 
information). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion. 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For 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(S), IF NECESSARY 
 
Cytotoxic 
 
 
8. EXPIRY DATE 
 
EXP  
 
9. SPECIAL STORAGE CONDITIONS 
 
 



43 
 

 
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 
 
Menarini International Operations Luxembourg S.A. 
1, Avenue de la Gare  
L-1611 Luxembourg 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1055/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
CIAMBRA 100 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN  
  



44 
 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS  
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
CIAMBRA 100 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 
 
100 mg 
 
 
6. OTHER 
 
 
 
 



45 
 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
CIAMBRA 500 mg powder for concentrate for solution for infusion 
pemetrexed 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One vial contains 500 mg of pemetrexed (as pemetrexed disodium hemipentahydrate). 
 
After reconstitution, each vial contains 25 mg/ml of pemetrexed. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: Mannitol (E 421), hydrochloric acid, sodium hydroxide  (see package leaflet for further 
information). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for concentrate for solution for infusion. 
1 vial 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For 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(S), IF NECESSARY 
 
Cytotoxic  
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



46 
 

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 
 
Menarini International Operations Luxembourg S.A. 
1, Avenue de la Gare  
L-1611 Luxembourg 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1055/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
CIAMBRA 500 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 



47 
 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS  
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
CIAMBRA 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 
 
 
 
 
  



48 
 

 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



49 
 

Package leaflet: Information for the user 
 

CIAMBRA 100 mg powder for concentrate for solution for infusion 
CIAMBRA 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 CIAMBRA is and what it is used for  
2. What you need to know before you use CIAMBRA  
3. How to use CIAMBRA  
4. Possible side effects  
5. How to store CIAMBRA  
6. Contents of the pack and other information 
 
 
1. What CIAMBRA is and what it is used for 
 
CIAMBRA is a medicine used in the treatment of cancer. 
 
CIAMBRA 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. 
 
CIAMBRA is also given in combination with cisplatin for the initial treatment of patients with 
advanced stage of lung cancer. 
 
CIAMBRA 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. 
 
CIAMBRA 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 CIAMBRA 
 
Do not use CIAMBRA 
 
- if you are allergic (hypersensitive) to pemetrexed or any of the other ingredients of CIAMBRA 

(listed in section 6). 
- if you are breast-feeding; you must discontinue breast-feeding during treatment with 

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



50 
 

 
Warnings and precautions  
 
Talk to your doctor or pharmacist before receiving CIAMBRA. 
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 CIAMBRA. 
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 CIAMBRA. 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 CIAMBRA. 
 
If you have been recently vaccinated, please tell your doctor, as this can possibly cause bad effects 
with CIAMBRA. 
 
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 CIAMBRA. 
 
Children and adolescents 
 
CIAMBRA is not to be given to children and adolescents because no studies were performed in these 
groups. 
 
Other medicines and CIAMBRA 
 
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 CIAMBRA 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 CIAMBRA should be avoided during pregnancy. Your doctor will discuss with you the 
potential risk of taking CIAMBRA during pregnancy. Women must use effective contraception during 
treatment with CIAMBRA. 
 
Breast-feeding 
 
If you are breast-feeding, tell your doctor. 
Breast-feeding must be discontinued during treatment with CIAMBRA. 
 
Fertility 
 
Men are advised not to father a child during and up to 6 months following treatment with CIAMBRA 
and should therefore use effective contraception during treatment with CIAMBRA and for up to 6 



51 
 

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 
 
CIAMBRA may make you feel tired. Be careful when driving a car or using machines. 
 
CIAMBRA contains sodium 
 
CIAMBRA 100 mg contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 
‘sodium-free’. 
CIAMBRA 500 mg contains 54 mg sodium (main component of cooking salt) in each vial. This 
is equivalent to 2,7% of the recommended maximum daily dietary intake of sodium for an adult. 
 
3. How to use CIAMBRA 
 
The dose of CIAMBRA 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 CIAMBRA powder with 9 mg/ml (0.9 %) sodium chloride 
solution for injection before it is given to you. 
 
You will always receive CIAMBRA by infusion into one of your veins. The infusion will last 
approximately 10 minutes. 
 
When using CIAMBRA 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 CIAMBRA 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 mg of dexamethasone 
twice a day) that you will need to take on the day before, on the day of, and the day after CIAMBRA 
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 
CIAMBRA. You must take at least 5 doses during the seven days before the first dose of CIAMBRA. 
You must continue taking the folic acid for 21 days after the last dose of CIAMBRA. You will also 
receive an injection of vitamin B12 (1000 micrograms) in the week before administration of 
CIAMBRA and then approximately every 9 weeks (corresponding to 3 courses of CIAMBRA 
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: 



52 
 

 Fever or infection: 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). Infection (sepsis) 
may be severe and could lead to death. 

 If you start feeling chest pain or having a fast heart rate. 
 If you have pain, redness, swelling or sores in your mouth. 
 Allergic reaction: if you develop skin rash / burning or prickling sensation, or fever. 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). 
 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). 
 If you experience sudden breathlessness, intense chest pain or cough with bloody sputum (may 

indicate a blood clot in the blood vessels of the lungs) 
 
Side effects with CIAMBRA may include: 
 
Very common (may affect more than 1 in 10 people) 
Infection 
Pharyngitis (a sore throat) 
Low number of neutrophil granulocytes (a type of white blood cell) 
Low white blood cells 
Low haemoglobin level  
Pain, redness, swelling or sores in your mouth 
Loss of appetite 
Vomiting 
Diarrhoea  
Nausea 
Skin rash 
Flaking skin 
Abnormal blood tests showing reduced functionality of kidneys  
Fatigue (tiredness) 
 
Common (may affect up to 1 in 10 people) 
Blood infection 
Fever with low number of neutrophil granulocytes (a type of white blood cell) 
Low platelet count 
Allergic reaction 
Loss of body fluids 
Taste change 
Damage to the motor nerves which may cause muscle weakness and atrophy (wasting) primary in the 
arms and legs) 
Damage to the sensory nerves that may cause lost of sensation, burning pain and unsteady gait 
Dizziness 
Inflammation or swelling of the conjunctiva (the membrane that lines the eyelids and covers the white 
of the eye 
Dry eye 
Watery eyes 
Dryness of the conjunctiva (the membrane that lines the eyelids and covers the white of the eye) and 
cornea (the clear layer in front of the iris and pupil. 
Swelling of the eyelids 
Eye disorder with dryness, tearing, irritation, and/or pain 
Cardiac Failure (Condition that affects the pumping power of your heart muscles) 
Irregular heart rhythm 
Indigestion 



53 
 

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) 
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) 



54 
 

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 the 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 CIAMBRA 
 
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 vial label after 
EXP. The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Chemical and physical in-use stability of the infusion solution of pemetrexed was demonstrated for 24 
hours at 2°C-8°C or 15-25°C. The reconstituted solution should be used immediately to prepare the 
infusion solution. From a microbiological point of view, the infusion solution should be used 
immediately. If not used immediately, in-use storage times and conditions prior to use are the 
responsibility of the user and should not be longer than 24 hours at 2°C to 8°C or 15°C to 25°C.  
 
This medicine is for single use only; any unused solution must be disposed of in accordance with local 
requirement. 
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 CIAMBRA contains  
 
- The active substance is pemetrexed. 
 
CIAMBRA 100 mg: One vial of powder contains 100 mg of pemetrexed (as pemetrexed disodium 
hemipentahydrate). 
CIAMBRA 500 mg: Each vial contains 500 mg of pemetrexed (as pemetrexed disodium 
hemipentahydrate). 
 
After reconstitution, the solution contains 25 mg/ml of pemetrexed. Further dilution by a healthcare 
provider is required prior to administration. 
 

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


55 
 

- The other ingredients are mannitol (E 421), hydrochloric acid (for pH adjustment) and sodium 
hydroxide (for pH adjustment) (see section 2, “Ciambra contains sodium”). 

 
What CIAMBRA looks like and contents of the pack 
 
CIAMBRA is a powder for concentrate for solution for infusion in a vial. It is a white to almost white 
lyophilised powder. 
Each pack of CIAMBRA consists of one glass vial with rubber stopper and an aluminium seal with 
flip off cap, and it is covered with a shrink-wrapped plastic sleeve. The vial contains 100 mg or 
500 mg of pemetrexed (as pemetrexed disodium hemipentahydrate).  
Each pack contains 1 vial. 
 
Marketing Authorisation Holder  
MENARINI INTERNATIONAL OPERATIONS LUXEMBOURG S.A.,  
1, Avenue de la Gare 
L-1611 Luxembourg 
Luxembourg 
 
Manufacturer: 
Oncotec Pharma Produktion GmbH 
Am Pharmapark 
06861 Dessau-Roßlau 
 Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
AT A. Menarini Pharma GmbH Tel: +43 1 879 95 85-0 
BE Menarini Benelux NV/SA Tél/Tel: + 32 (0)2 721 4545 
BG Берлин-Хеми/А. Менарини България ЕООД Тел.: +359 2 454 0950 
CY MENARINI HELLAS AE Τηλ: +30 210 8316111-13 
CZ Berlin-Chemie/A.Menarini Ceska republika s.r.o. Tel: +420 267 199 333 
DE Berlin-Chemie AG Tel: +49 (0) 30 67070 
DK Berlin-Chemie/A.Menarini Danmark ApS Tlf: +4548 217 110 
EE OÜ Berlin-Chemie Menarini Eesti Tel: +372 667 5001 
ES Laboratorios Menarini S.A. Tel: +34-93 462 88 00 
FI Berlin-Chemie/A.Menarini Suomi OY Puh/Tel: +358 403 000 760 
FR MENARINI France Tél: +33 (0)1 45 60 77 20 
GR MENARINI HELLAS AE Τηλ: +30 210 8316111-13 
HR Berlin-Chemie Menarini Hrvatska d.o.o. Tel: + 385 1 4821 361 
HU Berlin-Chemie/A. Menarini Kft. Tel.: +36 23501301 
IE A. Menarini Pharmaceuticals Ltd Tel: +353 1 284 6744 
IS Menarini International Operations Luxembourg S.A. Sími: +352 264976 
IT A. Menarini Industrie Farmaceutiche Riunite s.r.l. Tel: +39-055 56801 
LT UAB “BERLIN-CHEMIE MENARINI BALTIC” Tel: +370 52 691 947 
LU Menarini Benelux NV/SA Tél/Tel: + 32 (0)2 721 4545 
LV SIA Berlin-Chemie/Menarini Baltic Tel: +371 67103210 
MT Menarini International Operations Luxembourg S.A. Tel: +352 264976 
NO Menarini International Operations Luxembourg S.A. Tlf: +352 264976 
NL Menarini Benelux NV/SA Tel: +32 (0)2 721 4545 
PL Berlin-Chemie/Menarini Polska Sp. z o.o. Tel.: +48 22 566 21 00 
PT A. Menarini Portugal – Farmacêutica, S.A. Tel: +351 210 935 500 
RO Berlin-Chemie A.Menarini S.R.L. Tel: +40 21 232 34 32 
SE Menarini International Operations Luxembourg S.A. Tel: +352 264976 
SK Berlin-Chemie / A. Menarini Distribution Slovakia s.r.o.  Tel: +421 2 544 30 730 
SI Berlin-Chemie / A. Menarini Distribution Ljubljana d.o.o. Tel: +386 01 300 2160 
UK A. Menarini Farmaceutica Internazionale S.R.L. Tel: +44 (0)1628 856400 
 



56 
 

This leaflet was last revised in  
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.There are also links to other websites about rare diseases and treatments. 
 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 
------------------------------------------------------------------------------------------------------------------------ 
 
The following information is intended for healthcare professionals only 
 
Instructions for use, handling and disposal. 
 
1. Use aseptic techniques during the reconstitution and further dilution of pemetrexed for 
intravenous infusion administration. 
 
2. Calculate the dose and the number of CIAMBRA vials needed. Each vial contains an excess of 
pemetrexed to facilitate delivery of the label amount. 
 
3. CIAMBRA 100 mg: 
Reconstitute each 100 mg vial with 4.2 ml of 9 mg/ml (0.9%) sodium chloride solution for 
injection, without preservative, resulting in a solution containing 25 mg/ml pemetrexed. 
 
CIAMBRA 500 mg: 
Reconstitute each 500 mg vial with 20 ml of 9 mg/ml (0.9%) sodium chloride solution for 
injection, without preservative, resulting in a solution containing 25 mg/ml pemetrexed. 
 
Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear 
and ranges in colour from colourless to yellow or green-yellow without adversely affecting 
product quality. The pH of the reconstituted solution is between 6.6 and 7.8. Further dilution is 
required. 
 
4. The appropriate volume of reconstituted pemetrexed solution must be further diluted to 100 ml 
with 9 mg/ml (0.9 %) sodium chloride solution for injection, without preservative, and 
administered as an intravenous infusion over 10 minutes. 
 
5. Pemetrexed infusion solutions prepared as directed above are compatible with polyvinyl 
chloride and polyolefin lined administration sets and infusion bags. Pemetrexed is incompatible 
with diluents containing calcium, including lactated Ringer’s Injection and Ringer’s Injection. 
 
6. Parenteral medicinal products should be inspected visually for particulate matter and 
discolouration prior to administration. If particulate matter is observed, do not administer. 
 
7. Pemetrexed solutions are for single use only. Any unused product or waste material should be 
disposed of in accordance with local requirements. 
 
Preparation and administration precautions: As with other potentially toxic anticancer agents, 
care should be exercised in the handling and preparation of pemetrexed infusion solutions. The use of 
gloves is recommended. If a pemetrexed solution contacts the skin, wash the skin immediately and 
thoroughly with soap and water. If pemetrexed solutions contact the mucous membranes, flush 
thoroughly with water. Pemetrexed is not a vesicant. There is not a specific antidote for extravasation 
of pemetrexed. There have been a few reported cases of pemetrexed extravasation, which were not 
assessed as serious by the investigator. Extravasation should be managed by local standard practice as 
with other non-vesicants. 

 
 

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	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
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