PEMETREXED FRESENIUS KABI 25mg / ml perfusive solution concentrate medication leaflet

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

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

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

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

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

One vial of 4 ml concentrate contains 964 mg hydroxypropylbetadex.

One vial of 20 ml concentrate contains 4820 mg hydroxypropylbetadex.

One vial of 40 ml concentrate contains 9640 mg hydroxypropylbetadex.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

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

The pH is between 6.8 and 7.8.

Malignant pleural mesothelioma

Pemetrexed Fresenius Kabi in combination with cisplatin is indicated for the treatment ofchemotherapy naïve patients with unresectable malignant pleural mesothelioma.

Pemetrexed Fresenius Kabi in combination with cisplatin is indicated for the first line treatmentof patients with locally advanced or metastatic non-small cell lung cancer other thanpredominantly squamous cell histology (see section 5.1).

Pemetrexed Fresenius Kabi is indicated as monotherapy for the maintenance treatment of locallyadvanced or metastatic non-small cell lung cancer other than predominantly squamous cellhistology in patients whose disease has not progressed immediately following platinum-basedchemotherapy (see section 5.1).

Pemetrexed Fresenius Kabi is indicated as monotherapy for the second line treatment of patientswith locally advanced or metastatic non-small cell lung cancer other than predominantlysquamous cell histology (see section 5.1).

Pemetrexed Fresenius Kabi must only be administered under the supervision of a physicianqualified in the use of anti-cancer chemotherapy.

Pemetrexed Fresenius Kabi in combination with cisplatin

The recommended dose of Pemetrexed Fresenius Kabi is 500 mg/m2 of body surface area (BSA)administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.

The recommended dose of cisplatin is 75 mg/m2 BSA infused over two hours approximately30 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/orafter receiving cisplatin (see section 6.2 and cisplatin Summary of Product Characteristics forspecific dosing advice).

Pemetrexed Fresenius Kabi as single agent

In patients treated for non-small cell lung cancer after prior chemotherapy, the recommendeddose of Pemetrexed Fresenius Kabi is 500 mg/m2 BSA administered as an intravenous infusionover 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 dayprior to, on the day of, and the day after pemetrexed administration. The corticosteroid should beequivalent 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 duringthe seven days preceding the first dose of pemetrexed, and dosing must continue during the fullcourse of therapy and for 21 days after the last dose of pemetrexed. Patients must also receive anintramuscular injection of vitamin B12 (1000 micrograms) in the week preceding the first dose ofpemetrexed and once every three cycles thereafter. Subsequent vitamin B12 injections may begiven on the same day as pemetrexed.

Patients receiving pemetrexed should be monitored before each dose with a complete bloodcount, including a differential white cell count (WCC) and platelet count. Prior to eachchemotherapy administration blood chemistry tests should be collected to evaluate renal andhepatic function. Before the start of any cycle of chemotherapy, patients are required to have thefollowing: absolute neutrophil count (ANC) should be ≥ 1500 cells/mm3 and platelets should be≥ 100,000 cells/mm3.

Creatinine clearance should be ≥ 45 ml/min.

The total bilirubin should be ≤ 1.5 times upper limit of normal. Alkaline phosphatase (AP),aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT)should be ≤ 3 times upper limit of normal. Alkaline phosphatase, AST and ALT ≤ 5 times upperlimit of normal is acceptable if liver has tumour involvement.

Dose adjustments at the start of a subsequent cycle should be based on nadir haematologiccounts or maximum non-haematologic toxicity from the preceding cycle of therapy. Treatmentmay be delayed to allow sufficient time for recovery. Upon recovery patients should be retreatedusing the guidelines in Tables 1, 2 and 3, which are applicable for Pemetrexed Fresenius Kabiused as a single agent or in combination with cisplatin.

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

Nadir ANC < 500 /mm3 and nadir platelets 75 % of previous dose (both pemetrexed and≥ 50,000/mm3 cisplatin)

Nadir platelets < 50,000 /mm3 regardless of nadir 75 % of previous dose (both pemetrexed and

ANC cisplatin)

Nadir platelets < 50,000 /mm3 with bleedinga, 50 % of previous dose (both pemetrexed andregardless of nadir ANC cisplatin)a These criteria meet the National Cancer Institute Common Toxicity Criteria (CTC v2.0;

NCI 1998) definition of ≥ CTC Grade 2 bleeding.

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

Fresenius Kabi should be withheld until resolution to less than or equal to the patient’spre-therapy value. Treatment should be resumed according to the guidelines in Table 2.

Table 2 - Dose modification table for pemetrexed (as single agent or in combination) anda, bcisplatin-Non-haematologic toxicities

Dose of pemetrexed Dose for cisplatin2 2(mg/m ) (mg/m )

Any Grade 3 or 4 toxicities except 75 % of previous dose 75 % of previous dosemucositis

Any diarrhoea requiring 75 % of previous dose 75 % of previous dosehospitalisation (irrespective of grade)or grade 3 or 4 diarrhoea.

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

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

In the event of neurotoxicity, the recommended dose adjustment for Pemetrexed Fresenius Kabiand cisplatin is documented in Table 3. Patients should discontinue therapy if Grade 3 or 4neurotoxicity is observed.

Table 3 - Dose modification table for pemetrexed (as single agent or in combination) andcisplatin-Neurotoxicitya 2

CTC Grade Dose of pemetrexed (mg/m ) Dose for cisplatin(mg/m )0-1 100 % of previous dose 100 % of previous dose2 100 % of previous dose 50 % of previous dosea National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998)

Treatment with Pemetrexed Fresenius Kabi should be discontinued if a patient experiences anyhaematologic or non-haematologic Grade 3 or 4 toxicity after 2 dose reductions or immediatelyif Grade 3 or 4 neurotoxicity is observed.

In clinical studies, there has been no indication that patients 65 years of age or older are atincreased risk of adverse reaction compared to patients younger than 65 years old. No dosereductions other than those recommended for all patients are necessary.

There is no relevant use of Pemetrexed Fresenius Kabi in the paediatric population in malignantpleural mesothelioma and non-small cell lung cancer.

Patients with renal impairment (standard cockcroft and gault formula or glomerular filtrationrate measured Tc99m-DPTA serum clearance method)

Pemetrexed is primarily eliminated unchanged by renal excretion. In clinical studies, patientswith creatinine clearance of ≥ 45 ml/min required no dose adjustments other than thoserecommended for all patients. There are insufficient data on the use of pemetrexed in patientswith creatinine clearance below 45 ml/min; therefore the use of pemetrexed is not recommended(see section 4.4).

No relationships between AST (SGOT), ALT (SGPT), or total bilirubin and pemetrexedpharmacokinetics 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 ofnormal (hepatic metastases absent) or > 5.0 times the upper limit of normal (hepatic metastasespresent) have not been specifically studied.

Pemetrexed Fresenius Kabi is for intravenous use. Pemetrexed Fresenius Kabi should beadministered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.

For precautions to be taken before handling or administering Pemetrexed Fresenius Kabi, andfor instructions on dilution of Pemetrexed Fresenius Kabi before administration, see section 6.6.

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).

Pemetrexed can suppress bone marrow function as manifested by neutropenia,thrombocytopenia and anaemia (or pancytopenia) (see section 4.8). Myelosuppression is usuallythe dose-limiting toxicity. Patients should be monitored for myelosuppression during therapyand pemetrexed should not be given to patients until absolute neutrophil count (ANC) returns to≥ 1500 cells/mm3 and platelet count returns to ≥ 100,000 cells/mm3. Dose reductions forsubsequent cycles are based on nadir ANC, platelet count and maximum non-haematologictoxicity seen from the previous cycle (see section 4.2).

Less toxicity and reduction in Grade 3/4 haematologic and non-haematologic toxicities such asneutropenia, febrile neutropenia and infection with Grade 3/4 neutropenia were reported whenpre-treatment with folic acid and vitamin B12 was administered. Therefore, all patients treatedwith pemetrexed must be instructed to take folic acid and vitamin B12 as a prophylactic measureto reduce treatment-related toxicity (see section 4.2).

Skin reactions have been reported in patients not pre-treated with a corticosteroid. Pre-treatmentwith dexamethasone (or equivalent) can reduce the incidence and severity of skin reactions (seesection 4.2).

An insufficient number of patients has been studied with creatinine clearance of below45 ml/min. Therefore, the use of pemetrexed in patients with creatinine clearance of < 45 ml/minis 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, andacetylsalicylic acid (> 1.3 g daily) for 2 days before, on the day of, and 2 days followingpemetrexed administration (see section 4.5).

In patients with mild to moderate renal insufficiency eligible for pemetrexed therapy NSAIDswith 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 orin association with other chemotherapeutic agents. Many of the patients in whom these occurredhad underlying risk factors for the development of renal events including dehydration orpre-existing hypertension or diabetes. Nephrogenic diabetes insipidus and renal tubular necrosiswere also reported in post marketing setting with pemetrexed alone or with otherchemotherapeutic agents. Most of these events resolved after pemetrexed withdrawal. Patientsshould be regularly monitored for acute tubular necrosis, decreased renal function and signs andsymptoms of nephrogenic diabetes insipidus (e.g. hypernatraemia).

The effect of third space fluid, such as pleural effusion or ascites, on pemetrexed is not fullydefined. A phase 2 study of pemetrexed in 31 solid tumour patients with stable third space fluiddemonstrated no difference in pemetrexed dose normalized plasma concentrations or clearancecompared to patients without third space fluid collections. Thus, drainage of third space fluidcollection prior to pemetrexed treatment should be considered, but may not be necessary. Due tothe gastrointestinal toxicity of pemetrexed given in combination with cisplatin, severedehydration has been observed. Therefore, patients should receive adequate antiemetic treatmentand appropriate hydration prior to and/or after receiving treatment.

Serious cardiovascular events, including myocardial infarction and cerebrovascular events havebeen uncommonly reported during clinical studies with pemetrexed, usually when given incombination with another cytotoxic agent. Most of the patients in whom these events have beenobserved had pre-existing cardiovascular risk factors (see section 4.8).

Immunodepressed status is common in cancer patients. As a result, concomitant use of liveattenuated vaccines is not recommended (see section 4.3 and 4.5).

Pemetrexed can have genetically damaging effects. Sexually mature males are advised not tofather a child during the treatment and up to 3 months thereafter. Contraceptive measures orabstinence are recommended. Owing to the possibility of pemetrexed treatment causingirreversible infertility, men are advised to seek counselling on sperm storage before startingtreatment.

Women of childbearing potential must use effective contraception during treatment withpemetrexed and for 6 months following completion of treatment (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 thesepatients and caution exercised with use of other radiosensitising agents.

Cases of radiation recall have been reported in patients who received radiotherapy weeks oryears previously.

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

Pemetrexed is mainly eliminated unchanged renally by tubular secretion and to a lesser extent byglomerular filtration. Concomitant administration of nephrotoxic drugs (e.g. aminoglycoside,loop diuretics, platinum compounds, cyclosporin) could potentially result in delayed clearance ofpemetrexed. This combination should be used with caution. If necessary, creatinine clearanceshould be closely monitored.

Concomitant administration of pemetrexed with OAT3 (organic anion transporter 3) inhibitors(e.g. probenecid, penicillin, proton pump inhibitors (PPIs)) results in delayed clearance ofpemetrexed. Caution should be made when these medicinal products are combined withpemetrexed.

In patients with normal renal function (creatinine clearance ≥80 ml/min), high doses ofnon-steroidal anti-inflammatory medicinal product (NSAIDs, such as ibuprofen > 1600 mg/day)and acetylsalicylic acid at higher dose (≥1.3 g daily) may decrease pemetrexed elimination and,consequently, increase the occurrence of pemetrexed adverse reactions. Therefore, cautionshould 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 to79 ml/min), the concomitant administration of pemetrexed with NSAIDs (e.g. ibuprofen) oracetylsalicylic acid at higher dose should be avoided for 2 days before, on the day of, and 2 daysfollowing pemetrexed administration (see section 4.4).

In the absence of data regarding potential interaction with NSAIDs having longer half-lives suchas piroxicam or rofecoxib, the concomitant administration with pemetrexed in patients with mildto 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 concomitantadministration 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 humanliver microsomes indicated that pemetrexed would not be predicted to cause clinically significantinhibition of the metabolic clearance of medicinal product metabolised by CYP3A, CYP2D6,

CYP2C9, and CYP1A2.

Interactions common to all cytotoxics

Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation treatmentis frequent. The high intra-individual variability of the coagulation status during diseases and thepossibility of interaction between oral anticoagulants and anticancer chemotherapy requireincreased frequency of INR (International Normalised Ratio) monitoring, if it is decided to treatthe patient with oral anticoagulants.

Concomitant use contraindicated: Yellow fever vaccine: risk of fatal generalised vaccinaledisease (see section 4.3).

Concomitant use not recommended: Live attenuated vaccines (except yellow fever, for whichconcomitant use is contraindicated): risk of systemic, possibly fatal, disease. The risk isincreased in subjects who are already immunosuppressed by their underlying disease. Use aninactivated vaccine where it exists (poliomyelitis) (see section 4.4).

Women of childbearing potential/ Contraception in males and females

Pemetrexed can have genetically damaging effects. Women of childbearing potential must useeffective contraception during treatment with pemetrexed and for 6 months followingcompletion of treatment..

Sexually mature males are advised to use effective contraceptive measures and not to father achild during the treatment and up to 3 months thereafter.

There are no data from the use of pemetrexed in pregnant women but pemetrexed, like otheranti-metabolites, is suspected to cause serious birth defects when administered duringpregnancy. Animal studies have shown reproductive toxicity (see section 5.3). Pemetrexedshould not be used during pregnancy unless clearly necessary, after a careful consideration ofthe needs of the mother and the risk for the foetus (see section 4.4).

It is unknown whether pemetrexed is excreted in human milk and adverse reactions on thebreast-feeding child cannot be excluded. Breast-feeding must be discontinued duringpemetrexed therapy (see section 4.3).

Owing to the possibility of pemetrexed treatment causing irreversible infertility, men are advisedto seek counselling on sperm storage before starting treatment.

No studies on the effects on the ability to drive and use machines have been performed.

However, it has been reported that pemetrexed may cause fatigue. Therefore patients shouldbe cautioned against driving or operating machines if this event occurs.

The most commonly reported undesirable effects related to pemetrexed, whether used asmonotherapy or in combination, are bone marrow suppression manifested as anaemia,neutropenia, leukopenia, thrombocytopenia; and gastrointestinal toxicities, manifested asanorexia, nausea, vomiting, diarrhoea, constipation, pharyngitis, mucositis, and stomatitis. Otherundesirable effects include renal toxicities, increased aminotransferases, alopecia, fatigue,dehydration, rash, infection/sepsis and neuropathy. Rarely seen events include Stevens-Johnsonsyndrome and toxic epidermal necrolysis.

The table 4 lists the adverse drug events regardless of causality associated with pemetrexed usedeither as a monotherapy treatment or in combination with cisplatin from the pivotal registrationstudies (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 usedfor classification of frequency:

very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare(≥ 1/10,000 to < 1/1000); very rare (< 1/10,000) and not known (cannot be estimated fromavailable data). Within each frequency grouping, undesirable effects are presented in order ofdecreasing seriousness.

Table 4. Frequencies of all grades adverse drug events regardless of causality from thepivotal registration studies: JMEI (pemetrexed vs docetaxel), JMDB (pemetrexed andcisplatin versus gemcitabine and cisplatin, JMCH (pemetrexed plus cisplatin versuscisplatin), JMEN and PARAMOUNT (pemetrexed plus best supportive care versusplacebo plus best supportive care) and from post-marketing period.

System Very Common Uncommon Rare Very rare Not

Organ Class common known(MedDRA)

Infections and Infectiona Sepsisb Dermo-infestations Pharyngitis hypodermitis

Blood and Neutropenia Febrile neutropenia Pancytopenia Autoimmunelymphatic Leukopenia Platelet count haemolyticsystem Haemoglobi decreased anaemiadisordersn decreased

Immune Hypersensiti-vity Anaphylac-

System tic shockdisorders

Metabolism Dehydrationand nutritiondisorders

Nervous Taste disorder Cerebrovasculasystem Peripheral motor r accidentdisorders neuropathy Ischaemic

Peripheral sensory strokeneuropathy Haemorrhage

Dizziness intracranial

Eye disorders Conjunctivitis

Dry eye

Lacrimationincreased

Keratoconjunctiviti

System Very Common Uncommon Rare Very rare Not

Organ Class common known(MedDRA)s sicca

Eyelid oedema

Ocular surfacedisease

Cardiac Cardiac failure Anginadisorders Arrhythmia Myocardialinfarction

Coronary arterydisease

Arrhythmiasupraventricular

Vascular Peripheraldisorders ischaemiac

Respiratory, Pulmonarythoracic and embolismmediastinal Interstitialdisorders pneumonitisbd

Gastrointes- Stomatitis Dyspepsia Rectaltinal disorders Anorexia Constipation haemorrhage

Vomiting Abdominal pain Gastrointestinalhaemorrhage

Intestinal

Nauseaperforation

Oesophagitis

Colitis e

Hepatobiliary Aalanine Hepatitisdisorders aminotransferaseincreased

Aspartateaminotransferaseincreased

Skin and Rash Hyperpigmentation Erythema Stevens-subcutaneous Skin Pruritus Johnsontissueexfoliation Erythema syndromebdisordersmultiforme

Toxic

Alopeciaepidermal

Urticarianecrolysisb

Pemphigoid

Dermatitisbullous

Acquiredepidermolysisbullosa

Erythema-tous oedemaf

Pseudocellu-litis

Dermatitis

Eczema

System Very Common Uncommon Rare Very rare Not

Organ Class common known(MedDRA)

Prurigo

Renal and Creatinine Renal failure Nephroge-urinary clearance Glomerular nicdisorders decreased filtration rate diabetesdecreased insipidus

Bloodcreatinine

Renalincreasedetubularnecrosis

General Fatigue Pyrexiadisorders and Painadministration Oedemasite

Chest painconditions

Mucosalinflammation

Investigations Gamma-glutamyltransferaseincreased

Injury, Radiation Recallpoisoning and oesophagitis pheno-procedural Radiation menoncomplications pneumonitisa with and without neutropeniab in some cases fatalc sometimes leading to extremity necrosisd with respiratory insufficiencyeseen only in combination with cisplatinf mainly of the lower limbs

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. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reportingsystem listed in Appendix V.

Reported symptoms of overdose include neutropenia, anaemia, thrombocytopenia, mucositis,sensory polyneuropathy and rash. Anticipated complications of overdose include bone marrowsuppression as manifested by neutropenia, thrombocytopenia and anaemia. In addition, infectionwith or without fever, diarrhoea, and/or mucositis may be seen. In the event of suspectedoverdose, patients should be monitored with blood counts and should receive supportive therapyas necessary. The use of calcium folinate/folinic acid in the management of pemetrexedoverdose should be considered.

Pharmacotherapeutic group: antineoplastic agents, folic acid analogues, ATC code: L01BA04

Pemetrexed is a multi-targeted anti-cancer antifolate agent that exerts its action by disruptingcrucial folate-dependent metabolic processes essential for cell replication.

In vitro studies have shown that pemetrexed behaves as a multitargeted antifolate by inhibitingthymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotideformyltransferase (GARFT), which are key folate-dependent enzymes for the de novobiosynthesis of thymidine and purine nucleotides. Pemetrexed is transported into cells by boththe reduced folate carrier and membrane folate binding protein transport systems. Once in thecell, pemetrexed is rapidly and efficiently converted to polyglutamate forms by the enzymefolylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are even morepotent inhibitors of TS and GARFT. Polyglutamation is a time-and concentration-dependentprocess that occurs in tumour cells and, to a lesser extent, in normal tissues. Polyglutamatedmetabolites have an increased intracellular half-life resulting in prolonged drug action inmalignant cells.

Mesothelioma

EMPHACIS, a multicentre, randomised, single-blind phase 3 study of pemetrexed plus cisplatinversus cisplatin in chemonaive patients with malignant pleural mesothelioma, has shown thatpatients treated with pemetrexed and cisplatin had a clinically meaningful 2.8-month mediansurvival advantage over patients receiving cisplatin alone.

During the study, low-dose folic acid and vitamin B12 supplementation was introduced topatients’ therapy to reduce toxicity. The primary analysis of this study was performed on thepopulation of all patients randomly assigned to a treatment arm who received study drug(randomised and treated). A subgroup analysis was performed on patients who received folicacid and vitamin B12 supplementation during the entire course of study therapy (fullysupplemented). The results of these analyses of efficacy are summarised in the table below:

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

Randomised and treated Fully supplemented patientspatients

Efficacy parameter Pemetrexed/ Cisplatin Pemetrexed/ Cisplatincisplatin cisplatin(N = 226) (N = 222) (N = 168) (N = 163)

Median overall survival (months) 12.1 9.3 13.3 10.0(95 % CI) (10.0-14.4) (7.8-10.7) (11.4-14.9) (8.4-11.9)

Log Rank p-valuea 0.020 0.051

Median time to tumour progression 5.7 3.9 6.1 3.9(months)(95 % CI) (4.9-6.5) (2.8-4.4) (5.3-7.0) (2.8-4.5)

Log Rank p-value a 0.001 0.008

Randomised and treated Fully supplemented patientspatients

Efficacy parameter Pemetrexed/ Cisplatin Pemetrexed/ Cisplatincisplatin cisplatin(N = 226) (N = 222) (N = 168) (N = 163)

Time to treatment failure (months) 4.5 2.7 4.7 2.7(95 % CI) (3.9-4.9) (2.1-2.9) (4.3-5.6) (2.2-3.1)

Log Rank p-value a 0.001 0.001

Overall response rateb (95 % CI) 41.3% 16.7% 45.5% 19.6%(34.8-48.1) (12.0-22.2) (37.8-53.4) (13.8-26.6)

Fisher’s exact p-valuea < 0.001 < 0.001

Abbreviation: CI=confidence intervalap-value refers to comparison between arms.bIn 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. Theseparation between the treatment arms was achieved by improvement in lung function in thepemetrexed /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 pemetrexedalone. Pemetrexed at a dose of 500 mg/m2 was studied as a single-agent in 64 chemonaivepatients 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 patientswith locally advanced or metastatic NSCLC after prior chemotherapy has shown mediansurvival times of 8.3 months for patients treated with pemetrexed (Intent to Treat populationn = 283) and 7.9 months for patients treated with docetaxel (ITT n= 288). Prior chemotherapydid not include pemetrexed. An analysis of the impact of NSCLC histology on the treatmenteffect on overall survival (OS) was in favour of pemetrexed versus docetaxel for other thanpredominantly 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 carcinomahistology (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 pemetrexedwithin the histology subgroups.

Limited clinical data from a separate randomised, Phase 3, controlled trial, suggest that efficacydata (OS, progression free survival (PFS)) for pemetrexed are similar between patientspreviously pre treated with docetaxel (n = 41) and patients who did not receive previousdocetaxel treatment (n=540).

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

Pemetrexed Docetaxel

Survival time (months) (N = 283) (N = 288) Median (m) 8.3 7.9 95% CI for median (7.0-9.4) (6.3-9.2) HR 0.99 95% CI for HR (0.82-1.20) * Non-inferiority p-value (HR) 0.226

Progression-free survival (months) (N = 283) (N = 288) Median 2.9 2.9 HR (95% CI) 0.97 (0.82-1.16)

Time to treatment failure (TTTF-months) (N = 283) (N = 288) Median 2.3 2.1 HR (95% CI) 0.84 (0.71-0.997)

Response (n: qualified for response) (N = 264) (N = 274) Response rate (%) (95% CI) 9.1 (5.9-13.2) 8.8 (5.7-12.8) Stable disease (%) 45.8 46.4

Abbreviations: CI = confidence interval; HR = hazard ratio; ITT = intent to treat; N = totalpopulation size.

NSCLC, first-line treatment

A multicentre, randomised, open-label, Phase 3 study of pemetrexed plus cisplatin versusgemcitabine plus cisplatin in chemonaive patients with locally advanced or metastatic (Stage

IIIb or IV) non-small cell lung cancer (NSCLC) showed that pemetrexed plus cisplatin(Intent-To-Treat [ITT] population n = 862) met its primary endpoint and showed similar clinicalefficacy as gemcitabine plus cisplatin (ITT n = 863) in OS (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 mainefficacy endpoints were also assessed on the Protocol Qualified (PQ) population. The efficacyanalyses using PQ population are consistent with the analyses for the ITT population andsupport the non-inferiority of PC versus GC.

PFS and overall response rate were similar between treatment arms: median PFS was 4.8 monthsfor pemetrexed plus cisplatin versus 5.1 months for gemcitabine plus cisplatin (adjusted hazardratio 1.04; 95% CI = 0.94-1.15), and overall response rate was 30.6% (95% CI = 27.3-33.9) forpemetrexed plus cisplatin versus 28.2% (95% CI=25.0-31.4) for gemcitabine plus cisplatin. PFSdata were partially confirmed by an independent review (400/1725 patients were randomlyselected for review).

The analysis of the impact of NSCLC histology on OS demonstrated clinically relevantdifferences in survival according to histology, see table below.

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

ITT population and histology subgroups.

Median overall survival in months Adjusted

ITT population (95% CI) hazard ratio Superiorityand histology Gemcitabine + (HR) (95% p-value

Pemetrexed + Cisplatinsubgroups Cisplatin CI)

ITT population 10.3 N=862 10.3 N=863 0.94a 0.259(N = 1725) (9.8 - 11.2) (9.6 - 10.9) (0.84 - 1.05)

Adenocarcinoma 12.6 N=436 10.9 N=411 0.84 0.033(N=847) (10.7 - 13.6) (10.2 - 11.9) (0.71-0.99)

Large cell 10.4 N=76 6.7 N=77 0.67 0.027(N=153) (8.6 - 14.1) (5.5 - 9.0) (0.48-0.96)

Other 8.6 N=106 9.2 N=146 1.08 0.586(N=252) (6.8 - 10.2) (8.1 - 10.6) (0.81-1.45)

Squamous cell 9.4 N=244 10.8 N=229 1.23 0.050(N=473) (8.4 - 10.2) (9.5 - 12.1) (1.00-1.51)

Abbreviations: CI = confidence interval; ITT = intent-to-treat; N = total population size.aStatistically significant for noninferiority, with the entire confidence interval for HR well belowthe 1.17645 noninferiority margin (p <0.001).

Kaplan Meier plots of overall survival by histology

Abbreviations: PC=pemetrexed+cisplatin; GC= gemcitabine+cisplatin

There were no clinically relevant differences observed for the safety profile of pemetrexed pluscisplatin 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 oferythropoietin/darbopoietin (10.4% versus 18.1%, p< 0.001), G-CSF/GM-CSF (3.1% versus6.1%, 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), comparedthe 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 linedoublet therapy containing cisplatin or carboplatin in combination with gemcitabine, paclitaxel,or docetaxel. First line doublet therapy containing pemetrexed was not included. All patientsincluded in this study had an ECOG performance status 0 or 1. Patients received maintenancetreatment until disease progression. Efficacy and safety were measured from the time ofrandomisation after completion of first line (induction) therapy. Patients received a median of5 cycles of maintenance treatment with pemetrexed and 3.5 cycles of placebo. A total of 213patients (48.3%) completed ≥ 6 cycles and a total of 103 patients (23.4%) completed ≥ 10 cyclesof treatment with pemetrexed.

The study met its primary endpoint and showed a statistically significant improvement in PFS inthe pemetrexed arm over the placebo arm (n = 581, independently reviewed population; medianof 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 investigatorassessment of PFS. The median OS for the overall population (n=663) was 13.4 months for thepemetrexed 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 histologywas observed in JMEN. For patients with NSCLC other than predominantly squamous cellhistology (n = 430, independently reviewed population) median PFS was 4.4 months for thepemetrexed 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 cellhistology (n = 481) was 15.5 months for the pemetrexed arm and 10.3 months for the placeboarm, 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 monthsfor 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 forpemetrexed over placebo.

There were no clinically relevant differences observed for the safety profile of pemetrexedwithin the histology subgroups.

JMEN: Kaplan Meier plots of progression-free survival (PFS) and overall survival (OS)pemetrexed versus placebo in patients with NSCLC other than predominantly squamouscell 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 whodid not progress after 4 cycles of first line doublet therapy of pemetrexed in combination withcisplatin. Of the 939 patients treated with pemetrexed plus cisplatin induction, 539 patients wererandomised 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 pemetrexedplus 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 cisplatininduction therapy to the start of maintenance treatment was 2.96 months on both the pemetrexedarm and the placebo arm. Randomised patients received maintenance treatment until diseaseprogression. Efficacy and safety were measured from the time of randomisation after completionof first-line (induction) therapy. Patients received a median of 4 cycles of maintenance treatmentwith pemetrexed and 4 cycles of placebo. A total of 169 patients (47.1%) completed ≥ 6 cyclesmaintenance 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 inthe pemetrexed arm over the placebo arm (n = 472, independently reviewed population; medianof 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 lineinduction treatment, the median investigator-assessed PFS was 6.9 months for the pemetrexedarm 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 wasstatistically superior to placebo for OS (median 13.9 months versus 11.0 months, hazardratio= 0.78, 95% CI= 0.64-0.96, p= 0.0195). At the time of this final survival analysis, 28.7% ofpatients 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 andage) and similar to that observed in the unadjusted OS and PFS analyses. The 1 year and 2 yearsurvival rates for patients on pemetrexed were 58% and 32% respectively, compared to 45% and21% for patients on placebo. From the start of pemetrexed plus cisplatin first line inductiontreatment, the median OS of patients was 16.9 months for the pemetrexed arm and 14.0 monthsfor the placebo arm (hazard ratio= 0.78, 95% CI= 0.64-0.96). The percentage of patients thatreceived 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 fromrandomisation)

The pemetrexed maintenance safety profiles from the two studies JMEN and PARAMOUNTwere similar.

The European Medicines Agency has waived the obligation to submit the results of studies withthe reference medicinal product containing pemetrexed in all subsets of the paediatric populationin the granted indications (see section 4.2 for information on paediatric use).

The pharmacokinetic properties of pemetrexed following single-agent administration have beenevaluated in 426 cancer patients with a variety of solid tumours at doses ranging from 0.2 to838 mg/m2 infused over a 10-minute period.

Pemetrexed has a steady-state volume of distribution of 9 l/m2. In vitro studies indicate thatpemetrexed is approximately 81 % bound to plasma proteins. Binding was not notably affectedby 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 beingrecovered unchanged in urine within the first 24 hours following administration. In vitro studiesindicate that pemetrexed is actively secreted by OAT3 (organic anion transporter). Pemetrexedtotal systemic clearance is 91.8 ml/min and the elimination half-life from plasma is 3.5 hours inpatients with normal renal function (creatinine clearance of 90 ml/min). Between patientvariability in clearance is moderate at 19.3%.

The pharmacokinetic properties of pemetrexed are not influenced by concurrently administeredcisplatin. Oral folic acid and intramuscular vitamin B12 supplementation do not affect thepharmacokinetics of pemetrexed.

Pemetrexed total systemic exposure (AUC) and maximum plasma concentration increaseproportionally with dose. The pharmacokinetics of pemetrexed are consistent over multipletreatment cycles.

Administration of pemetrexed to pregnant mice resulted in decreased foetal viability, decreasedfoetal weight, incomplete ossification of some skeletal structures and cleft palate.

Administration of pemetrexed to male mice resulted in reproductive toxicity characterised byreduced fertility rates and testicular atrophy. In a study conducted in beagle dog by intravenousbolus injection for 9 months, testicular findings (degeneration/necrosis of the seminiferousepithelium) 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 Chinesehamster ovary cells, or the Ames test. Pemetrexed has been shown to be clastogenic in the invivo micronucleus test in the mouse.

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

Hydroxypropylbetadex

Hydrochloric acid (E 507) (pH adjustment)

Trometamol (pH adjustment)

Water for injections

Pemetrexed is physically incompatible with diluents containing calcium, including lactated

Ringer’s injection and Ringer’s injection. In the absence of other compatibility studies thismedicinal product must not be mixed with other medicinal products.

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

Pemetrexed Fresenius Kabi.

Unopened vial2 years.

Infusion solution

Chemical and physical in-use stability of diluted solution was demonstrated for 21 days atrefrigerated temperature and 7 days at 25°C. When prepared as directed, infusion solutions of

Pemetrexed Fresenius Kabi contain no antimicrobial preservatives. From a microbiological pointof view, the product should be used immediately. If not used immediately, in-use storage timesand conditions prior to use are the responsibility of the user and would not be longer than24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated asepticconditions.

Store below 25°C.

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

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

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

Type I, clear, colourless glass vial, with 20 mm rubber stopper and sealed with green flip-offaluminium seal, containing 4 ml concentrate. Each pack contains one vial.

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

Type I, clear, colourless glass vial, with 20 mm rubber stopper and sealed with blue flip-offaluminium seal, containing 20 ml concentrate. Each pack contains one vial.

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

Type I, clear, colourless glass vial, with 20 mm rubber stopper and sealed with red flip-offaluminium seal, containing 40 ml concentrate. Each pack contains one vial.

Not all pack sizes may be marketed.

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

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

- The appropriate volume of Pemetrexed Fresenius Kabi must be diluted to 100 ml withsodium chloride 9 mg/ml (0.9 %) solution for injection or 5% glucose intravenousinfusion and administered as an intravenous infusion over 10 minutes.

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

- Parenteral medicinal products must be inspected visually for particulate matter anddiscolouration prior to administration. If particulate matter is observed, do notadminister.

- Pemetrexed solutions are for single use only. Any unused medicinal product or wastematerial 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 andpreparation of pemetrexed infusion solutions. The use of gloves is recommended. If apemetrexed solution contacts the skin, wash the skin immediately and thoroughly with soap andwater. If pemetrexed solutions contact the mucous membranes, flush thoroughly with water.

Pregnant women must avoid contact with cytostatic medicinal product. Pemetrexed is not avesicant. There is not a specific antidote for extravasation of pemetrexed. There have been fewreported cases of pemetrexed extravasation, which were not assessed as serious by theinvestigator. Extravasation should be managed by local standard practice as with othernon-vesicants.

Fresenius Kabi Deutschland GmbH

Else-Kröner-Straße 1,61352 Bad Homburg v.d.Höhe

Germany

EU/1/16/1115/003

EU/1/16/1115/004

EU/1/16/1115/005

Date of first authorisation: 22 July 2016

Date of latest renewal: 21 April 2021

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

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