PEMETREXED KRKA 500mg 25mg / ml powder for concentrate infusion solution medication leaflet

Pemetrexed Krka 100 mg powder for concentrate for solution for infusion

Pemetrexed Krka 500 mg powder for concentrate for solution for infusion

Pemetrexed Krka 100 mg powder for concentrate for solution for infusion

Each vial contains 100 mg pemetrexed (as pemetrexed disodium hemipentahydrate).

After reconstitution (see section 6.6), each vial contains 25 mg/ml pemetrexed.

Each vial contains approximately 11 mg (0.48 mmol) sodium.

Pemetrexed Krka 500 mg powder for concentrate for solution for infusion

Each vial contains 500 mg pemetrexed (as pemetrexed disodium hemipentahydrate).

After reconstitution (see section 6.6), each vial contains 25 mg/ml pemetrexed.

Each vial contains approximately 54 mg (2.35 mmol) sodium.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion (powder for concentrate).

White to either light yellow or green yellow lyophilized cake or powder.

Malignant pleural mesothelioma

Pemetrexed Krka in combination with cisplatin is indicated for the treatment of chemotherapy naïvepatients with unresectable malignant pleural mesothelioma.

Pemetrexed Krka in combination with cisplatin is indicated for the first-line treatment of patients withlocally advanced or metastatic non-small cell lung cancer other than predominantly squamous cellhistology (see section 5.1).

Pemetrexed Krka is indicated as monotherapy for the maintenance treatment of locally advanced ormetastatic non-small cell lung cancer other than predominantly squamous cell histology in patientswhose disease has not progressed immediately following platinum-based chemotherapy (see section5.1).

Pemetrexed Krka is indicated as monotherapy for the second-line treatment of patients with locallyadvanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology(see section 5.1).

Pemetrexed Krka must only be administered under the supervision of a physician qualified in the useof anti-cancer chemotherapy.

Pemetrexed in combination with cisplatin

The recommended dose of Pemetrexed Krka is 500 mg/m2 of body surface area (BSA) administered asan intravenous infusion over 10-minutes on the first day of each 21-day cycle. The recommended doseof cisplatin is 75 mg/m2 BSA infused over two hours approximately 30 minutes after completion ofthe pemetrexed infusion on the first day of each 21-day cycle. Patients must receive adequateanti-emetic treatment and appropriate hydration prior to and/or after receiving cisplatin (see alsocisplatin Summary of Product Characteristics for specific dosing advice).

Pemetrexed as single agent

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

Pemetrexed Krka is 500 mg/m2 BSA administered as an intravenous infusion over 10 minutes on thefirst 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 priorto, on the day of, and the day after pemetrexed administration. The corticosteroid should be equivalentto 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 (seesection 4.4). Patients must take oral folic acid or a multivitamin containing folic acid (350 to 1 000micrograms) on a daily basis. At least five doses of folic acid must be taken during the seven dayspreceding the first dose of pemetrexed, and dosing must continue during the full course of therapy andfor 21 days after the last dose of pemetrexed. Patients must also receive an intramuscular injection ofvitamin B12 (1 000 micrograms) in the week preceding the first dose of pemetrexed and once everythree cycles thereafter. Subsequent vitamin B12 injections may be given on the same day aspemetrexed.

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 chemotherapyadministration blood chemistry tests should be collected to evaluate renal and hepatic function. Beforethe start of any cycle of chemotherapy, patients are required to have the following: absolute neutrophilcount (ANC) should be ≥ 1 500 cells/mm3 and platelets should be ≥ 100 000 cells/mm3.

Creatinine clearance should be ≥ 45 ml/min.

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

Dose adjustments at the start of a subsequent cycle should be based on nadir haematologic counts ormaximum non-haematologic toxicity from the preceding cycle of therapy. Treatment may be delayedto allow sufficient time for recovery. Upon recovery, patients should be re-treated using the guidelinesin Tables 1, 2, and 3, which are applicable for Pemetrexed Krka used as a single agent or incombination with cisplatin.

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

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

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

ANC cisplatin)

Nadir platelets < 50 000/mm3 with bleedinga, 50% of previous dose (both Pemetrexed Krka 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 Krkashould be withheld until resolution to less than or equal to the patient's pre-therapy value. Treatmentshould be resumed according to the guidelines in Table 2.

Table 2 - Dose modification table for Pemetrexed Krka (as single agent or in combination) andcisplatin - Non-haematologic toxicities a, b

Dose of Pemetrexed Krka Dose for cisplatin (mg/m2)(mg/m2)

Any Grade 3 or 4 toxicities 75% of previous dose 75% of previous doseexcept mucositis

Any diarrhoea requiring 75% of previous dose 75% of previous dosehospitalisation (irrespective ofgrade) or Grade 3 or 4 diarrhoea

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

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

Table 3 - Dose modification table for Pemetrexed Krka (as single agent or in combination) andcisplatin - Neurotoxicity

CTC a Grade Dose of Pemetrexed Krka Dose for cisplatin (mg/m2)(mg/m2)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 Krka should be discontinued if a patient experiences any haematologic ornon-haematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4neurotoxicity is observed.

In clinical studies, there has been no indication that patients 65 years of age or older are at increasedrisk of adverse reaction compared to patients younger than 65 years old. No dose reductions other thanthose recommended for all patients are necessary.

There is no relevant use of Pemetrexed Krka in the paediatric population in malignant pleuralmesothelioma and non-small cell lung cancer.

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

Pemetrexed is primarily eliminated unchanged by renal excretion. In clinical studies, patients withcreatinine clearance of ≥ 45 ml/min required no dose adjustments other than those recommended forall patients. There are insufficient data on the use of pemetrexed in patients with creatinine clearancebelow 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 of normal(hepatic metastases absent) or > 5.0-times the upper limit of normal (hepatic metastases present), havenot been specifically studied.

Pemetrexed Krka is for intravenous use. Pemetrexed Krka should be administered as an intravenousinfusion over 10 minutes on the first day of each 21-day cycle.

For precautions to be taken before handling or administering Pemetrexed Krka and for instructions onreconstitution and dilution of Pemetrexed Krka 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, andanaemia (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 begiven to patients until absolute neutrophil count (ANC) returns to ≥ 1 500 cells/mm3 and platelet countreturns 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 asneutropenia, 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 withpemetrexed must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reducetreatment-related toxicity (see section 4.2).

Skin reactions have been reported in patients not pre-treated with a corticosteroid. Pre-treatment withdexamethasone (or equivalent) can reduce the incidence and severity of skin reactions (see section4.2).

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 notrecommended (see section 4.2).

Patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min) shouldavoid taking non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, and acetylsalicylicacid (>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 withlong elimination half-lives should be interrupted for at least 5 days prior to, on the day of, and at least2 days following pemetrexed administration (see section 4.5).

Serious renal events, including acute renal failure, have been reported with pemetrexed alone or inassociation with other chemotherapeutic agents. Many of the patients in whom these occurred hadunderlying risk factors for the development of renal events, including dehydration or pre-existinghypertension or diabetes. Nephrogenic diabetes insipidus and renal tubular necrosis were also reportedin post marketing setting with pemetrexed alone or with other chemotherapeutic agents. Most of theseevents resolved after pemetrexed withdrawal. Patients should be regularly monitored for acute tubularnecrosis, 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 demonstratedno difference in pemetrexed dose normalized plasma concentrations or clearance compared to patientswithout third-space fluid collections. Thus, drainage of third-space fluid collection prior to pemetrexedtreatment should be considered, but may not be necessary.

Due to the gastrointestinal toxicity of pemetrexed given in combination with cisplatin, severedehydration has been observed. Therefore, patients should receive adequate anti-emetic treatment andappropriate hydration prior to and/or after receiving treatment.

Serious cardiovascular events, including myocardial infarction and cerebrovascular events, have beenuncommonly reported during clinical studies with pemetrexed, usually when given in combinationwith another cytotoxic agent. Most of the patients in whom these events have been observed hadpre-existing cardiovascular risk factors (see section 4.8).

Immunodepressed status is common in cancer patients. As a result, concomitant use of live attenuatedvaccines is not recommended (see sections 4.3 and 4.5).

Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to father achild during the treatment and up to 3 months thereafter. Contraceptive measures or abstinence arerecommended. Owing to the possibility of pemetrexed treatment causing irreversible infertility, menare advised to seek counselling on sperm storage before starting treatment.

Women of childbearing potential must use effective contraception during treatment with pemetrexedand 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 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 yearspreviously.

Pemetrexed Krka 100 mg powder for concentrate for solution for infusion

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially“sodium-free”.

Pemetrexed Krka 500 mg powder for concentrate for solution for infusion

This medicinal product contains 54 mg sodium per vial, equivalent to 2.7% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

Pemetrexed is mainly eliminated unchanged renally by tubular secretion and to a lesser extent byglomerular filtration. Concomitant administration of nephrotoxic substances (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 clearance shouldbe 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 thesesubstances are combined with pemetrexed. If necessary, creatinine clearance should be closelymonitored.

In patients with normal renal function (creatinine clearance ≥ 80 ml/min), high doses of non-steroidalanti-inflammatory drugs (NSAIDs, such as ibuprofen > 1 600 mg/day) and acetylsalicylic acid athigher doses (≥ 1.3 g daily) may decrease pemetrexed elimination and, consequently, increase theoccurrence of pemetrexed adverse reactions. Therefore, caution should be made when administeringhigher doses of NSAIDs or acetylsalicylic acid, concurrently with pemetrexed to patients with normalfunction (creatinine clearance ≥ 80 ml/min).

In patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 ml/min), theconcomitant administration of pemetrexed with NSAIDs (e.g., ibuprofen) or acetylsalicylic acid athigher dose should be avoided for 2 days before, on the day of, and 2 days following pemetrexedadministration (see section 4.4).

In the absence of data regarding potential interaction with NSAIDs having longer half-lives such aspiroxicam or rofecoxib, the concomitant administration with pemetrexed in patients with mild tomoderate renal insufficiency should be interrupted for at least 5 days prior to, on the day of, and atleast 2 days following pemetrexed administration (see section 4.4). If concomitant administration of

NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppressionand gastrointestinal toxicity.

Pemetrexed undergoes limited hepatic metabolism. Results from in vitro studies with human livermicrosomes indicated that pemetrexed would not be predicted to cause clinically significant inhibitionof the metabolic clearance of substances 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 isfrequent. The high intra-individual variability of the coagulation status during diseases and thepossibility of interaction between oral anticoagulants and anti-cancer chemotherapy require increasedfrequency of INR (International Normalised Ratio) monitoring, if it is decided to treat the patient withoral anticoagulants.

Yellow fever vaccine: Risk of fatal generalised vaccinale disease (see section 4.3).

Live attenuated vaccines (except yellow fever, for which concomitant use is contraindicated): Risk ofsystemic, possibly fatal, disease. The risk is increased in subjects who are already immunosuppressedby their underlying disease. Use an inactivated vaccine where it exists (poliomyelitis) (see section4.4).

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

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

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. Animalstudies have shown reproductive toxicity (see section 5.3). Pemetrexed should not be used duringpregnancy unless clearly necessary, after a careful consideration of the needs of the mother and therisk 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 during pemetrexedtherapy (see section 4.3).

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

No studies on the effects on the ability to drive and use machines have been performed. However, ithas been reported that pemetrexed may cause fatigue. Therefore, patients should be cautioned againstdriving or operating machines if this event occurs.

The most commonly reported undesirable effects related to pemetrexed, whether used as monotherapyor 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.

The table 4 lists the adverse drug events regardless of causality associated with pemetrexed used eitheras 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. Within each frequency grouping, adversereactions are presented in order of decreasing seriousness. The following convention has been used forclassification of frequency: very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1 000to < 1/100; rare: ≥ 1/10 000 to < 1/1 000; very rare: < 1/10 000) and not known (cannot be estimatedfrom the available data).

Table 4. Frequencies of all grades adverse drug events regardless of causality from the pivotalregistration studies: JMEI (PEMETREXED vs docetaxel), JMDB (PEMETREXED andcisplatin versus GEMZAR and cisplatin, JMCH (PEMETREXED plus cisplatin versuscisplatin), JMEN and PARAMOUNT (Pemetrexed plus Best Supportive Care versus Placeboplus Best Supportive Care) and from post-marketing period.

System Very Common Uncommon Rare Very rare Not

Organ common known

Class(MedDRA)

Infections Infectiona Sepsisb Dermo-and Pharyngitis hypodermitiinfestations s

Blood and Neutropeni Febrile Pancytopenia Autoimmulymphatic a neutropenia nesystem Leukopenia Platelet count haemolyticdisorders Haemoglob decreased anaemiaindecreased

Immune Hypersensitivity Anaphylact

System ic shockdisorders

Metabolism Dehydrationandnutritiondisorders

Nervous Taste disorder Cerebrovascusystem Peripheral motor lar accidentdisorders neuropathy Ischaemic

Peripheral strokesensory Haemorrhageneuropathy intracranial

Dizziness

Eye Conjunctivitisdisorders Dry eye

Lacrimationincreased

Keratoconjunctivitis sicca

Eyelid oedema

Ocular surfacedisease

Cardiac Cardiac failure Anginadisorders Arrhythmia Myocardialinfarction

Coronaryartery disease

Arrhythmiasupraventricular

Vascular Peripheraldisorders ischaemiac

Respiratory, Pulmonarythoracic and embolismmediastinal Interstitialdisorders pneumonitisbd

Gastrointes- Stomatitis Dyspepsia Rectaltinal Anorexia Constipation haemorrhagedisorders Vomiting Abdominal pain Gastrointestina

Diarrhoea l haemorrhage

Nausea Intestinalperforation

Oesophagitis

Colitis e

Hepatobiliar Alanine Hepatitisy disorders aminotransferaseincreased

Aspartateaminotransferaseincreased

Skin and Rash Hyperpigmentati Erythema Stevens-subcutaneou Skin on Johnsons tissue exfoliation Pruritus syndromebdisorders Erythema Toxicmultiforme epidermal

Alopecia necrolysisb

Urticaria Pemphigoid

Dermatitisbullous

Acquiredepidermolysis bullosa

Erythema-tousoedemaf

Pseudocellulitis

Dermatitis

Eczema

Prurigo

Renal and Creatinine Renal failure Nephrourinary clearance Glomerular genicdisorders decreased filtration rate diabetes

Blood decreased insipiducreatinine sincreasede Renaltubularnecrosis

General Fatigue Pyrexiadisorders Painand Oedemaadministrati Chest painon site Mucosalconditions inflammation

Investigatio Gamma-ns glutamyltransferase increased

Injury, Radiation Recallpoisoning oesophagitis pheno-and Radiation menonprocedural pneumonitiscomplicationsa with and without neutropeniab in some cases fatalc sometimes leading to extremity necrosisd with respiratory insufficiencye seen only in combination with cisplatinf mainly of the lower limbs

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Reported symptoms of overdose include neutropenia, anaemia, thrombocytopenia, mucositis, sensorypolyneuropathy, and rash. Anticipated complications of overdose include bone marrow suppression asmanifested by neutropenia, thrombocytopenia, and anaemia. In addition, infection with or withoutfever, diarrhoea, and/or mucositis may be seen. In the event of suspected overdose, patients should bemonitored with blood counts and should receive supportive therapy as necessary. The use of calciumfolinate/folinic acid in the management of pemetrexed overdose should be considered.

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

Pemetrexed Krka (pemetrexed) is a multi-targeted anti-cancer antifolate agent that exerts its action bydisrupting crucial folate-dependent metabolic processes essential for cell replication.

In vitro studies have shown that pemetrexed behaves as a multi-targeted antifolate by inhibitingthymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotideformyltransferase (GARFT), which are key folate-dependent enzymes for the de novo biosynthesis ofthymidine and purine nucleotides. Pemetrexed is transported into cells by both the reduced folatecarrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is rapidlyand efficiently converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. Thepolyglutamate 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 alesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-liferesulting in prolonged substance action in malignant cells.

The European Medicines Agency has waived the obligation to submit the results of studies withpemetrexed in all subsets of the paediatric population in the granted indications (see section 4.2).

Mesothelioma

EMPHACIS, a multi-centre, randomised, single-blind Phase 3 study of pemetrexed plus cisplatinversus cisplatin in chemonaive patients with malignant pleural mesothelioma, has shown that patientstreated with pemetrexed and cisplatin had a clinically meaningful 2.8-month median survivaladvantage 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 allpatients randomly assigned to a treatment arm who received study substance (randomised and treated).

A subgroup analysis was performed on patients who received folic acid and vitamin B12supplementation during the entire course of study therapy (fully supplemented). The results of theseanalyses of efficacy are summarised in the table below.

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

Randomised and treated Fully supplemented patientspatients

Efficacy parameter Pemetrexed/ Cisplatin Pemetrexed/ Cisplatin

Cisplatin (N=222) Cisplatin (N=163)(N=226) (N=168)

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

Log rank p-valuea 0.001 0.008

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

Log rank p-valuea 0.001 0.001

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

Fisher's exact p-valuea <0.001 <0.001

Abbreviation: CI = confidence interval.a p-value refers to comparison between arms.b In the pemetrexed/cisplatin arm, randomized and treated (N=225) and fully supplemented (N=167).

A statistically significant improvement of the clinically relevant symptoms (pain and dyspnoea)associated with malignant pleural mesothelioma in the pemetrexed/cisplatin arm (212 patients) versusthe cisplatin arm alone (218 patients) was demonstrated using the Lung Cancer Symptom Scale.

Statistically significant differences in pulmonary function tests were also observed. The separationbetween the treatment arms was achieved by improvement in lung function in the pemetrexed/cisplatinarm 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 withmalignant pleural mesothelioma. The overall response rate was 14.1%.

NSCLC, second-line treatment

A multi-centre, randomised, open-label Phase 3 study of pemetrexed versus docetaxel in patients withlocally advanced or metastatic NSCLC after prior chemotherapy has shown median survival times of8.3 months for patients treated with pemetrexed (Intent-To-Treat [ITT] population N=283) and 7.9months for patients treated with docetaxel (ITT N=288). Prior chemotherapy did not includepemetrexed. An analysis of the impact of NSCLC histology on the treatment effect on overall survivalwas in favour of pemetrexed versus docetaxel for other than predominantly squamous histologies(N=399, 9.3 versus 8.0 months, adjusted hazard ratio (HR) = 0.78; 95% CI=0.61-1.00, p=0.047) andwas 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 differencesobserved for the safety profile of pemetrexed within the histology subgroups.

Limited clinical data from a separate randomized, Phase 3, controlled study, suggest that efficacy data(overall survival, progression-free survival) for pemetrexed are similar between patients previouslypre-treated with docetaxel (N=41) and patients who did not receive previous docetaxel treatment(N=540).

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

Pemetrexed Docetaxel

Survival time (months) (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 (N=283) (N=288)(months) 2.9 2.9

* Median 0.97 (0.82-1.16)

* HR (95% CI)

Time to treatment failure (N=283) (N=288)(TTTF - months) 2.3 2.1

* Median 0.84 (0.71-0.997)

* HR (95% CI)

Response (n: qualified for (N=264) (N=274)response) 9.1 (5.9-13.2) 8.8 (5.7-12.8)

* Response rate (%) (95% CI) 45.8 46.4

* Stable disease (%)

Abbreviations: CI = confidence interval; HR = hazard ratio; ITT = intent-to-treat; N = total populationsize.

NSCLC, first-line treatment

A multi-centre, randomised, open-label, Phase 3 study of pemetrexed plus cisplatin versus gemcitabineplus cisplatin in chemonaive patients with locally advanced or metastatic (Stage IIIb or IV) non-smallcell lung cancer (NSCLC) showed that pemetrexed plus cisplatin (Intent-To-Treat [ITT] population

N=862) met its primary endpoint and showed similar clinical efficacy as gemcitabine plus cisplatin(ITT N=863) in overall survival (adjusted hazard ratio (HR) 0.94; 95% CI=0.84-1.05). All patientsincluded 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 efficacyendpoints 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-inferiorityof 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 pluscisplatin (adjusted hazard ratio (HR) 1.04; 95% CI=0.94-1.15), and overall response rate was 30.6%(95% CI=27.3- 33.9) for pemetrexed plus cisplatin versus 28.2% (95% CI=25.0-31.4) for gemcitabineplus cisplatin. PFS data were partially confirmed by an independent review (400/1725 patients wererandomly selected for review).

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

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

ITT population Median overall survival in months Adjusted Superiorityand histology (95% CI) hazard p-valuesubgroups Pemetrexed + Cisplatin Gemcitabine + ratio (HR)

Cisplatin (95% 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) (0.71-0.99)(10.7 - (10.2 -13.6) 11.9)

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.

a Statistically significant for non-inferiority, with the entire confidence interval for HR well below the1.17645 non-inferiority margin (p < 0.001).

Kaplan-Meier plots of overall survival by histology

Adenocarcinoma Large Cell Carcinoma1.0 1.00.9 0.9

AC AC0.8 GC 0.8 GC0.7 0.70.6 0.60.5 0.50.4 0.40.3 0.30.2 0.20.1 0.10.0 0.00 6 12 18 24 30 0 6 12 18 24 30

Survival Time (months) Survival Time (months)

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% versus 6.1%,p=0.004), and iron preparations (4.3% versus 7.0%, p=0.021).

Non-small cell lung cancer (NSCLC), maintenance treatment

JMEN

A multi-centre, randomised, double-blind, placebo-controlled Phase 3 study (JMEN), compared theefficacy 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) ormetastatic (Stage IV) NSCLC who did not progress after 4 cycles of first-line doublet therapycontaining Cisplatin or Carboplatin in combination with Gemcitabine, Paclitaxel, or Docetaxel. First-

Survival Probability

Survival Probabilityline doublet therapy containing pemetrexed was not included. All patients included in this study hadan ECOG performance status 0 or 1. Patients received maintenance treatment until diseaseprogression. Efficacy and safety were measured from the time of randomisation after completion offirst-line (induction) therapy. Patients received a median of 5 cycles of maintenance treatment withpemetrexed and 3.5 cycles of placebo. A total of 213 patients (48.3%) completed ≥ 6 cycles and a totalof 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 thepemetrexed arm over the placebo arm (N=581, independently reviewed population; median of 4.0months and 2.0 months, respectively) (hazard ratio = 0.60, 95% CI = 0.49-0.73, p < 0.00001). Theindependent review of patient scans confirmed the findings of the investigator assessment of PFS. Themedian overall survival (OS) for the overall population (N=663) was 13.4 months for the pemetrexedarm 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 wasobserved 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 1.8months for the placebo arm, hazard ratio = 0.47 (95% CI=0.37-0.60, p=0.00001). The median OS forpatients with NSCLC other than predominantly squamous cell histology (N=481) was 15.5 months forthe 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 thanpredominantly squamous cell histology was 18.6 months for the pemetrexed arm and 13.6 months forthe 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 pemetrexed within thehistology subgroups.

JMEN: Kaplan-Meier plots of PFS and OS pemetrexed versus placebo in patients with NSCLCother than predominantly squamous cell histology:

Progression-Free Survival Overall Survival1.0 1.0

Pemetrexed0.9 Pemetrexed 0.9

Placebo0.8 Placebo 0.80.7 0.70.6 0.60.5 0.50.4 0.40.3 0.30.2 0.20.1 0.10.0 0.00 6 12 18 0 6 12 18 24 30 36 42

PFS Time (months) Survival Time (months)

PARAMOUNT

A multi-centre, randomised, double-blind, placebo-controlled Phase 3 study (PARAMOUNT),compared the efficacy and safety of continuation maintenance treatment with pemetrexed plus BSC(N=359) with that of placebo plus BSC (N=180) in patients with locally advanced (Stage IIIB) ormetastatic (Stage IV) NSCLC other than predominantly squamous cell histology who did not progressafter 4 cycles of first-line doublet therapy of pemetrexed in combination with cisplatin. Of the 939patients treated with pemetrexed plus cisplatin induction, 539 patients were randomised to

PFS Probability

Survival Probabilitymaintenance treatment with pemetrexed or placebo. Of the randomised patients, 44.9% had acomplete/partial response and 51.9% had a response of stable disease to pemetrexed plus cisplatininduction. Patients randomised to maintenance treatment were required to have an ECOG performancestatus 0 or 1. The median time from the start of pemetrexed plus cisplatin induction therapy to the startof 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 safetywere 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 ofplacebo. A total of 169 patients (47.1%) completed ≥ 6 cycles maintenance treatment withpemetrexed, representing at least 10 total cycles of pemetrexed.

The study met its primary endpoint and showed a statistically significant improvement in PFS in thepemetrexed arm over the placebo arm (N=472, independently reviewed population; median of 3.9months and 2.6 months, respectively) (hazard ratio = 0.64, 95% CI=0.51-0.81, p=0.0002). Theindependent review of patient scans confirmed the findings of the investigator assessment of PFS. Forrandomised patients, as measured from the start of pemetrexed plus cisplatin first-line inductiontreatment, the median investigator-assessed PFS was 6.9 months for the pemetrexed arm and 5.6months 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 statisticallysuperior 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 aliveor lost to follow up on the pemetrexed arm versus 21.7% on the placebo arm. The relative treatmenteffect of pemetrexed was internally consistent across subgroups (including disease stage, inductionresponse, ECOG PS, smoking status, gender, histology and age) and similar to that observed in theunadjusted OS and PFS analyses. The 1 year and 2 year survival rates for patients on pemetrexed were58% and 32% respectively, compared to 45% and 21% for patients on placebo. From the start ofpemetrexed plus cisplatin first-line induction treatment, the median OS of patients was 16.9 monthsfor 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 PFS and OS for continuation pemetrexed maintenanceversus placebo in patients with NSCLC other than predominantly squamous cell histology(measured from randomisation)

Progression-Free Survival Overall Survival1.0 1.00.9 0.9

Pemetrexed Pemetrexed0.8 0.8_ _ _ Placebo0.7 Placebo 0.70.6 0.60.5 0.50.4 0.40.3 0.30.2 0.20.1 0.10.0 0.00 3 6 9 12 15 0 3 6 9 12 15 18 21 24 27 30 33 36

Time (Months)

PFS Time (Months) OS Time (Months)

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

PSFurSvi vPalr Porobbaabbiillitiyty

O S P rob ab ility

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 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 undergoeslimited hepatic metabolism. Pemetrexed is primarily eliminated in the urine, with 70% to 90% of theadministered dose being recovered unchanged in urine within the first 24 hours followingadministration. In vitro studies indicate that pemetrexed is actively secreted by OAT3 (organic aniontransporter).

Pemetrexed total systemic clearance is 91.8 ml/min and the elimination half-life from plasma is 3.5hours in patients with normal renal function (creatinine clearance of 90 ml/min). Between-patientvariability in clearance is moderate at 19.3%. Pemetrexed total systemic exposure (AUC) andmaximum plasma concentration increase proportionally with dose. The pharmacokinetics ofpemetrexed are consistent over multiple treatment cycles.

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.

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

Administration of pemetrexed to male mice resulted in reproductive toxicity characterised by reducedfertility rates and testicular atrophy. In a study conducted in beagle dog by intravenous bolus injectionfor 9 months, testicular findings (degeneration/necrosis of the seminiferous epithelium) have beenobserved. This suggests that pemetrexed may impair male fertility. Female fertility was notinvestigated.

Pemetrexed was not mutagenic in either the in vitro chromosome aberration test in Chinese hamsterovary cells, or the Ames test. Pemetrexed has been shown to be clastogenic in the in vivomicronucleus test in the mouse.

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

Mannitol

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment) (E524)

Pemetrexed is physically incompatible with diluents containing calcium, including lactated Ringer'sinjection and Ringer's injection. In the absence of other compatibility studies this medicinal productmust not be mixed with other medicinal products.

Unopened vial3 years

Reconstituted and diluted solution

Chemical and physical in-use stability of reconstituted and infusion solutions of pemetrexed weredemonstrated for 24 hours at 2°C to 8°C (and 25°C). From a microbiological point of view, theproduct should be used immediately. If not used immediately, in-use storage times and conditionsprior to use are the responsibility of the user and would not be longer than 24 hours at 2°C to 8°C.

This medicinal product does not require any special storage conditions.

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

Pemetrexed Krka 100 mg powder for concentrate for solution for infusion10 ml vial (transparent type I glass) with bromobutyl rubber stopper and aluminium cap with tear offpart made of polypropylene (embossed with sign “FLIP OFF”): containing 100 mg pemetrexed. Packof 1 vial is available in a box.

Pemetrexed Krka 500 mg powder for concentrate for solution for infusion50 ml vial (transparent type I glass) with bromobutyl rubber stopper and aluminium cap with tear offpart made of polypropylene (embossed with sign “FLIP OFF”): containing 500 mg pemetrexed. Packof 1 vial is available in a box.

1. Use aseptic technique during the reconstitution and further dilution of pemetrexed for intravenousinfusion administration.

2. Calculate the dose and the number of Pemetrexed Krka vials needed. Each 100 mg vial contains anexcess of pemetrexed to facilitate delivery of label amount.

3. Pemetrexed Krka 100 mg powder for concentrate for solution for infusion

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

Pemetrexed Krka 500 mg powder for concentrate for solution for infusion

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 andranges in colour from colourless to yellow or green-yellow without adversely affecting productquality. 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 withsodium chloride 9 mg/ml (0.9%) solution for injection, without preservative, and administered as anintravenous 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 discolourationprior to administration. If particulate matter is observed, do not administer.

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

Preparation and administration precautions

As with other potentially toxic anti-cancer agents, care should be exercised in the handling andpreparation of pemetrexed infusion solutions. The use of gloves is recommended. If a pemetrexedsolution contacts the skin, wash the skin immediately and thoroughly with soap and water. Ifpemetrexed solutions contact the mucous membranes, flush thoroughly with water. Pemetrexed is nota vesicant. 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 the investigator.

Extravasation should be managed by local standard practice as with other non-vesicants.

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

EU/1/18/1283/001

EU/1/18/1283/002

Date of first authorisation: 22 May 2018

Date of latest renewal:

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

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