Pemetrexed Lilly - summary of medicine characteristics

2.  QUALITATIVE AND QUANTITATIVE COMPOSITION

3. PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion.

White to either light yellow or green-yellow lyophilised powder.

4.1 Therapeutic indications

Malignant pleural mesotheli

Pemetrexed Lilly in combination with cisplatin is indicated for the treatment of chemotherapy naïve

e malignant pleural mesothelioma.

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

Pemetrexed Lilly is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy (see section 5.1).

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

4.2 Posology and method of administration

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

Posology

Pemetrexed Lilly in combination with cisplatin

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

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Pemetrexed Lilly as single agent

In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended dose of Pemetrexed Lilly is 500 mg/m2 BSA administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.

Pre-medication regimen

To reduce the incidence and severity of skin reactions, a corticosteroid should be given the day prior to, on the day of, and the day after pemetrexed administration. The corticosteroid should be equivalent to 4 mg of dexamethasone administered orally twice a day (see section 4.4).

To reduce toxicity, patients treated with pemetrexed must also receive vitamin supplementation (see section 4.4). Patients must take oral folic acid or a multivitamin containing folic acid (350 to 1000 micrograms) on a daily basis. At least five doses of folic acid must be taken during the seven days preceding the first dose of pemetrexed, and dosing must continue during the full course of therapy and for 21 days after the last dose of pemetrexed. Patients must also receive an intramuscular injection of vitamin B12 (1000 micrograms) in the week preceding the first dose of pemetrexed and once every three cycles thereafter. Subsequent vitamin B12 injections may be given on the same day as pemetrexed.

Monitoring

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

Creatinine clearance should be > 45 mL/min.

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

Dose adjustments

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

a These criteria meet the National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998) definition of >CTC Grade 2 bleeding

Special populations

Elderly

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

4.3 Contraindications

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

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

An insufficient number of patients has been studied with creatinine clearance of below 45 mL/min. Therefore, the use of pemetrexed in patients with creatinine clearance of < 45 mL/min is not recommended (see section 4.2).

Patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) should avoid taking non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, and acetylsalicylic acid (> 1.3 g daily) for 2 days before, on the day of, and 2 days following pemetrexed administration (see section 4.5).

In patients with mild to moderate renal insufficiency eligible for pemetrexed therapy NSAIDs with long elimination half-lives should be interrupted for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration (see section 4.5).

Serious renal events, including acute renal failure, have been reported with pemetrexed alone or in association with other chemotherapeutic agents. Many of the patients in whom these occurred had

underlying risk factors for the development of renal events including dehydration or pre-existing hypertension or diabetes. Nephrogenic diabetes insipidus and renal tubular necrosis were also reported in post marketing setting with pemetrexed alone or with other chemotherapeutic agents. Most of these events resolved after pemetrexed withdrawal. Patients should be regularly monitored for      tubular

necrosis, decreased renal function and signs and symptoms of nephrogenic diabetes insip (e.g. hypernatraemia). re

The effect of third space fluid, such as pleural effusion or ascites, on pemetrexed is not fully defined. A phase 2 study of pemetrexed in 31 solid tumour patients with stable third space fluid demonstrated no difference in pemetrexed dose normalized plasma concentrations or clearance compared to patients without third space fluid collections. Thus, drainage of third space fluid collection prior to pemetrexed treatment should be considered, but may not be necessary.

Due to the gastrointestinal toxicity of pemetrexed given in c dehydration has been observed. Therefore, patients shoul appropriate hydration prior to and/or after receiving tre

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

Immunodepressed status is common cer patients. As a result, concomitant use of live attenuated vaccines is not recommended (see section 4.3 and 4.5).

Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to father a child during the treatment and up to 6 months thereafter. Contraceptive measures or abstinence are recommended. Owing to the possibility of pemetrexed treatment causing irreversible infertility, men

selling on sperm storage before starting treatment.

aring potential must use effective contraception during treatment with pemetrexed

Cases of radiation pneumonitis have been reported in patients treated with radiation either prior, during or subsequent to their pemetrexed therapy. Particular attention should be paid to these patients and caution exercised with use of other radiosensitising agents.

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

Excipients

Pemetrexed Lilly 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 Lilly 500 mg powder for concentrate for solution for infusion

This medicinal product contains 54 mg sodium per vial, equivalent to 2,7 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5 Interaction with other medicinal products and other forms of interaction

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

Concomitant administration of substances that are also tubularly secreted (e.g. probenecid, penicillin) could potentially result in delayed clearance of pemetrexed. Caution should be made when these drugs are combined with pemetrexed. If necessary, creatinine clearance should be closely monitored.

In patients with normal renal function (creatinine clearance > 80 mL/min), high doses of non-steroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen > 1600 mg/day) and acetylsalicylic acid at higher dose (> 1.3 g daily) may decrease pemetrexed elimination and, consequently, increase the occurrence of pemetrexed adverse reactions. Therefore, caution should be made when administering higher doses of NSAIDs or acetylsalicylic acid, concurrently with pemetrexed to patients with normal function (creatinine clearance > 80 mL/min).

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

In the absence of data regarding potential interaction with NSAIDs having longer half-lives such as piroxicam or rofecoxib, the concomitant administration with pemetrexed in patients with mild to moderate renal insufficiency should be interrupted for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration (see section 4.4). If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression and gastrointestinal toxicity.

Pemetrexed undergoes limited hepatic metabolism. Results from in vitro studies with human liver microsomes indicated that pemetrexed would not be predicted to cause clinically significant inhibition of the metabolic clearance of drugs metabolised by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

Interactions common to all cytotoxics

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

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

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

4.6 Fertility, pregnancy and lactation

Women of childbearing potential / Contraception in males and females

Women of childbearing potential must use effective contraception during treatment with pemetrexed. Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to father a child during the treatment and up to 6 months thereafter. Contraceptive measures or abstinence are recommended.

Pregnancy

There are no data from the use of pemetrexed in pregnant women but pemetrexed, like other anti-metabolites, is suspected to cause serious birth defects when administered during pregnancy. Animal studies have shown reproductive toxicity (see section 5.3). Pemetrexed should not b during pregnancy unless clearly necessary, after a careful consideration of the needs of th the risk for the foetus (see section 4.4).

Breast-feeding

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

Fertility

Owing to the possibility of pemetrexed treatment causing ir seek counselling on sperm storage before starting treatment

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

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

Tabulated list of adverse reactions

The table 4 lists the adverse drug events regardless of causality associated with pemetrexed used either as a monotherapy treatment or in combination with cisplatin from the pivotal registration studies (JMCH, JMEI, JMBD, JMEN and PARAMOUNT) and from the post marketing period.

ADRs are listed by MedDRA body system organ class. The following convention has been used for classification of frequency: very common: > 1/10; common: > 1/100 to < 1/10; uncommon: > 1/1,000 to < 1/100; rare: > 1/10,000 to < 1/1,000; very rare: < 1/10,000) and not known (cannot be estimated from the available data).

Table 4. Frequencies of all grades adverse drug events regardless of causality from the pivotal registration studies: JMEI (ALIMTA vs Docetaxel), JMDB (ALIMTA and Cisplatin versus GEMZAR and Cisplatin, JMCH (ALIMTA plus Cisplatin versus Cisplatin), JMEN and PARAMOUNT (Pemetrexed plus Best Supportive Care versus Placebo plus Best Supportive Care) and from post-marketing period.

a with and without neutropenia

b in some cases fatal

c sometimes leading to extremity necrosis

d with respiratory insufficiency

eseen only in combination with cisplatin

f mainly of the lower limbs

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is impo allows continued monitoring of the benefit/risk balance of the medicinal product. Healthca professionals are asked to report any suspected adverse reactions via the national reporting listed in Appendix V.

4.9 Overdose

Reported symptoms of overdose include neutropenia, anaemia, thromboc

polyneuropathy and rash. Anticipated complications of overdose incl manifested by neutropenia, thrombocytopenia and anaemia. In additi fever, diarrhoea, and/or mucositis may be seen. In the event of suspec monitored with blood counts and should receive supportive therapy a

The use of calcium folinate / folinic acid in the manage considered.

Pharmacotherapeutic group: Antineoplastic agents, antimetabolites, folic acid analogues, ATC code: L01BA04

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

hown that pemetrexed behaves as a multitargeted antifolate by inhibiting ase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide se (GARFT), which are key folate-dependent enzymes for the de novo biosynthesis of

d purine nucleotides. Pemetrexed is transported into cells by both the reduced folate membrane folate binding protein transport systems. Once in the cell, pemetrexed is rapidly and efficiently converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are even more potent inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumour cells and, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells.

Clinical efficacy

Mesothelioma

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

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

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

a p-value refers to comparison between arms.

b In the pemetrexed/cis­platin arm, randomized and treated (N = 225) and fully supplemented (N = 167)

A statistically significant improvement of the clinically relevant symptoms (pain and dyspnoea) associated with malignant pleural mesothelioma in the pemetrexed/cis­platin arm (212 patients) versus the cisplatin arm alone (218 patients) was demonstrated using the Lung Cancer Symptom Scale. Statistically significant differences in pulmonary function tests were also observed. The separation between the treatment arms was achieved by improvement in lung function in the pemetrexed /cisplatin arm and deterioration of lung function over time in the control arm.

There are limited data in patients with malignant pleural mesothelioma treated with pemetrexed alone. Pemetrexed at a dose of 500 mg/m2 was studied as a single-agent in 64 chemonaive patients with malignant pleural mesothelioma. The overall response rate was 14.1 %.

NSCLC, second-line treatment

A multicentre, randomised, open label phase 3 study of pemetrexed versus docetaxel in patients with locally advanced or metastatic NSCLC after prior chemotherapy has shown median survival times of 8.3 months for patients treated with pemetrexed (Intent To Treat population n = 283) and 7.9 months for patients treated with docetaxel (ITT n = 288). Prior chemotherapy did not include pemetrexed. An analysis of the impact of NSCLC histology on the treatment effect on overall survival was in favour of pemetrexed versus docetaxel for other than predominantly squamous histologies (n = 399, 9.3 versus 8.0 months, adjusted HR = 0.78; 95 % CI = 0.61–1.00, p = 0.047) and was in favour of docetaxel for squamous cell carcinoma histology (n = 172, 6.2 versus 7.4 months, adjusted HR = 1.56;

95% CI = 1.08–2.26, p = 0.018). There were no clinically relevant differences observed for the safety profile of pemetrexed within the histology subgroups.

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

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

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

n size.

HR well below

Abbreviations: CI = confidence interval; ITT = intent-to-treat; N = total po a Statistically significant for noninferiority, with the entire confidence inter the 1.17645 nonin­feriority margin (p < 0.001).

Kaplan Meier plots of overall survival by histology

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vant differences observed for the safety profile of pemetrexed plus y subgroups.

Patients treated with pemetrexed and cisplatin required fewer transfusions (16.4 % versus 28.9 %, p < 0.001), red blood cell transfusions (16.1 % versus 27.3 %, p < 0.001) and platelet transfusions (1.8 % versus 4.5 %, p = 0.002). Patients also required lower administration of erythropoietin/dar­bopoietin (10.4 % versus 18.1 %, p < 0.001), G-CSF/GM-CSF (3.1 % versus 6.1 %, p = 0.004), and iron preparations (4.3 % versus 7.0 %, p = 0.021).

NSCLC, maintenance treatment JMEN

A multicentre, randomised, double-blind, placebo-controlled Phase 3 study (JMEN), compared the efficacy and safety of maintenance treatment with pemetrexed plus best supportive care (BSC)

(n = 441) with that of placebo plus BSC (n = 222) in patients with locally advanced (Stage IIIB) or metastatic (Stage IV) Non Small Cell Lung Cancer (NSCLC) who did not progress after 4 cycles of first line doublet therapy containing Cisplatin or Carboplatin in combination with Gemcitabine, Paclitaxel, or Docetaxel. First line doublet therapy containing pemetrexed was not included. All patients included in this study had an ECOG performance status 0 or 1. Patients received maintenance treatment until disease progression. Efficacy and safety were measured from the time of randomisation after completion of first line (induction) therapy. Patients received a median of 5 cycles of maintenance treatment with pemetrexed and 3.5 cycles of placebo. A total of 213 patients (48.3 completed > 6 cycles and a total of 103 patients (23.4 %) completed > 10 cycles of treatment wi pemetrexed.

The study met its primary endpoint and showed a statistically significant improvement i in the pemetrexed arm over the placebo arm (n = 581, independently reviewed population; median of 4.0 months and 2.0 months, respectively) (hazard ratio = 0.60, 95% CI = 0.49–0.73,< 0.00001). The

independent review of patient scans confirmed the findings of the investigato median OS for the overall population (n = 663) was 13.4 months for the 10.6 months for the placebo arm, hazard ratio = 0.79 (95% CI = 0.65–0.9

Consistent with other pemetrexed studies, a difference in efficacy observed in JMEN. For patients with NSCLC other than predomin

(n = 430, independently reviewed population) median PFS and 1.8 months for the placebo arm, hazard ratio = 0.47 (9 median OS for patients with NSCLC other than predomina

15.5 months for the pemetrexed arm and 10.3 months for the placebo arm, hazard ratio = 0.70 (95% CI = 0.56–0.88, p = 0.002). Including the induction phase the median OS for patients with NSCLC other than predominantly squamous cell histology was 18.6 months for the pemetrexed arm and 13.6 months for the placebo arm, hazard ratio = 0.71 (95 % CI = 0.56–0.88, p = 0.002).

The PFS and OS results in patients pemetrexed over placebo.

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

JMEN: Kaplan Meier plots of progression-free survival (PFS) and overall survival pemetrexed versus placebo in patients with NSCLC other than predominantly squamous cell histology:

Progression-Free Survival

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PARAMOUNT

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

Randomised patients received mainten reatment until disease progression. Efficacy and safety were measured from the time of rando     on after completion of first line (induction) therapy.

Patients received a median of 4 cycles of maintenance treatment with pemetrexed and 4 cycles of placebo. A total of 169 patients (47.1 %) completed > 6 cycles maintenance treatment with pemetrexed, representing at least 1 0 total cycles of pemetrexed.

dpoint and showed a statistically significant improvement in PFS in the lacebo arm (n = 472, independently reviewed population; median of

nths, respectively) (hazard ratio = 0.64, 95 % CI = 0.51–0.81, p = 0.0002). The independent r of patient scans confirmed the findings of the investigator assessment of PFS. For randomised p nts, as measured from the start of pemetrexed plus cisplatin first line induction treat e median investigator-assessed PFS was 6.9 months for the pemetrexed arm and 5. for the placebo arm (hazard ratio = 0.59 95 % CI = 0.47–0.74).

Following pemetrexed plus cisplatin induction (4 cycles), treatment with pemetrexed was statistically superior to placebo for OS (median 13.9 months versus 11.0 months, hazard ratio = 0.78, 95 % CI = 0.64–0.96, p = 0.0195). At the time of this final survival analysis, 28.7 % of patients were alive or lost to follow up on the pemetrexed arm versus 21.7 % on the placebo arm. The relative treatment effect of pemetrexed was internally consistent across subgroups (including disease stage, induction response, ECOG PS, smoking status, gender, histology and age) and similar to that observed in the unadjusted OS and PFS analyses. The 1 year and 2 year survival rates for patients on pemetrexed were 58 % and 32 % respectively, compared to 45 % and 21 % for patients on placebo. From the start of pemetrexed plus cisplatin first line induction treatment, the median OS of patients was 16.9 months for the pemetrexed arm and 14.0 months for the placebo arm (hazard ratio = 0.78, 95 % CI = 0.64–0.96). The percentage of patients that received post study treatment was 64.3 % for pemetrexed and 71.7 % for placebo.

PARAMOUNT:Kaplan Meier plot of progression-free survival (PFS) and Overall Survival (OS) for continuation pemetrexed maintenance versus placebo in patients with NSCLC other than predominantly squamous cell histology (measured from randomisation)

Progression-Free Survival

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

Paediatric population

5.2 Pharmacokinetic properties

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

5.3 Preclinical safety data

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

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

6.2 Incompatibilities

6.3 Shelf life

icinal product does not require any special storage conditions.

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

6.5 Nature and contents of container

Pemetrexed Lilly 100 mg powder for concentrate for solution for infusion

Type I glass vial with rubber stopper containing 100 mg of pemetrexed. Pack of 1 vial.

Pemetrexed Lilly 500 mg powder for concentrate for solution for infusion

Type I glass vial with rubber stopper containing 500 mg of pemetrexed.

Pack of 1 vial.

6.6 Special precautions for disposal and other handling

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

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

• 3. Pemetrexed Lilly 100 mg powder for concentrate for solution for infusion

♦ ^0

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 Lilly 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 and ranges in colour from colourless to yellow or green-yellow without adversely affecting

product quality. The pH of the reconstituted solution is between 6.6 and 7.8. Further dilution is required.

The appropriate volume of reconstituted pemetrexed solution must be further diluted to 100 mL with sodium chloride 9 mg/mL (0.9 %) solution for injection, without preservative, and administered as an intravenous infusion over 10 minutes.

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

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

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

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

  must be di

  
  

7. MARKETING AUTHORISATION HOLDER

Eli Lilly Nederland B.V. Papendorpseweg 83 3528 BJ Utrecht

The Netherlands

8. MARKETING AUTHORISATION NUMBER

EU/1/15/1034/001

EU/1/15/1034/002