Pemetrexed Disodium

Malignant pleural mesothelioma

Pemetrexed Disodium Seacross in combination with cisplatin is indicated for the treatment of chemotherapy naïve patients with unresectable malignant pleural mesothelioma.

Non-small cell lung cancer

Pemetrexed Disodium Seacross 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.

Pemetrexed Disodium Seacross 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.

Pemetrexed Disodium Seacross 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.

Posology:

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

Pemetrexed Disodium Seacross in combination with cisplatin

The recommended dose of Pemetrexed Disodium Seacross 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 Disodium 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).

Pemetrexed Disodium Seacross as single agent

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

Premedication 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 Disodium administration. The corticosteroid should be equivalent to 4 mg of dexamethasone administered orally twice a day.

To reduce toxicity, patients treated with Pemetrexed Disodium must also receive vitamin supplementation. 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 Disodium, and dosing must continue during the full course of therapy and for 21 days after the last dose of Pemetrexed Disodium. Patients must also receive an intramuscular injection of Vitamin B12 (1000 micrograms) in the week preceding the first dose of Pemetrexed Disodium and once every three cycles thereafter. Subsequent Vitamin B12 injections may be given on the same day as Pemetrexed Disodium.

Monitoring

Patients receiving Pemetrexed Disodium 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 Disodium used as a single agent or in combination with cisplatin.

^aThese 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 Disodium should be withheld until resolution to less than or equal to the patient's pre-therapy value. Treatment should be resumed according to the guidelines in Table 2.

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

^b Excluding neurotoxicity

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

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

Treatment with Pemetrexed Disodium Seacross should be discontinued if a patient experiences any haematologic or non-haematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

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

Paediatric population

There is no relevant use of Pemetrexed Disodium Seacross in the paediatric population in malignant pleural mesothelioma and non-small cell lung cancer.

Patients with renal impairment: (Standard Cockcroft and Gault formula or Glomerular Filtration Rate measured Tc99m-DPTA serum clearance method): Pemetrexed Disodium is primarily eliminated unchanged by renal excretion. In clinical studies, patients with creatinine clearance of > 45 ml/min required no dose adjustments other than those recommended for all patients. There are insufficient data on the use of Pemetrexed Disodium in patients with creatinine clearance below 45 ml/min; therefore the use of Pemetrexed Disodium is not recommended.

Patients with hepatic impairment: No relationships between AST (SGOT), ALT (SGPT), or total bilirubin and Pemetrexed Disodium pharmacokinetics were identified. However patients with hepatic impairment such as bilirubin > 1.5 times the upper limit of normal and/or aminotransferase > 3.0 times the upper limit of normal (hepatic metastases absent) or > 5.0 times the upper limit of normal (hepatic metastases present) have not been specifically studied.

Method of administration:

Pemetrexed Disodium Seacross, a clear, colorless to yellow or yellow-green colored solution, once reconstituted; should be administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.

-

- Breast-feeding.

- Concomitant yellow fever vaccine.

Pemetrexed Disodium can suppress bone marrow function as manifested by neutropenia, thrombocytopenia and anaemia (or pancytopenia). Myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy and Pemetrexed Disodium 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 for subsequent cycles are based on nadir ANC, platelet count and maximum non-haematologic toxicity seen from the previous cycle.

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 Disodium must be instructed to take folic acid and Vitamin B12 as a prophylactic measure to reduce treatment-related toxicity.

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.

An insufficient number of patients has been studied with creatinine clearance of below 45 ml/min. Therefore, the use of Pemetrexed Disodium in patients with creatinine clearance of < 45 ml/min is not recommended.

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 aspirin (> 1.3 g daily) for 2 days before, on the day of, and 2 days following Pemetrexed Disodium administration. In patients with mild to moderate renal insufficiency eligible for Pemetrexed Disodium 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 Disodium administration.

Serious renal events, including acute renal failure, have been reported with Pemetrexed Disodium 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.

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

Due to the gastrointestinal toxicity of Pemetrexed Disodium given in combination with cisplatin, severe dehydration has been observed. Therefore, patients should receive adequate antiemetic treatment and appropriate hydration prior to and/or after receiving treatment.

Serious cardiovascular events, including myocardial infarction and cerebrovascular events have been uncommonly reported during clinical studies with Pemetrexed Disodium, 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.

Immunodepressed status is common in cancer patients. As a result, concomitant use of live attenuated vaccines is not recommended.

Pemetrexed Disodium 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 Disodium treatment causing irreversible infertility, men are advised to seek counselling on sperm storage before starting treatment.

Women of childbearing potential must use effective contraception during treatment with Pemetrexed Disodium.

Cases of radiation pneumonitis have been reported in patients treated with radiation either prior, during or subsequent to their Pemetrexed Disodium 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.

This medicinal product contains less than 1mmol (11 mg) of sodium per vial and is therefore considered essentially “sodium-free”.

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

Summary of the safety profile

The most commonly reported undesirable effects related to Pemetrexed Disodium, 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 below provides the frequency and severity of undesirable effects that have been reported in > 5 % of 168 patients with mesothelioma who were randomised to receive cisplatin and Pemetrexed Disodium and 163 patients with mesothelioma randomised to receive single agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folic acid and Vitamin B₁₂.

Adverse reactions

Frequency estimate: Very common (>1/10), Common (>1/100 and <1/10), Uncommon (>1/1000 and <1/100), Rare (>1/10,000 and <1/1000), Very rare (<1/10,000) and not known (cannot be estimated from available data-spontaneous reports).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

* Refer to National Cancer Institute CTC version 2 for each grade of toxicity except the term “creatinine clearance decreased”

** which is derived from the term “renal/genitourinary other”.

*** According to National Cancer Institute CTC (v2.0; NCI 1998), taste disturbance and alopecia should only be reported as Grade 1 or 2.

For the purpose of this table a cut off of 5 % was used for inclusion of all events where the reporter considered a possible relationship to Pemetrexed Disodium and cisplatin.

Clinically relevant CTC toxicities that were reported in > 1 % and < 5 % of the patients that were randomly assigned to receive cisplatin and Pemetrexed Disodium include: renal failure, infection, pyrexia, febrile neutropenia, increased AST, ALT, and GGT, urticaria and chest pain.

Clinically relevant CTC toxicities that were reported in < 1 % of the patients that were randomly assigned to receive cisplatin and Pemetrexed Disodium include arrhythmia and motor neuropathy.

The table below provides the frequency and severity of undesirable effects that have been reported in > 5 % of 265 patients randomly assigned to receive single agent Pemetrexed Disodium with folic acid and Vitamin B12 supplementation and 276 patients randomly assigned to receive single agent docetaxel. All patients were diagnosed with locally advanced or metastatic non-small cell lung cancer and received prior chemotherapy.

*Refer to National Cancer Institute CTC version 2 for each grade of toxicity.

**According to National Cancer Institute CTC (v2.0; NCI 1998), alopecia should only be reported as Grade 1 or 2.

For the purpose of this table a cut off of 5 % was used for inclusion of all events where the reporter considered a possible relationship to Pemetrexed Disodium.

Clinically relevant CTC toxicities that were reported in > 1 % and < 5 % of the patients that were randomly assigned to Pemetrexed Disodium include: infection without neutropenia, febrile neutropenia, allergic reaction / hypersensitivity, increased creatinine, motor neuropathy, sensory neuropathy, erythema multiforme, and abdominal pain.

Clinically relevant CTC toxicities that were reported in < 1 % of the patients that were randomly assigned to Pemetrexed Disodium include supraventricular arrhythmias.

Clinically relevant Grade 3 and Grade 4 laboratory toxicities were similar between integrated Phase 2 results from three single agent Pemetrexed Disodium studies (n = 164) and the Phase 3 single agent Pemetrexed Disodium study described above, with the exception of neutropenia (12.8 % versus 5.3 %, respectively) and alanine aminotransferase elevation (15.2 % versus 1.9 %, respectively). These differences were likely due to differences in the patient population, since the Phase 2 studies included both chemonaive and heavily pre-treated breast cancer patients with pre-existing liver metastases and/or abnormal baseline liver function tests.

The table below provides the frequency and severity of undesirable effects considered possibly related to study drug that have been reported in >5% of 839 patients with NSCLC who were randomized to receive cisplatin and Pemetrexed Disodium and 830 patients with NSCLC who were randomized to receive cisplatin and gemcitabine. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and Vitamin B₁₂.

*P-values <0.05 comparing Pemetrexed Disodium/cisplatin to gemcitabine/cisplatin, using Fisher Exact test.

**Refer to National Cancer Institute CTC (v2.0; NCI 1998) for each Grade of Toxicity.

***According to National Cancer Institute CTC (v2.0; NCI 1998), taste disturbance and alopecia should only be reported as Grade 1 or 2.

For the purpose of this table, a cut-off of 5% was used for inclusion of all events where the reporter considered a possible relationship to Pemetrexed Disodium and cisplatin.

Clinically relevant toxicity that was reported in > 1% and ≤ 5% of the patients that were randomly assigned to receive cisplatin and Pemetrexed Disodium include: AST increase, ALT increase, infection, febrile neutropenia, renal failure, pyrexia, dehydration, conjunctivitis, and creatinine clearance decrease. Clinically relevant toxicity that was reported in < 1% of the patients that were randomly assigned to receive cisplatin and Pemetrexed Disodium include: GGT increase, chest pain, arrhythmia, and motor neuropathy.

Clinically relevant toxicities with respect to gender were similar to the overall population in patients receiving Pemetrexed Disodium plus cisplatin.

The table below provides the frequency and severity of undesirable effects considered possibly related to study drug that have been reported in > 5% of 800 patients randomly assigned to receive single agent Pemetrexed Disodium and 402 patients randomly assigned to receive placebo in the single-agent Pemetrexed Disodium maintenance (JMEN: N= 663) and continuation Pemetrexed Disodium maintenance (PARAMOUNT: N=539) studies. All patients were diagnosed with Stage IIIB or IV NSCLC and had received prior platinum-based chemotherapy. Patients in both study arms were fully supplemented with folic acid and Vitamin B₁₂.

Common Terminology Criteria for Adverse Event; NCI = National Cancer Institute; SGOT = serum glutamic oxaloacectic aminotransferase; SGPT = serum glutamic pyruvic aminotransferase.

* Definition of frequency terms: Very common - > 10%; Common - > 5% and < 10%. For the purpose of this table, a cutoff of 5% was used for inclusion of all events where the reporter considered a possible relationship to Pemetrexed Disodium.

** Refer to NCI CTCAE Criteria (Version 3.0; NCI 2003) for each grade of toxicity. The reporting rates shown are according to CTCAE version 3.0.

*** Integrated adverse reactions table combines the results of the JMEN Pemetrexed Disodium maintenance (N=663) and PARAMOUNT continuation Pemetrexed Disodium maintenance (N=539) studies.

**** Combined term includes increased serum/blood creatinine, decreased glomerular filtration rate, renal failure and renal/genitourinary- other.

Clinically relevant

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

Pharmacotherapeutic group: Folic acid analogues, ATC code: L01BA04

Mechanism of action

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

Pharmacodynamic effects

In vitro studies have shown that Pemetrexed Disodium behaves as a multitargeted antifolate by inhibiting thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are key folate-dependent enzymes for the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed Disodium is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, Pemetrexed Disodium 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 Disodium plus cisplatin versus cisplatin in chemonaive patients with malignant pleural mesothelioma, has shown that patients treated with Pemetrexed Disodium 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:

Efficacy of Pemetrexed Disodium plus cisplatin vs. cisplatin in Malignant pleural mesothelioma

Abbreviation: CI = confidence interval

* p-value refers to comparison between arms.

** In the Pemetrexed Disodium/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 Disodium/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 Disodium /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 Disodium alone. Pemtrexed 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 Disodium 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 Disodium (Intent To Treat population n = 283) and 7.9 months for patients treated with docetaxel (ITT n = 288). Prior chemotherapy did not include Pemetrexed Disodium. An analysis of the impact of NSCLC histology on the treatment effect on overall survival was in favour of Pemetrexed Disodium 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 Disodium 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 Disodium are similar between patients previously pretreated with docetaxel (n = 41) and patients who did not receive previous docetaxel treatment (n = 540).

Efficacy of Pemetrexed Disodium vs docetaxel in NSCLC - ITT population

Abbreviations: CI = confidence interval; HR = hazard ratio; ITT = intent to treat; n = total population size.

NSCLC, first-line treatment:

A multicentre, randomised, open-label, Phase 3 study of Pemetrexed Disodium plus cisplatin versus gemcitabine plus cisplatin in chemonaive patients with locally advanced or metastatic (Stage IIIb or IV) non-small cell lung cancer (NSCLC) showed that Pemetrexed Disodium 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 0.94; 95% CI = 0.84-1.05). All patients included in this study had an ECOG performance status 0 or 1.

The primary efficacy analysis was based on the ITT population. Sensitivity analyses of main efficacy endpoints were also assessed on the Protocol Qualified (PQ) population. The efficacy analyses using PQ population are consistent with the analyses for the ITT population and support the non-inferiority of AC versus GC.

Progression free survival (PFS) and overall response rate were similar between treatment arms: median PFS was 4.8 months for Pemetrexed Disodium plus cisplatin versus 5.1 months for gemcitabine plus cisplatin (adjusted hazard ratio 1.04; 95% CI = 0.94-1.15), and overall response rate was 30.6% (95% CI = 27.3-33.9) for Pemetrexed Disodium plus cisplatin versus 28.2% (95% CI = 25.0-31.4) for gemcitabine plus cisplatin. PFS data were partially confirmed by an independent review (400/1725 patients were randomly selected for review).

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

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

Abbreviations: CI = confidence interval; ITT = intent-to-treat; N = total population size.

^a Statistically significant for noninferiority, with the entire confidence interval for HR well below the 1.17645 noninferiority margin (p <0.001).

There were no clinically relevant differences observed for the safety profile of Pemetrexed Disodium plus cisplatin within the histology subgroups.

Patients treated with Pemetrexed Disodium 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 Disodium 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 Disodium 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 Disodium and 3.5 cycles of placebo. A total of 213 patients (48.3%) completed > 6 cycles and a total of 103 patients (23.4%) completed > 10 cycles of treatment with Pemetrexed Disodium.

The study met its primary endpoint and showed a statistically significant improvement in PFS in the Pemetrexed Disodium arm over the placebo arm (n = 581, independently reviewed population; median of 4.0 months and 2.0 months, respectively) (hazard ratio = 0.60, 95% CI = 0.49-0.73, p < 0.00001). The independent review of patient scans confirmed the findings of the investigator assessment of PFS. The median OS for the overall population (n = 663) was 13.4 months for the Pemetrexed Disodium 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 Disodium studies, a difference in efficacy according to NSCLC histology was observed in JMEN. For patients with NSCLC other than predominantly squamous cell histology (n = 430, independently reviewed population) median PFS was 4.4 months for the Pemetrexed Disodium arm and 1.8 months for the placebo arm, hazard ratio = 0.47 (95% CI = 0.37-0.60, p = 0.00001). The median OS for patients with NSCLC other than predominantly squamous cell histology (n = 481) was 15.5 months for the Pemetrexed Disodium 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 Disodium 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 Disodium over placebo.

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

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

PARAMOUNT

A multicentre, randomised, double-blind, placebo-controlled Phase 3 study (PARAMOUNT), compared the efficacy and safety of continuation maintenance treatment with Pemetrexed Disodium 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 Disodium in combination with cisplatin. Of the 939 patients treated with Pemetrexed Disodium plus cisplatin induction, 539 patients were randomised to maintenance treatment with Pemetrexed Disodium or placebo. Of the randomised patients, 44.9% had a complete/partial response and 51.9% had a response of stable disease to Pemetrexed Disodium 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 Disodium plus cisplatin induction therapy to the start of maintenance treatment was 2.96 months on both the Pemetrexed Disodium arm and the placebo arm. Randomised patients received maintenance treatment until disease progression. Efficacy and safety were measured from the time of randomisation after completion of first line (induction) therapy. Patients received a median of 4 cycles of maintenance treatment with Pemetrexed Disodium and 4 cycles of placebo. A total of 169 patients (47.1%) completed > 6 cycles maintenance treatment with Pemetrexed Disodium, representing at least 10 total cycles of Pemetrexed Disodium.

The study met its primary endpoint and showed a statistically significant improvement in PFS in the Pemetrexed Disodium arm over the placebo arm (n = 472, independently reviewed population; median of 3.9 months and 2.6 months, respectively) (hazard ratio = 0.64, 95% CI = 0.51-0.81, p = 0.0002). The independent review of patient scans confirmed the findings of the investigator assessment of PFS. For randomised patients, as measured from the start of Pemetrexed Disodium plus cisplatin first line induction treatment, the median investigator-assessed PFS was 6.9 months for the Pemetrexed Disodium arm and 5.6 months for the placebo arm (hazard ratio = 0.59 95% CI = 0.47-0.74).

Following Pemetrexed Disodium plus cisplatin induction (4 cycles), treatment with Pemetrexed Disodium 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 Disodium arm versus 21.7% on the placebo arm. The relative treatment effect of Pemetrexed Disodium 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 Disodium were 58% and 32% respectively, compared to 45% and 21% for patients on placebo. From the start of Pemetrexed Disodium plus cisplatin first line induction treatment, the median OS of patients was 16.9 months for the Pemetrexed Disodium 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 Disodium and 71.7% for placebo.

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

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

The pharmacokinetic properties of Pemetrexed Disodium following single-agent administration have been evaluated in 426 cancer patients with a variety of solid tumours at doses ranging from 0.2 to 838 mg/m2 infused over a 10-minute period. Pemetrexed Disodium has a steady-state volume of distribution of 9 l/m2. In vitro studies indicate that Pemetrexed Disodium is approximately 81 % bound to plasma proteins. Binding was not notably affected by varying degrees of renal impairment. Pemetrexed Disodium undergoes limited hepatic metabolism. Pemetrexed Disodium is primarily eliminated in the urine, with 70 % to 90 % of the administered dose being recovered unchanged in urine within the first 24 hours following administration. In vitro studies indicate that Pemetrexed Disodium is actively secreted by OAT3 (organic anion transporter. Pemetrexed Disodium total systemic clearance is 91.8 ml/min and the elimination half-life from plasma is 3.5 hours in patients with normal renal function (creatinine clearance of 90 ml/min). Between patient variability in clearance is moderate at 19.3 %. Pemetrexed Disodium total systemic exposure (AUC) and maximum plasma concentration increase proportionally with dose. The pharmacokinetics of Pemetrexed Disodium are consistent over multiple treatment cycles.

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

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

Administration of Pemetrexed Disodium to male mice resulted in reproductive toxicity characterised by reduced fertility rates and testicular atrophy. In a study conducted in beagle dog by intravenous bolus injection for 9 months, testicular findings (degeneration/necrosis of the seminiferous epithelium) have been observed. This suggests that Pemetrexed Disodium may impair male fertility. Female fertility was not investigated.

Pemetrexed Disodium was not mutagenic in either the in vitro chromosome aberration test in Chinese hamster ovary cells, or the Ames test. Pemetrexed Disodium has been shown to be clastogenic in the in vivo micronucleus test in the mouse.

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

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

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

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

3. Reconstitute 100-mg vials with 4.2 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection, without preservative, resulting in a solution containing 25 mg/ml Pemetrexed Disodium. Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in colour from colourless to yellow or green-yellow without adversely affecting product quality. The pH of the reconstituted solution is between 6.6 and 7.8. Further dilution is required.

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

5. Pemetrexed Disodium 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 Disodium solutions are for single use only. Any unused medicinal product or waste material must be disposed of in accordance with local requirements for cytotoxic medicinal products.

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

The reconstituted solution is a clear, colorless to yellow or yellow-green colored solution.