Lekarna

Malignant pleural mesothelioma:

Lekarna in combination with cisplatin is indicated for the treatment of chemotherapy naive patients with unresectable malignant pleural mesothelioma.

Non-small cell lung cancer:

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

Lekarna 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.

Lekarna 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.

Malignant pleural mesothelioma

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

Non-small cell lung cancer

Lekarna 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.

Lekarna 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.

Lekarna 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

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

Lekarna in combination with cisplatin

The recommended dose of Lekarna is 500mg/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 75mg/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).

Lekarna as single agent

In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended dose of Lekarna is 500mg/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 4mg of dexamethasone administered orally twice a day.

To reduce toxicity, patients treated with pemetrexed must also receive vitamin supplementation. Patients must take oral folic acid or a multivitamin containing folic acid (350 to 1,000 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 (1,000 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 > 1,500 cells/mm³ and platelets should be > 100,000 cells/mm³.

Creatinine clearance should be > 45ml/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 re-treated using the guidelines in Tables 1, 2, and 3, which are applicable for Lekarna used as a single agent or in combination with cisplatin.

If patients develop non-haematologic toxicities > Grade 3 (excluding neurotoxicity), Lekarna 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.

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

Treatment with Lekarna 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 Lekarna in the paediatric population in malignant pleural mesothelioma and non-small cell lung cancer.

Patients with renal impairment (standard Cockcroft and Gault formula or Glomerular Filtration Rate measured Tc99m DPTA serum clearance method)

Pemetrexed is primarily eliminated unchanged by renal excretion. In clinical studies, patients with creatinine clearance of > 45ml/min required no dose adjustments other than those recommended for all patients. There are insufficient data on the use of pemetrexed in patients with creatinine clearance below 45ml/min; therefore, the use of pemetrexed is not recommended.

Patients with hepatic impairment

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

Method of administration

Lekarna should be administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle.

Posology:

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

Lekarna Seacross in combination with cisplatin

The recommended dose of Lekarna 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 Lekarna 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).

Lekarna Seacross as single agent

In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended dose of Lekarna 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 Lekarna administration. The corticosteroid should be equivalent to 4 mg of dexamethasone administered orally twice a day.

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

Monitoring

Patients receiving Lekarna 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 Lekarna 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), Lekarna 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 Lekarna 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 Lekarna 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 Lekarna 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): Lekarna 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 Lekarna in patients with creatinine clearance below 45 ml/min; therefore the use of Lekarna is not recommended.

Patients with hepatic impairment: No relationships between AST (SGOT), ALT (SGPT), or total bilirubin and Lekarna 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:

Lekarna 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.

-

- Breast-feeding.

- Concomitant yellow fever vaccine.

Pemetrexed 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 should not be given to patients until absolute neutrophil count (ANC) returns to > 1,500 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 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 45ml/min. Therefore, the use of pemetrexed in patients with creatinine clearance of <45ml/min is not recommended.

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

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.

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 monitored for acute tubular necrosis and decreased renal function and signs and symptoms of nephrogenic diabetes insipidus (e.g. hypernatraemia).

The effect of third-space fluid, such as pleural effusion or ascites, on pemetrexed is not fully defined. A Phase 2 study of pemetrexed in 31 solid tumour patients with stable third-space fluid demonstrated no difference in pemetrexed dose 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 combination with cisplatin, severe dehydration has been observed. Therefore, patients should receive adequate anti-emetic treatment and appropriate hydration prior to and/or after receiving treatment.

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

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

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

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

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.

100mg vial: This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially 'sodium-free'.

500mg vial: This medicinal product contains approximately 54mg of sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

Lekarna 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 Lekarna 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 Lekarna 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 Lekarna 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 Lekarna administration. In patients with mild to moderate renal insufficiency eligible for Lekarna 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 Lekarna administration.

Serious renal events, including acute renal failure, have been reported with Lekarna 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 Lekarna is not fully defined. A phase 2 study of Lekarna in 31 solid tumour patients with stable third space fluid demonstrated no difference in Lekarna dose normalized plasma concentrations or clearance compared to patients without third space fluid collections. Thus, drainage of third space fluid collection prior to Lekarna treatment should be considered, but may not be necessary.

Due to the gastrointestinal toxicity of Lekarna 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 Lekarna, 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.

Lekarna 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 Lekarna 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 Lekarna.

Cases of radiation pneumonitis have been reported in patients treated with radiation either prior, during or subsequent to their Lekarna 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 may cause fatigue. Therefore, patients should be cautioned against driving or operating machines if this event occurs.

No studies on the effects on the ability to drive and use machines have been performed. However, it has been reported that Lekarna 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, 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, 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.

Frequency estimate: 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 available data).

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

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 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 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 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 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.

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.

Clinically relevant CTC toxicities that were reported in > 1% and ≤ 5% of the patients that were randomly assigned to pemetrexed 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 include supraventricular arrhythmias.

Clinically relevant Grade 3 and Grade 4 laboratory toxicities were similar between integrated Phase 2 results from three single-agent pemetrexed studies (N = 164) and the Phase 3 single-agent pemetrexed 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 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.

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 and cisplatin.

Clinically relevant toxicity that was reported in > 1% and ≤ 5% of the patients that were randomly assigned to receive cisplatin and pemetrexed 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 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 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 and 402 patients randomly assigned to receive placebo in the single-agent pemetrexed maintenance (JMEN: N= 663) and continuation pemetrexed 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.

Clinically relevant CTC toxicity of any grade that was reported in >1% and ≤5% of the patients that were randomly assigned to pemetrexed

Summary of the safety profile

The most commonly reported undesirable effects related to Lekarna, 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 Lekarna 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 Lekarna and cisplatin.

Clinically relevant CTC toxicities that were reported in > 1 % and < 5 % of the patients that were randomly assigned to receive cisplatin and Lekarna 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 Lekarna 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 Lekarna 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 Lekarna.

Clinically relevant CTC toxicities that were reported in > 1 % and < 5 % of the patients that were randomly assigned to Lekarna 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 Lekarna include supraventricular arrhythmias.

Clinically relevant Grade 3 and Grade 4 laboratory toxicities were similar between integrated Phase 2 results from three single agent Lekarna studies (n = 164) and the Phase 3 single agent Lekarna 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 Lekarna 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 Lekarna/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 Lekarna and cisplatin.

Clinically relevant toxicity that was reported in > 1% and ≤ 5% of the patients that were randomly assigned to receive cisplatin and Lekarna 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 Lekarna 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 Lekarna 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 Lekarna and 402 patients randomly assigned to receive placebo in the single-agent Lekarna maintenance (JMEN: N= 663) and continuation Lekarna 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 Lekarna.

** 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 Lekarna maintenance (N=663) and PARAMOUNT continuation Lekarna 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 overdose should be considered.

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 Lekarna overdose should be considered.

Pharmacotherapeutic group: Folic acid analogues. ATC code: L01BA04.

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

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

The European Medicines Agency has waived the obligation to submit the results of studies with Lekarna in all subsets of the paediatric population in the granted indications.

Clinical efficacy

Mesothelioma

EMPHACIS, a multi-centre, randomised, single-blind Phase 3 study of Lekarna plus cisplatin versus cisplatin in chemonaive patients with malignant pleural mesothelioma, has shown that patients treated with Lekarna 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 Lekarna plus cisplatin vs. cisplatin in malignant pleural mesothelioma

A statistically significant improvement of the clinically relevant symptoms (pain and dyspnoea) associated with malignant pleural mesothelioma in the Lekarna/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 Lekarna/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 Lekarna alone. Lekarna at a dose of 500mg/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 multi-centre, randomised, open-label Phase 3 study of Lekarna 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 Lekarna (Intent-To-Treat [ITT] population N = 283) and 7.9 months for patients treated with docetaxel (ITT N = 288). Prior chemotherapy did not include Lekarna. An analysis of the impact of NSCLC histology on the treatment effect on overall survival was in favour of Lekarna 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) 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 Lekarna 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).

Efficacy of Lekarna vs. Docetaxel in NSCLC - ITT population

NSCLC, first-line treatment

A multi-centre, randomised, open-label, Phase 3 study of Lekarna 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 Lekarna 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 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 Lekarna plus cisplatin versus 5.1 months for gemcitabine plus cisplatin (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 Lekarna 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 Lekarna + cisplatin vs. gemcitabine + cisplatin in first-line non-small cell lung cancer - ITT population and histology subgroups

Kaplan-Meier plots of overall survival by histology

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

Patients treated with Lekarna 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 multi-centre, randomised, double-blind, placebo-controlled Phase 3 study (JMEN), compared the efficacy and safety of maintenance treatment with Lekarna 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 Lekarna 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 Lekarna 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 Lekarna.

The study met its primary endpoint and showed a statistically significant improvement in PFS in the Lekarna 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 Lekarna 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 Lekarna 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 Lekarna 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 Lekarna 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 Lekarna arm and 13.6 months for the placebo arm, hazard ratio = 0.71 (95% CI = 0.56-0.88, p = 0.002).

The PFS and OS results in patients with squamous cell histology suggested no advantage for Lekarna over placebo.

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

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

PARAMOUNT

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

The study met its primary endpoint and showed a statistically significant improvement in PFS in the Lekarna 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 Lekarna plus cisplatin first-line induction treatment, the median investigator-assessed PFS was 6.9 months for the Lekarna arm and 5.6 months for the placebo arm (hazard ratio = 0.59, 95% CI = 0.47-0.74).

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

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

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

Pharmacotherapeutic group: Folic acid analogues, ATC code: L01BA04

Mechanism of action

Lekarna Seacross (Lekarna) 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 Lekarna 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. Lekarna is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, Lekarna 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 Lekarna plus cisplatin versus cisplatin in chemonaive patients with malignant pleural mesothelioma, has shown that patients treated with Lekarna 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 Lekarna plus cisplatin vs. cisplatin in Malignant pleural mesothelioma

Abbreviation: CI = confidence interval

* p-value refers to comparison between arms.

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

Efficacy of Lekarna 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 Lekarna 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 Lekarna 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 Lekarna 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 Lekarna 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 Lekarna + 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 Lekarna plus cisplatin within the histology subgroups.

Patients treated with Lekarna 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 Lekarna 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 Lekarna 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 Lekarna 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 Lekarna.

The study met its primary endpoint and showed a statistically significant improvement in PFS in the Lekarna 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 Lekarna 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 Lekarna 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 Lekarna 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 Lekarna 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 Lekarna 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 forLekarna over placebo.

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

JMEN: Kaplan Meier plots of progression-free survival (PFS) and overall survival Lekarnaversus 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 Lekarna 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 Lekarna in combination with cisplatin. Of the 939 patients treated with Lekarna plus cisplatin induction, 539 patients were randomised to maintenance treatment with Lekarna or placebo. Of the randomised patients, 44.9% had a complete/partial response and 51.9% had a response of stable disease to Lekarna 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 Lekarna plus cisplatin induction therapy to the start of maintenance treatment was 2.96 months on both the Lekarna 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 Lekarna and 4 cycles of placebo. A total of 169 patients (47.1%) completed > 6 cycles maintenance treatment with Lekarna, representing at least 10 total cycles of Lekarna.

The study met its primary endpoint and showed a statistically significant improvement in PFS in the Lekarna 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 Lekarna plus cisplatin first line induction treatment, the median investigator-assessed PFS was 6.9 months for the Lekarna arm and 5.6 months for the placebo arm (hazard ratio = 0.59 95% CI = 0.47-0.74).

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

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

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

The pharmacokinetic properties of pemetrexed following single-agent administration have been evaluated in 426 cancer patients with a variety of solid tumours at doses ranging from 0.2 to 838mg/m² infused over a 10-minute period. Pemetrexed has a steady-state volume of distribution of 9 l/m². In vitro studies indicate that pemetrexed is approximately 81% bound to plasma proteins. Binding was not notably affected by varying degrees of renal impairment. Pemetrexed undergoes limited hepatic metabolism. Pemetrexed is primarily eliminated in the urine, with 70% to 90% of the administered dose being recovered unchanged in urine within the first 24 hours following administration. In vitro studies indicate that pemetrexed is actively secreted by OAT3 (organic anion transporter).

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

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

The pharmacokinetic properties of Lekarna 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. Lekarna has a steady-state volume of distribution of 9 l/m2. In vitro studies indicate that Lekarna is approximately 81 % bound to plasma proteins. Binding was not notably affected by varying degrees of renal impairment. Lekarna undergoes limited hepatic metabolism. Lekarna 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 Lekarna is actively secreted by OAT3 (organic anion transporter. Lekarna 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 %. Lekarna total systemic exposure (AUC) and maximum plasma concentration increase proportionally with dose. The pharmacokinetics of Lekarna are consistent over multiple treatment cycles.

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

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

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

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

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

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

Administration of Lekarna 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 Lekarna may impair male fertility. Female fertility was not investigated.

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

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

Pemetrexed 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.

Lekarna 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 for intravenous infusion administration.

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

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

Reconstitute 500mg vials with 20ml of sodium chloride 9mg/ml (0.9%) solution for injection, without preservative, resulting in a solution containing 25mg/ml pemetrexed. Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in colour from colourless to yellow or green-yellow without adversely affecting product quality. The pH of the reconstituted solution is between 6.6 and 7.8. Further dilution is required.

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

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

6. Parenteral medicinal products must be inspected visually for particulate matter and discolouration prior to administration. If particulate matter is observed, do not administer.

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

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

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

2. Calculate the dose and the number of Lekarna Seacross vials needed. Each vial contains an excess of Lekarna 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 Lekarna. 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 Lekarna 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. Lekarna 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. Lekarna 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 Lekarna infusion solutions, especially by pregnant staff. The use of gloves is recommended. If a Lekarna solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If Lekarna solutions contact the mucous membranes, flush thoroughly with water. Lekarna is not a vesicant. There is not a specific antidote for extravasation of Lekarna. There have been few reported cases of Lekarna 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.