Malignant pleural mesothelioma

Pemetrexed in combination with cisplatin

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

Pre-medication regimen

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

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 1000 micrograms) on a daily basis. At least five doses of folic acid must be taken during the seven days preceding the first dose of pemetrexed, and dosing must continue during the full course of therapy and for 21 days after the last dose of pemetrexed. Patients must also receive an intramuscular injection of vitamin B₁₂ (1000 micrograms) in the week preceding the first dose of pemetrexed and once every three cycles thereafter. Subsequent vitamin B₁₂ injections may be given on the same day as pemetrexed.

Monitoring

Patients receiving pemetrexed should be monitored before each dose with a complete blood count, including a differential white cell count (WCC) and platelet count. Prior to each chemotherapy administration blood chemistry tests should be collected to evaluate renal and hepatic function. Before the start of any cycle of chemotherapy, patients are required to have the following: absolute neutrophil count (ANC) should be ≥1500 cells/mm³ and platelets should be ≥100,000 cells/mm³. Creatinine clearance should be ≥45 ml/min. The total bilirubin should be ≤1.5 times upper limit of normal. Alkaline phosphatase (AP), aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) should be ≤3 times upper limit of normal. Alkaline phosphatase, AST and ALT ≤5 times upper limit of normal is acceptable if liver has tumour involvement.

Dose adjustments

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

Table 1. Dose modification table for pemetrexed (as single agent or in combination) and cisplatin – Haematologic toxicities:

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

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

Table 2. Dose modification table for pemetrexed (as single agent or in combination) and cisplatin – Non-haematologic toxicities^a,b:

^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 and cisplatin is documented in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is observed.

Table 3. Dose modification table for pemetrexed (as single agent or in combination) and cisplatin – Neurotoxicity:

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

Treatment with pemetrexed 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.

Intravenous infusion over 10 minutes.