Posology : מינונים

4.2 Posology and method of administration

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

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

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

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

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

Creatinine clearance should be ≥ 45 ml/min.
The total bilirubin should be ≤ 1.5 times upper limit of normal. Alkaline phosphatase (AP), aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) should be ≤ 3 times upper limit of normal. Alkaline phosphatase, AST and ALT ≤ 5 times upper limit of normal is acceptable if liver has tumour involvement.

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

Table 1. Dose modification table for Pemetrexed EVER Pharma (as single agent or in combination) and cisplatin - Haematologic toxicities
Nadir ANC <500 /mm3 and nadir platelets 75 % of previous dose (both Pemetrexed ≥ 50,000 /mm3                                EVER Pharma and cisplatin) Nadir platelets <50,000 /mm3 regardless of 75 % of previous dose (both Pemetrexed nadir ANC                                    EVER Pharma and cisplatin) 3
Nadir    platelets    <50,000/mm      with 50% of previous dose (both Pemetrexed bleedinga, regardless of nadir ANC.          EVER Pharma and cisplatin) a
These criteria meet the National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998) definition of ≥ CTC Grade 2 bleeding

If patients develop non-haematologic toxicities ≥ Grade 3 (excluding neurotoxicity), Pemetrexed EVER Pharma 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 EVER Pharma (as single agent or in combination) and cisplatin - Non-Haematologic toxicitiesa, b
Dose of      Pemetrexed       Dose     for    cisplatin
2            2
EVER Pharma (mg/m )           (mg/m )
Any Grade 3 or 4 toxicities
75% of previous dose          75% of previous dose except mucositis
Any diarrhoea requiring hospitalisation
75% of previous dose          75% of previous dose
(irrespective of grade) or grade 3 or 4 diarrhoea.
Grade 3 or 4 mucositis        50% of previous dose          100% of previous dose 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 EVER Pharma 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 EVER Pharma (as single agent or in combination) and cisplatin - Neurotoxicity
CTCa Grade                    Dose    of pemetrexed        Dose for cisplatin 2
(mg/m )                      (mg/m2)
0-1                           100% of previous dose        100% of previous dose 2                             100% of previous dose        50% of previous dose a
National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998) 
Treatment with Pemetrexed EVER Pharma 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.

Special populations

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

Paediatric population:
There is no relevant use of Pemetrexed EVER Pharma 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 ≥ 45 ml/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 45 ml/min; therefore, the use of pemetrexed is not recommended (see section 4.4).

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

For precautions to be taken before handling or administering Pemetrexed EVER Pharma and for instructions on dilution of Pemetrexed EVER Pharma before administration, see section 6.6.