ARMISARTE Concentrate for solution for infusion Ref.[8457] Active ingredients: Pemetrexed

Posology

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

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 (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 (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.

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 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).

Patient 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

For precautions to be taken before handling or administering pemetrexed, see section 6.6.

Armisarte should be administered as an intravenous infusion over 10 minutes on the first day of each 21-day cycle. For instructions on dilution of Armisarte before administration, see section 6.6.

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.

Unopened vial: 18 months.

Diluted solution: Chemical and physical in-use stability of infusion solution of pemetrexed was demonstrated for 3 days at room temperature and 21 days at refrigerated temperature. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Store and transport refrigerated (2°C to 8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

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

Colourless glass vial (type I) with type I rubber (bromobutyl) serum stopper and an aluminium cap with polypropylene disk. Vials may or may not be sheathed in a protective sleeve.

Pack sizes:

1 × 4 ml vial (100 mg/4 ml)
1 × 20 ml vial (500 mg/20 ml)
1 × 34 ml vial (850 mg/34 ml)
1 × 40 ml vial (1000 mg/40 ml)

Not all pack sizes may be marketed.

1. Use aseptic technique during dilution of pemetrexed for intravenous infusion administration.
2. Calculate the dose and the number of Armisarte vials needed.
3. Armisarte must only be diluted with 5% glucose solution, without preservative. The appropriate volume of pemetrexed concentrate must be diluted to 100 ml with 5% glucose solution and administered as an intravenous infusion over 10 minutes.
4. Pemetrexed infusion solutions prepared as directed above are compatible with polyvinyl chloride and polyolefin lined administration sets and infusion bags.
5. Parenteral medicinal products must be inspected visually for particulate matter and discolouration prior to administration. If particulate matter is observed, do not administer.
6. 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 anticancer 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.