CIAMBRA Powder for concentrate for solution for infusion Ref.[49900] Active ingredients: Pemetrexed

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

Posology

CIAMBRA in combination with cisplatin

The recommended dose of CIAMBRA 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 Characteristicsfor specific dosing advice).

CIAMBRA as single agent

In patients treated for non-small cell lung cancer after prior chemotherapy, the recommended dose of CIAMBRA 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. AP, 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 CIAMBRA used as a single agent or in combination with cisplatin.

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

If patients develop non-haematologic toxicities ≥ Grade 3 (excluding neurotoxicity), CIAMBRA 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 CIAMBRA (as single agent or in combination) and cisplatin– Non-haematologic toxicities^a,b:

In the event of neurotoxicity, the recommended dose adjustment for CIAMBRA 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 CIAMBRA (as single agent or in combination) and cisplatin – Neurotoxicity:

Treatment with CIAMBRA 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 Population

Elderly

In clinical studies, there has been no indication that patients 65 years of age or older are at increased risk of adverse reactions 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 CIAMBRA 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

CIAMBRA is for intravenous use. CIAMBRA 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 CIAMBRA, see section 6.6.

For instructions on reconstitution and dilution of CIAMBRA 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:

2 years.

Reconstituted and infusion solutions:

Chemical and physical in-use stability of the infusion solution of pemetrexed was demonstrated for 24 hours at 2°C-8°C or 15-25°C. The reconstituted solution should be used immediately to prepare the infusion solution. From a microbiological point of view, the infusion solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C or 15°C to 25°C.

This medicinal product does not require any special storage conditions.

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

Type I glass vial with chlorobutyl rubber stopper and an aluminium seal with flip off cap. The vial is covered with a shrink-wrapped plastic sleeve. Each 10 ml vial contains 100 mg of pemetrexed (as pemetrexed disodium hemipentahydrate).

Pack of 1 vial.

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

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

3. Reconstitute 100 mg vials with 4.2 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection, without preservative, resulting in a solution containing 25 mg/ml pemetrexed. 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 100 ml with sodium chloride 9 mg/ml (0.9 %) solution for injection, without preservative, and administered as an intravenous infusion over 10 minutes.

5. Pemetrexed 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 or discolouration 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 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.