CALCIUM FOLINATE Solution for injection / infusion Ref.[7910] Active ingredients: Calcium folinate

Posology

Calcium Folinate Rescue in methotrexate therapy

Refer to the applied intermediate- or high-dose methotrexate protocol for posology and method of administration of calcium folinate. The methotrexate protocol will dictate the dosage regimen of Calcium Folinate Rescue because it depends heavily on the posology and method of the intermediate- or high-dose methotrexate administration.

The following guidelines may serve as an illustration of regimens used in adults, elderly and children:

Calcium folinate rescue has to be performed by parenteral administration in patients with malabsorption syndromes or other gastrointestinal disorders where enteral absorption is not assured.

Dosages above 25-50 mg should be given parenterally due to saturable enteral absorption of calcium folinate.

Calcium Folinate Rescue is necessary when methotrexate is given at doses exceeding 500 mg/m² body surface and has to be considered with doses of 100 mg – 500 mg/m² body surface.

Dosage and duration of use of Calcium folinate primarily depend on the type and dosage of methotrexate therapy, the occurrence of toxicity symptoms, and the individual excretion capacity for methotrexate. As a rule, the first dose of Calcium folinate is 15 mg (6-12 mg/m²) to be given 12-24 hours (24 hours at the latest) after the beginning of the methotrexate infusion. The same dose is given every 6 hours throughout a period of 72 hours. After several parenteral doses treatment can be switched over to the oral form.

In addition to calcium folinate administration, measures to ensure the rapid excretion of methotrexate (maintenance of high urine output and alkalinisation of urine) are integral parts of the Calcium Folinate Rescue treatment. Renal function should be monitored by measuring serum creatinine levels daily.

The residual methotrexate-level, in the blood, should be measured, forty-eight hours after the start of the methotrexate-infusion. If the residual methotrexate-level is >0.5 µmol/l, then the dosage of calcium folinate dosages should be adapted according to the following table:

In combination with 5-fluorouracil in cytotoxic therapy

Different regimens and different dosages are used, however, no optimal dosage or regimen have been determined.

The following regimens have been used in adults and the elderly in the treatment of advanced or metastatic colorectal cancer and are given as examples. There are no data on the use of calcium folinate in combination with 5-fluorouracil in children:

Bimonthly regimen

Calcium folinate 200mg/m² by intravenous infusion over two hours, followed by an intravenous bolus of 400 mg/m² of 5-Fluorouracil and a 22-hour intravenous infusion of 5-Fluorouracil (600 mg/m²) for 2 consecutive days, every 2 weeks on days 1 and 2.

Weekly regimen

Calcium folinate 20mg/m² by intravenous bolus. injection or 200 to 500 mg/m² intravenous. infusion over a period of 2 hours, plus 500 mg/m² 5-fluorouracil as an intravenous bolus injection in the middle, or at the end, of the calcium folinate infusion.

Monthly regimen

Calcium folinate 20 mg/m² by bolus i.v. injection or 200 to 500 mg/m² as i.v. infusion over a period of 2 hours immediately followed by 425 or 370 mg/m² 5-fluorouracil as an intravenous bolus injection over five consecutive days.

For the use of calcium folinate in combination with 5-fluorouracil, modification of the 5-fluorouacil dosage and the treatment-free interval may be necessary depending on patient condition, clinical response and dose limiting toxicity as stated in the product information of 5-fluorouracil. A reduction of calcium folinate dosage is not required.

The number of repeat cycles used is at the discretion of the clinician.

Antidote to the folic acid antagonists trimetrexate, trimethoprime, and pyrimethamine

Trimetrexate toxicity

• Prevention: Calcium folinate should be administered every day during treatment with trimetrexate and for 72 hours after the last dose of trimetrexate. Calcium folinate can be administered either intravenous route at a dose of 20 mg/m² for 5 to 10 minutes every 6 hours for a total daily dose of 80 mg/m², or by oral route with four doses of 20 mg/m² administered at equal time intervals. Daily doses of calcium folinate should be adjusted depending on the haematological toxicity of trimetrexate.
• Over dosage (possibly occurring with trimetrexate doses above 90 mg/m² without concomitant administration of calcium folinate): after stopping trimetrexate, calcium folinate 40 mg/m² IV every 6 hours for 3 days.

Trimethoprime toxicity

After stopping trimethoprime, 3-10 mg/day calcium folinate until recovery of a normal blood count.

Pyrimethamine toxicity

In cases of high dose pyrimethamine or prolonged treatment with low doses, calcium folinate 5 to 50 mg/day should be simultaneously administered, based on the results of the peripheral blood counts.

Method of administration

Calcium folinate should only be given by intramuscular or intravenous injection and must not be administered intrathecally.

Death has been reported when folinic acid has been administered intrathecally, following intrathecal overdose of methotrexate.

In the case of intravenous administration, no more than 160mg of calcium folinate should be injected per minute due to the calcium content of the solution.

For intravenous infusion, calcium folinate may be diluted with 0.9% sodium chloride solution or 5% glucose solution before use. For instructions on dilution of the product before administration, see section 6.6.

There have been no reported sequelae in patients who have received significantly more calcium folinate than the recommended dosage. However, excessive amounts of calcium folinate may nullify the chemotherapeutic effect of folic acid antagonists.

Should over-dosage of the combination of 5-fluorouracil and calcium folinate occur, the over-dosage instructions for 5-FU should be followed.

Unopened: 2 years.

After dilution for infusion: Chemical and physical in-use stability has been demonstrated for 28 days at 2°C to 8°C after dilution with sodium chloride 0.9 % to concentrations of 0.2 mg/ml and 4.0 mg/ml.

Chemical and physical in-use stability has been demonstrated for 4 days at 2°C to 8°C after dilution with glucose 5 % to a concentration of 0.2 mg/ml and for 28 days at 2°C to 8°C after dilution to a concentration of 4.0 mg/ml.

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 normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2-8°C).

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

The solution for injection/infusion is packed in amber glass type I vials with grey bromobutyl rubber stopper and sealed with aluminum flip-off seals.

Available pack sizes:

1, 5, 10 vial with 3 ml
1, 5, 10 vial with 5 ml
1 vial with 10 ml
1 vial with 20 ml
1 vial with 35 ml
1 vial with 50 ml
1 vial with 100 ml

Not all pack sizes may be marketed.

Prior to administration, calcium folinate should be inspected visually. The solution for injection/infusion should be a clear yellowish solution. If cloudy in appearance or particles are observed, the solution should be discarded.

Dilution for infusion

Based on the required dose for the patient expressed in mg, the corresponding amount of solution for injection/infusion containing 10 mg/ml calcium folinate is aseptically withdrawn from the vial(s) and then diluted with 0.9 % sodium chloride solution or 5 % glucose solution.

For single use only. Discard any unused solution immediately after initial use.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.