LEVOFOLINIC ACID Solution for injection/infusion Ref.[9512] Active ingredients: Levoleucovorin

Posology

Disodium levofolinate in combination with 5-fluorouracil in cytotoxic therapy

The combined use of disodium levofolinate and 5-fluorouracil is reserved for physicians experienced in the combination of folinates with 5-fluorouracil in cytotoxic therapy.

Different regimes and different doses are used, without any dose having been proven to be the optimal one. The following regimes have been used in adults and elderly in the treatment of advanced or metastatic colorectal cancer and are given as examples.

Bimonthly regimen: 100 mg/m² levofolinic acid (= 109.3 mg/m² disodium levofolinate) by intravenous infusion over two hours, followed by bolus 400 mg/m² of 5-fluorouracil and 22-hour infusion of 5-fluorouracil (600 mg/m²) for 2 consecutive days, every 2 weeks on days l and 2.

Weekly regimen: 10 mg/m² levofolinic acid (= 10.93 mg/m² disodium levofolinate) by bolus i.v. injection or 100 to 250 mg/m² levofolinic acid (= 109.3 mg/m² to 273.25 mg/m² disodium levofolinate) as i.v. infusion over a period of 2 hours plus 500 mg/m² 5-fluorouracil as i.v. bolus injection in the middle or at the end of the disodium levofolinate infusion.

Monthly regimen: 10 mg/m² levofolinic acid (= 10.93 mg/m² disodium levofolinate) by bolus i.v. injection or 100 to 250 mg/m² levofolinic acid (= 109.3 mg/m² to 273.25 mg/m² disodium levofolinate) as i.v. infusion over a period of 2 hours immediately followed by 425 or 370 mg/m² 5-fluorouracil as i.v. bolus injection during 5 consecutive days.

For the combination therapy with 5-fluorouracil, modification of the 5-fluorouracil dose 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 disodium levofolinate dose is not required.

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

Paediatric population

No data on the use of these combinations are available.

Disodium levofolinate rescue in methotrexate therapy

Since the disodium levofolinate rescue dose regimen depends heavily on the posology and method of the intermediate- or high-dose methotrexate administration, the methotrexate protocol will dictate the dose regimen of disodium levofolinate rescue. Therefore, it is best to refer to the applied intermediate or high dose methotrexate protocol for posology and method of administration of disodium levofolinate.

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

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

Doses above 12.5–25 mg levofolinic acid should be given parenterally due to saturable enteral absorption of disodium levofolinate.

Disodium levofolinate rescue is necessary when methotrexate is given at doses exceeding 500 mg/m² body surface and should be considered with doses of 100 mg–500 mg/m² body surface.

Dose and duration of disodium levofolinate rescue primarily depend on the type and dose of methotrexate therapy, the occurrence of toxicity symptoms, and the individual excretion capacity for methotrexate. As a rule, the first dose of levofolinic acid is 7.5 mg (3–6 mg/m²) to be given 12–24 hours (24 hours at the latest) after the beginning of 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 disodium levofolinate administration, measures to ensure the prompt excretion of methotrexate are important.

These measures include:

• Alkalinisation of urine so that the urinary pH is greater than 7.0 before methotrexate infusion (to increase solubility of methotrexate and its metabolites).
• Maintenance of urine output of 1800–2000 cc/m²/24 hr by increased oral or intravenous fluids on days 2, 3 and 4 following methotrexate therapy.
• Plasma methotrexate concentration, BUN and creatinine should be measured on days 2, 3 and 4.

These measures must be continued until the plasma methotrexate level is less than 10-7 molar (0.1 µM).

Delayed methotrexate excretion may be seen in some patients. This may be caused by a third space accumulation (as seen in ascites or pleural effusion for example), renal insufficiency or inadequate hydration. Under such circumstances, higher doses of disodium levofolinate or prolonged administration may be indicated. Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure.

Forty-eight hours after the start of the methotrexate infusion, the residual methotrexate-level should be measured. If the residual methotrexate-level is >0.5 µmol/l, disodium levofolinate doses should be adapted according to the following table:

Method of administration

Disodium levofolinate is administered intravenously, either undiluted by injection or by infusion after dilution. Disodium levofolinate should not be administered intrathecally.

Precautions to be taken before handling or administering the medicinal product

For instructions on dilution of the medicinal product before administration, see section 6.6.

There have been no reported sequelae in patients who have received significantly more disodium levofolinate than the recommended dose.

There is no specific antidote.

When using methotrexate, an overdose of disodium levofolinate may result in a decrease of efficacy of methotrexate (“over-rescue”).

Should overdose of the combination of 5-fluorouracil and disodium levofolinate occur, overdose instructions for 5-fluorouracil should be followed.

3 years.

After mixing with 5-fluorouracil or dilution with sodium chloride 9 mg/ml (0.9%) solution or 5% glucose solution (see section 6.6): Chemical and physical in-use stability has been demonstrated for 72 hours at 20–25°C.

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 2–8°C unless dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2°C–8°C). 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 vials type I with bromobutyl rubber stoppers and aluminium flip-off caps.

Pack sizes: Vials with 1 ml, 4 ml, or 9 ml solution for injection/infusion in packs of 1 or 5 vials. Not all pack sizes may be marketed.

Levofolinic acid is administered intravenously, either undiluted by injection or by infusion after dilution. Preparation of solution for infusion must take place in aseptic conditions. The solution for injection/infusion may be diluted with sodium chloride 9 mg/ml (0.9%) solution or 5% glucose solution.

Levofolinic acid is compatible with 5-fluorouracil.

Only clear solutions without visible particles should be used.

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