Medicinal Products

ELVORINE 100 mg / 10 mL

Generic drug of the therapeutic class: Oncology and Hematology
active ingredients: Calcium levofolinate
laboratory: Pfizer Holding France

Injectable solution
Box of 1 bottle of 10 ml
All forms

Indication

Calcium levofolinate is indicated:
in combination with 5-fluorouracil in cytotoxic therapy.
to reduce the toxicity and counteract the action of folic acid antagonists such as methotrexate in the case of use in cytotoxic therapy and in case of overdose in adults and children. In cytotoxic therapy, this procedure is commonly referred to as "folinic rescue".

Dosage ELVORINE 100 mg / 10 mL Solution for injection Box of 1 vial of 10 ml

- For intravenous and intramuscular administration only .
- In the case of intravenous administration, not more than 80 mg of calcium levofolinate per minute should be injected due to the amount of calcium contained in the solution.
For intravenous infusions calcium levofolinate may be diluted before use in 0.9% sodium chloride solution or in 5% glucose solution. See also sections special precautions for storage and instructions for use, handling and disposal.
- In combination with 5-fluorouracil in cytotoxic therapy :
Administration of calcium levofolinate should be given before 5-fluorouracil and vein only.
Different regimens and dosages are used, without any dosage being shown to be optimal.
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 these associations in children.
. Bi-monthly schedule: Calcium levofolinate 100 mg / m² intravenous infusion for 2 hours followed by bolus injection of 5-fluorouracil 400 mg / m² and infusion of 5-fluorouracil (600 mg / m²) 22 hours, on 2 consecutive days, every 2 weeks on days 1 and 2.
. Weekly schedule: 10 mg / m² calcium levofolinate by intravenous bolus injection or 100 to 250 mg / m² intravenous infusion over 2 hours plus 500 mg / m² 5-fluorouracil intravenous bolus injection, in the middle or at the end of the calcium levofolinate infusion.
. Monthly schedule: Calcium levofolinate 10 mg / m² intravenous bolus injection or 100 to 250 mg / m² intravenous infusion over 2 hours followed immediately by intravenous bolus injection of 425 or 370 mg / m² fluorouracil for 5 consecutive days.
For treatment with 5-fluorouracil, changes in 5-fluorouracil dosage and untreated intervals may be required depending on the patient's condition, clinical response and toxicity limit dose as mentioned. in the product information of 5-fluorouracil. A reduction in the dosage of calcium levofolinate is not required.
The number of repeated cycles to be administered will be determined by the clinician.
- Prevention of the toxicity of methotrexate (folinic rescue) :
. Since the folinic rescue regimen is strongly dependent on the dosage and method of administration of intermediate or high dose methotrexate, the methotrexate protocol will guide the folinic rescue regimen. Therefore, for the dosage and method of administration of calcium levofolinate, it is preferable to refer to the protocol applied when administering intermediate or high dose methotrexate.
The following guidelines can serve as an example of diagrams used in adults, the elderly and children:
Folinic salvage should be performed parenterally in patients with malabsorption syndromes or other gastrointestinal disorders when enteral absorption is not assured. Doses greater than 12.5-25 mg should be administered parenterally as enteral absorption with calcium levofolinate is saturable.
Folinic rescue is necessary when methotrexate is administered at doses exceeding 500 mg / m 2 body surface area and should be considered at doses of 100 mg to 500 mg / m 2 body surface area.
. The dose and duration of folinic rescue therapy depend mainly on the type and dosage of methotrexate therapy, the occurrence of toxicity symptoms, and the individual's ability to excrete methotrexate. As a rule, the first dose of levofolinate calcium is 7.5 mg (3-6 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 for a period of 72 hours. After several parenteral doses, the treatment may be reoriented to the use of the oral form.
. In addition to the administration of calcium levofolinate, measures to ensure rapid excretion of methotrexate (maintenance of high urine output and alkalinization of urine) are an integral part of folinic rescue treatment. Renal function should be evaluated daily by serum creatinine measurements.
. The residual level of methotrexate should be measured 48 hours after the beginning of the methotrexate infusion. If the residual level of methotrexate is> 0.5 μmol / L, the calcium levofolinate doses should be adjusted according to the following table:
Residual blood level of methotrexate 48 hours after the start of the administration of additional methotrexate / levofolinate calcium every 6 hours for 48 hours or at methotrexate levels below 0.05 μmol / L :
> = 0.5 μmol / L: 7.5 mg / m² .
> = 1.0 μmol / L: 50 mg / m² .
> = 2.0 μmol / L: 100 mg / m² .
- Antidote antagonists of folic acid, trimetrexate, trimethoprim and pyrimethamine :
. Toxicity of trimethoprim:
after stopping trimethoprim, administration of 1.5 to 5 mg per day of levofolinate calcium until normal blood count returns.
. Toxicity of pyrimethamine:
in the case of high doses of pyrimethamine or long-term low-dose treatment, 2.5 to 25 mg / day of levofolinic acid should be administered simultaneously, depending on the results of the peripheral blood counts.
. Toxicity of trimetrexate:
* Prevention : Calcium levofolinate should be administered daily during treatment with trimetrexate and for 72 hours after the last dose of trimetrexate. Calcium levofolinate can be administered either intravenously at a dose of 10 mg / m² for 5 to 10 minutes every 6 hours for a total daily dose of 40 mg / m². Daily doses of calcium levofolinate should be adjusted according to the haematological toxicity of trimetrexate.
* Overdose (possible with doses of trimetrexate greater than 90 mg / m² without concomitant administration of calcium levofolinate): after discontinuation of trimetrexate, administration of 20 mg / m² calcium levofolinate by intravenous injection every 6 hours for 3 days.

Against indications

- Known hypersensitivity to calcium levofolinate or to any of the excipients.
- Pernicious anemia or other anemia due to vitamin B12 deficiency.
When using calcium levofolinate in combination with 5-fluorouracil or methotrexate during pregnancy or lactation, refer to the Pregnancy and lactation section of the Summary of Product Characteristics for drugs containing methotrexate and 5- fluorouracil.
- Calcium levofolinate should be administered only intramuscularly or intravenously and should not be administered intrathecally.

Elvorine side effects

Immune system disorders

Very rare (<0.01%): allergic reactions, including anaphylactoid reactions and urticaria.

Psychiatric disorders

Rare (0.01-0.1%): insomnia, agitation and depression after high doses.

Gastrointestinal disorders

Rare (0.01-0.1%): gastrointestinal disorders after high doses.

Neurological disorders

Rare (0.01-0.1%): increased seizure frequency in epileptics (see also section Interactions with other drugs and other forms of interaction ).

General disorders and reactions at the injection site

Uncommon (0.1-1%): fever was observed after administration of calcium folinate injection.

Combined therapy with 5-fluorouracil:

Generally, the safety profile depends on the 5-fluorouracil administration regimen used due to the increase in 5-fluorouracil-induced toxicities:

Monthly plan:

Gastrointestinal disorders

Very common (> 10%): vomiting and nausea.

General Disorders and Conditions at the Administration Site

Very common (> 10%): mucosal toxicity (severe).

No increase in other toxicities induced by 5-fluorouracil (example neurotoxicity).

Weekly schedule:

Gastrointestinal disorders

Very common (> 10%): diarrhea with a high grade of toxicity, and dehydration, leading to hospitalization or even death.

Reporting of suspected adverse reactions

The reporting of suspected adverse reactions after authorization of the drug is important. It allows continuous monitoring of the benefit / risk ratio of the drug. Health professionals declare any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (Ansm) and the network of Regional Pharmacovigilance Centers. Website: www.ansm.sante.fr.

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