Summary of Product Characteristics Updated 31-May-2016 | Pfizer Limited
Excipients with known effect:Sodium hydroxideFor the full list of excipients, see section 6.1.
Calcium folinate rescue in methotrexate therapy:Since the calcium folinate rescue dosage regimen depends heavily on the posology and method of the intermediate- or high-dose methotrexate administration, the methotrexate protocol will dictate the dosage regimen of calcium folinate rescue. Therefore, it is best to refer to the applied intermediate or high dose methotrexate protocol for posology and method of administration of calcium folinate.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 should be considered with doses of 100 mg 500 mg/m2 body surface. Dosage and duration of calcium folinate rescue 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 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 prompt 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 through daily measurements of serum creatinine.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, calcium folinate dosages should be adapted according to the following table:
|Residual methotrexate blood level 48 hours after the start of the methotrexate administration:||Additional calcium folinate to be administered every 6 hours for 48 hours or until levels of methotrexate are lower than 0.05 µmol/l:|
|≥0.5 µmol/l||15 mg/m2|
|≥1.0 µmol/l||100 mg/m2|
|≥2.0 µmol/l||200 mg/m2|
Antidote to the folic acid antagonists trimetrexate, trimethoprim, 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 by the 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.• Overdosage (possibly occurring with trimetrexate doses above 90 mg/m2without concomitant administration of calcium folinate): after stopping trimetrexate, calcium folinate 40 mg/m2 IV every 6 hours for 3 days.
Trimethoprim toxicity:• After stopping trimethoprim, 3-10 mg/day calcium folinate until recovery of a normal blood count.
Pyrimethamine toxicity:• In case 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 administrationFor intravenous and intramuscular administration only. In the case of intravenous administration, no more than 160 mg 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. (see sections 6.3 and 6.6).
GeneralCalcium folinate should be used with methotrexate only under the direct supervision of a clinician experienced in the use of cancer chemotherapeutic agents.Calcium folinate treatment may mask pernicious anaemia and other anaemias resulting from vitamin B12 deficiency.Many cytotoxic medicinal products direct or indirect DNA synthesis inhibitors lead to macrocytosis (hydroxycarbamide, cytarabine, mecaptopurine, thioguanine). Such macrocytosis should not be treated with folinic acid.In epileptic patients treated with phenobarbital, phenytoin, primidone, and succinimides there is a risk to increase the frequency of seizures due to a decrease of plasma concentrations of anti-epileptic drugs. Clinical monitoring, possibly monitoring of the plasma concentrations and, if necessary, dose adaptation of the anti-epileptic drug during calcium folinate administration and after discontinuation is recommended (see also section 4.5 Interactions).
Calcium folinate/methotrexateFor specific details on reduction of methotrexate toxicity refer to the SPC of methotrexate.Calcium folinate has no effect on non-haematological toxicities of methotrexate such as the nephrotoxicity resulting from methotrexate and/or metabolite precipitation in the kidney. Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure and all toxicities associated with methotrexate (please refer to the SPC for methotrexate). The presence of pre-existing- or methotrexate-induced renal insufficiency is potentially associated with delayed excretion of methotrexate and may increase the need for higher doses or more prolonged use of calcium folinate.Excessive calcium folinate doses must be avoided since this might impair the antitumor activity of methotrexate, especially in CNS tumours where calcium folinate accumulates after repeated courses. Resistance to methotrexate as a result of decreased membrane transport implies also resistance to folinic acid rescue as both medicinal products share the same transport system.An accidental overdose with a folate antagonist, such as methotrexate, should be treated as a medical emergency. As the time interval between methotrexate administration and calcium folinate rescue increases, calcium folinate effectiveness in counteracting toxicity decreases.The possibility that the patient is taking other medications that interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be considered when laboratory abnormalities or clinical toxicities are observed.Refolinon solution for injection contains sodium 2.2mg/ml. To be taken into consideration by patients on a controlled sodium diet.
Breast-feedingIt is not known whether calcium folinate is excreted into human breast milk. Calcium folinate can be used during breast feeding when considered necessary according to the therapeutic indications.
Very common (≥1/10)
Common (≥1/100 to <1/10);
Uncommon (≥1/1000 to <1/100);
Rare (≥1/10,000 to <1/1000);
Very rare (<1/10,000);
Not known (cannot be estimated from the available data).Immune system disordersVery rare (<1/10,000): allergic reactions, including anaphylactoid/ anaphylactic reactions and urticaria. Psychiatric disordersRare (≥1/10,000 to <1/1000): insomnia, agitation and depression after high doses. Gastrointestinal disorders Rare (≥1/10,000 to <1/1000): gastrointestinal disorders after high doses. Neurological disordersRare (≥1/10,000 to <1/1000): increase in the frequency of attacks in epileptics (see also section 4.5). General disorders and administration site conditionsUncommon (≥1/1000 to <1/100): fever has been observed after administration of calcium folinate as solution for injection.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
Droperidol1. Droperidol 1.25 mg/0.5 ml with calcium folinate 5 mg/0.5 ml, immediate precipitation in direct admixture in syringe for 5 minutes at 25° C followed by 8 minutes of centrifugation. 2. Droperidol 2.5 mg/0.5 ml with calcium folinate 10 mg/0.5 ml, immediate precipitation when the drugs were injected sequentially into a Y-site without flushing the Y-side arm between injections.
FluorouracilCalcium folinate must not be mixed in the same infusion as 5-fluorouracil because a precipitate may form. Fluorouracil 50 mg/ml with calcium folinate 20 mg/ml, with or without dextrose 5% in water, has been shown to be incompatible when mixed in different amounts and stored at 4°C, 23°C, or 32° C in polyvinyl chloride containers.
FoscarnetFoscarnet 24 mg/ml with calcium folinate 20 mg/ml formation of a cloudy yellow solution reported.
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