• 19.06 mg calcium folinate-5 water

• lactose-1 water
• cellulose powder
• Carboxymethyl Starch, Sodium
• Corn starch, pregelatinized
• magnesium stearate

indication

• The medicine is a detoxifying agent when using certain medicines to treat cancer and a means of preventing folic acid deficiency symptoms.
• The medicinal product is used for
  • 1. Prevention of symptoms of poisoning with (medium) high-dose methotrexate therapy or persistently high methotrexate serum levels (also with low-dose methotrexate therapies).
    • A notice:
      • Persistently high methotrexate serum levels are to be expected in particular in the case of pleural effusions, ascites, renal insufficiency and insufficient fluid intake during methotrexate therapy.
  • 2. Treatment of symptoms of intoxication from methotrexate therapy that can be attributed to tetrahydrofolic acid deficiency.
  • 3. Treatment of folic acid deficiencies of various causes that cannot be remedied by dietary measures.
    • Hints:
      • With this treatment, a vitamin B12 deficiency should be excluded in the differential diagnosis.
      • In contrast to the areas of application mentioned under 1. and 2., the use of folic acid is sufficient here.

dosage

• Always take this medicine exactly as described or as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.
• The preventive use of previous methotrexate use in cancer therapy is reserved for physicians who have sufficient experience in high-dose methotrexate therapy.
• Unless otherwise prescribed by the doctor, the usual dose is:
  • 1) in the prevention of symptoms of intoxication caused by tetrahydrofolic acid deficiency in methotrexate therapy (calcium folinate rescue):
    • From a methotrexate dosage of about 100 mg/m ² body surface area (BSA), this treatment must be followed by the administration of calcium folinate. There are no uniform recommendations for the dosage and type of application of calcium folinate as an antidote in high-dose methotrexate shock therapy, so the following dosage recommendations are given as examples:
    • Calcium folinate rescue after methotrexate (MTX) therapy:
      • MTX serum level 24 - 30 h: 1 x 10 ^-8 mol/l to < 1.5 x 10 ^-6 mol/l
        • Calcium folinate dose: 10 - 15 mg/m ² BSA every 6 hours
        • Duration: 48 hours
      • MTX serum level 24 - 30 hours: 1.5 x 10 ^-6 mol/l to 5 x 10 ^-6 mol/l
        • Calcium folinate dose: 30 mg/m ² BSA every 6 h
        • Duration: until the plasma level is < 5 x 10 ^-8 mol/l
      • MTX serum level 24 - 30 hours: > 5 x 10 ^-6 mol/
        • Calcium folinate dose: 60 - 100 mg/m ² BSA every 6 hours
        • Duration: until the plasma level is < 5 x 10 ^-8 mol/l
    • Calcium folinate is used orally. However, patients with absorption disorders (e.g. vomiting) must be excluded from oral calcium folinate rescue. The absorption of orally administered calcium folinate is subject to a saturation mechanism. With oral administration of calcium folinate doses above 40 mg, the bioavailability is reduced.
    • Beginning of calcium folinate protection:
      • No later than 18-30 hours after the start of the methotrexate infusion.
    • End of Calcium Folinate Protection:
      • Not earlier than 72 hours after the start of the methotrexate infusion. Upon termination of calcium folinate use, the methotrexate serum level should be below 10 ^-7 mol/l, preferably below 10 ^-8 mol/l.
      • A dosage that goes beyond the protective function ("over-rescue") can lead to impairment of the effectiveness of methotrexate. If protection is insufficient, high-dose methotrexate shock therapy can lead to considerable toxic side effects (see instructions for use of methotrexate-containing medicines).
  • 2) in the treatment of symptoms of intoxication from low-dose methotrexate therapy (single dose < 100 mg/m ² KO), which can be attributed to tetrahydrofolic acid deficiency:
    • Immediately administer an amount of calcium folinate IV or IM equivalent to 6-12 mg of folinic acid. Then apply the same dose several times (at least four times) at intervals of 3 to 6 hours.
    • For more intensive calcium folinate rescue in the case of delayed methotrexate excretion under medium-high or high-dose methotrexate therapy, reference is made to the specialist literature.
    • A notice:
      • If the poisoning is caused by a significantly delayed excretion (e.g. [acute] kidney failure), dialysis can be considered.
    • To note:
      • The prophylactic administration of calcium folinate in methotrexate therapy requires the possibility of determining the methotrexate serum level.
  • 3) in the treatment of folic acid deficiencies:
    • 5 mg (up to a maximum of 15 mg) of folinic acid daily.

• If you take more than you should:
  • No special measures are required in the event of an overdose.

• If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

way

• For ingestion.

side effects

• Like all medicines, this medicine can cause side effects, although not everybody gets them.
• The following side effects have been observed:
  • Rare (may affect up to 1 in 1,000 people)
    • Increase in seizure frequency in patients with epilepsy
    • depression
    • restlessness
    • Disorders of the digestive system
    • sleep disorders (insomnia)
  • Very rare (may affect up to 1 in 10,000 people)
    • severe allergic reaction - you may have a sudden itchy rash (hives), swelling of your hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing), or fainting. It's a serious side effect. You may need urgent medical treatment.
    • wheals (urticaria)
  • Not known (cannot be estimated from the available data)
    • toxic epidermal necrolysis (TEN): severe skin reaction including loss of skin
    • Stevens-Johnson syndrome (SJS): severe skin reaction with a blistering rash and skin inflammation, particularly on the hands, feet and around the mouth, accompanied by fever.
• If you get any side effects, talk to your doctor or pharmacist. This also applies to side effects that are not specified.

interactions

• Taking with other medicines
  • Tell your doctor or pharmacist if you are taking/using, have recently taken/used or might take/use any other medicines.
  • Calcium folinate/ methotrexate
    • For specific details on reducing methotrexate toxicity, please refer to the methotrexate package insert.
    • The preparation has no effect on non-blood toxicity of methotrexate (non-haematological toxicity), such as toxicity to the kidney (nephrotoxicity, as a result of methotrexate and/or the precipitation of methotrexate degradation products in the kidney). Patients with delayed early elimination of methotrexate (methotrexate elimination) have a high probability of developing reversible renal failure and all methotrexate-related toxicities (please see methotrexate package insert).
    • Excessive doses of calcium folinate must be avoided as they can reduce the antitumor activity of methotrexate. This is particularly true in tumors of the central nervous system, in which the active substance of calcium folinate accumulates after repeated courses of treatment.
    • Insensitivity to methotrexate (methotrexate resistance) as a result of reduced transport across the membranes into the cells also suggests resistance to calcium folinate treatment since both drugs have the same transport mechanism.
    • An accidental overdose of a cancer drug like methotrexate should be treated as a medical emergency. The longer the time interval between methotrexate use and calcium folinate treatment (calcium folinate rescue), the less effective calcium folinate is as a countermeasure to reduce toxicity.
    • The possibility that the patient is taking other drugs that interact with methotrexate (eg, drugs that interfere with methotrexate elimination or binding to serum albumin) should always be considered if laboratory abnormalities or clinical toxicities are observed.
    • Calcium folinate/ 5-fluorouracil
      • Calcium folinate can increase the toxicity of fluorouracil.
    • Calcium folinate/ chloramphenicol
      • The concomitant use of chloramphenicol and folic acid in patients with a folic acid deficiency is not recommended, as it can negate the effectiveness of folic acid.
    • Calcium folinate/ other folic acid antagonists
      • Simultaneous therapy with a folic acid antagonist (e.g. cotrimoxazole, pyrimethamine) and calcium folinate is not recommended, since the effectiveness of the folic acid antagonist can either be reduced or completely reversed.
    • Calcium folinate/other medicines
      • Calcium folinate may reduce the effects of the antiepileptic drugs phenobarbital, primidone, phenytoin and succinimide, leading to an increase in seizure frequency.

Contraindications

• The drug must not be taken
  • if you are allergic to calcium folinate, folic acid or any of the other ingredients;
  • if you suffer from malignant anemia: calcium folinate is not suitable for treating malignant anemia and other anemias caused by vitamin B12 deficiency; Although improvements in the blood count can occur, the symptoms on the part of the nervous system continue to progress.
• Please refer to the "Pregnancy Advice" category regarding treatment of pregnant or breastfeeding women with calcium folinate and methotrexate or fluorouracil.
• Please also note the package leaflets for medicines containing methotrexate and other medicines containing folic acid antagonists and fluorouracil if you are taking or using them.

pregnancy and breast feeding period

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

• What needs to be considered during pregnancy if
  • only calcium folinate is used (monotherapy)?
    • There is no evidence that the active ingredient folinic acid causes harmful effects when given during pregnancy.
  • Calcium folinate is used with other medicines?
    • Methotrexate (a drug used in cancer therapy) should only be used during pregnancy if there is a strong indication that the benefit of the drug to the mother is weighed against the possible risk to the foetus. If treatment with methotrexate or other folic acid antagonists takes place despite pregnancy or lactation, there are no restrictions with regard to the use of the preparation to reduce toxicity or to counteract the effects.
• What must be considered during breastfeeding?
  • It is not known whether the active substance calcium folinate is excreted in human breast milk. Calcium folinate can be used during lactation if considered necessary based on the therapeutic indications.
  • The use of fluorouracil is generally not indicated during pregnancy and breast-feeding; this also applies to the combined use of calcium folinate with fluorouracil.
  • Please also read the package leaflets for medicines containing methotrexate and other folic acid antagonists and fluorouracil if you are taking or using them.

patient notes

• Warnings and Precautions
  • Please talk to your doctor or pharmacist before taking this medicine.
    • If you have epilepsy and are being treated for it:
      • In epileptics treated with the active substances phenobarbital, phenytoin, primidone and succinimides there is a risk that the frequency of seizures will increase due to a decrease in the plasma concentrations of the antiepileptic drugs. Clinical monitoring is recommended during use of calcium folinate (the active substance in Leucovorin) and after stopping it, possibly monitoring the amount of active substance in the blood plasma (plasma levels) and, if necessary, adjusting the dose of the antiepileptic drug.
  • General
    • Calcium folinate should be used with methotrexate only under the direct supervision of a physician experienced in the use of cancer chemotherapy drugs.
    • Treatment with calcium folinate can mask malignant anemia and other anemias caused by vitamin B12 deficiency.
    • Many cytotoxic drugs - direct or indirect inhibitors of the synthesis of the hereditary substance DNA - lead to an enlargement of the red blood cells (macrocytosis) (hydroxycarbamide, cytarabine, mercaptopurine, thioguanine). Such macrocytosis should not be treated with this preparation.

• Ability to drive and use machines
  • There is no evidence that the preparation affects the ability to drive or use machines.