Kalciumfolinat Stada
SUMMARY OF THE PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Kalciumfolinat STADA, 10 mg/ml, solution for injection.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml Kalciumfolinat STADA 10 mg/ml solution for injectioncontains 10.8 mg of calcium folinate, equivalent to 10 mg folinic acid.
One vial with 10 ml contains 108 mg of calcium folinate equivalent to 100 mg folinic acid
One vial with 20 ml contains 216 mg of calcium folinate equivalent to 200 mg folinic acid
One vial with 50 ml contains 540 mg of calcium folinate equivalent to 500 mg folinic acid
One vial with 100 ml contains 1080 mg of calcium folinate equivalent to 1000 mg folinic acid
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection
Clear, slightly yellow to yellow solution
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Calcium folinate is used to diminish the toxicity and counteract the action of folic acid antagonists such as methotrexate in cytotoxic therapy. This procedure is commonly known as “Calcium Folinate Rescue”.
Treatment of advanced colorectal cancer in combination with 5-fluorouracil (5-FU).
4.2 Posology and method of administration
Calcium folinate is administered parenterally as intramuscular injection or intravenous injection or infusion. Do not administer calcium folinate intrathecally. 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.
As a rule calcium folinate rescue has to be performed by parenteral administration in patients with malabsorption syndromes or other gastrointestinal disorders (vomiting, diarrhoea, subileus etc.) where enteral absorption is not assured. Dosages above 50 mg should be given parenterally.
For intravenous infusion, calcium folinate may be diluted with 0.9 % sodium chloride solution or 5 % glucose solution before use. Refer also to 6.3 and 6.6.
Calcium folinate rescue in methotrexate therapy:
Since the calcium folinate rescue dosage regimen heavily depends 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 for a calcium folinate rescue dosage regimen.
Calcium folinate rescue in intermediate- and high-dose methotrexate therapy:
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.
Since tolerance to folic acid antagonists depends on various factors there are no strict guidelines for the calcium folinate dosage as a function of the methotrexate dose.
Dosage and duration of use of calcium folinate primarily depend on the type and dosage of methotrexate therapy and/or on the occurrence of toxicity symptoms. 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.
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 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 |
Laboratory tests: Patients receiving calcium folinate after therapy with methotrexate, including overdosage or reduced clearance of methotrexate, should be monitored and the levels of creatinine and methotrexate in serum should be measured in 24 hr intervals. The dosage of calcium folinate should be adjusted according to the results of the laboratory tests.
In combination with 5-fluorouracil as treatment for advanced or metastatic colorectal cancer:
Different regimens and different dosages are used, without any dosage having been proven to be the optimal dosage.
The following regimens have been used in adults:
Weekly regimen: 20 or 200 mg/m² calcium folinate as IV infusion over a period of 2 hours plus 500 mg/m² 5-fluorouracil as IV bolus injection in the middle or at the end of the calcium folinate infusion.
Monthly regimen: once a month during 5 consecutive days: 20 or 200 mg/m² calcium folinate bolus immediately followed by 425 or 370 mg/m² 5-fluorouracil as IV bolus injection.
For the combination therapy with 5-fluorouracil, modification of the 5-fluorouracil 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.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Calcium folinate should not be used for the treatment of pernicious anaemia or other megaloblastic anaemias caused by vitamin B12 deficiency. Although haematological remissions may occur, the neurological manifestations remain progressive.
4.4 Special warnings and precautions for use
Calcium folinate should only be used with methotrexate or 5-fluorouracil under the direct supervision of a clinician experienced in the use of cancer chemotherapeutic agents.
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.
Excessive calcium folinate doses must be avoided since this might impair the antitumour 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.
For specific details on reduction of methotrexate toxicity refer to the SPC of methotrexate.
Many cytotoxic medicinal products – direct or indirect DNA synthesis inhibitors – lead to macrocytosis (hydroxycarbamide, cytarabine, mercaptopurine, thioguanine). Such a macrocytosis is not considered to be treated by folinic acid.
In combination regimen with 5-fluorouracil, the toxicity risk of 5-fluorouracil is increased by calcium folinate, particularly in older people or debilitated patients. The most common manifestations are leucopenia, mucositis, and/or diarrhoea which may be dose limiting. When calcium folinate and 5-fluorouracil are used in the treatment of colorectal cancer, the 5-fluorouracil dosage has to be reduced more in cases of toxicity than when 5-fluorouracil is used alone. The toxicities observed in patients treated with the combination therapy are qualitatively similar to those observed in patients treated with 5-fluorouracil monotherapy. Gastrointestinal toxicities are observed more commonly and may be more severe and even life threatening. In severe cases the combination of calcium folinate and 5-fluorouracil must be withdrawn.
When calcium folinate has been administered intrathecally following intrathecal overdose of methotrexate, a death has been reported.
In epileptic patients treated with phenobarbital, phenytoin, primidone, there is a risk to increase the frequency of seizures due to 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 4.5).
4.5 Interaction with other medicinal products and other forms of interaction
When calcium folinate is given in conjunction with a folic acid antagonist (e.g. cotrimoxazole, pyrimethamine) the efficacy of the folic acid antagonist may either be reduced or completely neutralised.
Calcium folinate may diminish the effect of anti-epileptic substances: phenobarbital, primidone, phenytoin and succinimides, and may increase the frequency of seizures (a decrease of plasma levels of enzymatic inductor anticonvulsant drugs may be observed because the hepatic metabolism is increased as folates are one of the cofactors).
Concomitant administration of calcium folinate with 5-fluorouracil has been shown to enhance the efficacy and toxicity of 5-fluorouracil (see section 4.2, 4.4 and 4.8).
4.6 Fertility, pregnancy and lactation
Methotrexate therapy is contraindicated during pregnancy and lactation. Should, after corresponding exact diagnosis, treatment with methotrexate take place despite pregnancy or lactation there are no limitations as to the use of calcium folinate for prophylaxis of methotrexate toxicity (calcium folinate rescue).
There is no experience in treatment of pregnant or nursing women with the combination of calcium folinate / 5-fluorouracil and/or other antineoplastic agents, however, such a treatment is generally contraindicated during pregnancy and lactation, even under inclusion of calcium folinate.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. Calcium folinate is however not expected to affect the ability.
If calcium folinate is used concomitantly with 5-fluorouracil, the risk of experiencing adverse events caused by 5-fluorouracil (e.g., dizziness, drowsiness, vision disorders, and nausea) may be enhanced. Therefore, patients receiving this combination should not drive or use machines.
4.8 Undesirable effects
Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000) very rare (< 1/10,000) and not known (cannot be estimated from the available data).
Both therapeutic indications:
Immune system disorders
Very rare: allergic reactions, including anaphylactoid / anaphylactic reactions, and urticaria.
Psychiatric disorders
Rare: insomnia, agitation and depression after high doses.
Gastrointestinal disorders
Rare: gastrointestinal disorders after high doses.
Nervous system disorders
Rare: increase in the frequency of attacks in epileptics (see also section 4.5).
General disorders and administration site conditions
Uncommon: fever has been observed after administration of calcium folinate as solution for injection.
Combination therapy with 5-fluorouracil:
Generally, the safety profile depends on the applied regimen of 5-fluorouracil due to enhancement of the 5-fluorouracil induced toxicities.
Metabolism and Nutritional Disorder
Not known: hyperammonaemia
Blood and lymphatic system disorders
Very common: bone marrow failure, including fatal cases
General disorders and administration site conditions
Very common: mucositis, including stomatitis and cheilitis. Fatalities have occurred as a result of mucositis
Skin and subcutaneous tissue disorders
Common: Palmar-Plantar Erythrodysaesthesia
Monthly regimen:
Gastrointestinal disorders
Very common: vomiting and nausea
No enhancement of other 5-fluorouracil induced toxicities (e.g. neurotoxicity).
Weekly regimen:
Gastrointestinal disorders
Very common: diarrhoea with higher grades of toxicity, and dehydration, resulting in hospital admission for treatment and even death.
Reporting of suspected adverse reactions
Reporting 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 national reporting system listed in Appendix V.
4.9 Overdose
The acute toxicity is low. Overdosing does not generally give any symptoms and symptomatic treatment of overdosing is probably not needed.
Should overdosage of the combination of 5-fluorouracil with calcium folinate occur, follow the overdosage instructions for 5-fluorouracil.
When using methotrexate, an overdosage of calcium folinate may result in a decrease of efficacy of methotrexate („over-rescue“) (see section 4.4).
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC code: V03AF03
Pharmacotherapeutic group: Detoxifying agents for antineoplastic treatment.
Folinic acid is a formyl derivate of folic acid, a nutritional factor essential for the human organism. It is involved in various metabolic processes, e.g. purine synthesis, pyrimidine nucleotide synthesis and amino acid metabolism.
Folinic acid is mainly used to cancel the effects of folic acid antagonists such as methotrexate. The substance on the other hand strengthens the effect of fluoropyrimidines such as 5-fluorouracil.
Methotrexate competitively inhibits the dihydrofolate reductase and thereby prevents the formation of reduced folates in the cell. As a consequence, it inhibits DNA, RNA and protein synthesis.
The folinic acid released from calcium folinate is rapidly converted into the active 5-methyl-tetrahydrofolic acid (calcium folinate rescue). Unlike folic acid, folinic acid does not require a reduction by dihydrofolate reductase. Therefore, dihydrofolate reductase blockers have no effect on folinic acid.
The effect of methotrexate primarily depends on the rate of cell division and therefore it exerts its cytostatic effect on all rapidly growing tissues, i.e. in addition to tumour tissue also on other rapidly proliferating tissues (skin and mucosa, hematopoietic bone marrow, gonads). These vital tissues and organs can be protected from the cellular toxicity of methotrexate by calcium folinate (5-formyl-THF = folinic acid = citrovorum factor).
The cytotoxic effect of 5-fluorouracil consists of the binding of FdUMP to thymidylate synthase, thereby inhibiting the activity of thymidylate synthase. Administration of calcium folinate results in higher amounts of folate cofactors, which enhance the binding between FdUMP and thymidylate synthase.
5.2 Pharmacokinetic properties
Absorption
Following intramuscular application of the aqueous solution, systemic availability is comparable to an intravenous application. However, lower peak serum levels (Cmax) are achieved.
Distribution
The distribution volume of folinic acid is not known.
Peak serum levels of the parent substance (D/L-5-formyl-tetrahydrofolic acid, folinic acid) are reached 10 minutes after IV administration.
AUC for L-5-formyl-THF and 5-methyl-THF were 28.4±3.5 mg.min/l and 129±112 mg.min/l after a dose of 25 mg. The inactive D-isomer is present in higher concentration than L-5-formyl-tetrahydrofolate.
Biotransformation
Calcium folinate is a racemate where the L-form (L-5-formyl-tetrahydrofolate, L-5-formyl-THF), is the active enantiomer.
The major metabolic product of folinic acid is 5-methyl-tetrahydrofolic acid (5-methyl-THF) which is predominantly produced in the liver and intestinal mucosa.
Elimination
The elimination half-life is 32 – 35 minutes for the active L-form and 352 – 485 minutes for the inactive D-form, respectively.
The total terminal half‑life of the active metabolites is about 6 hours (after intravenous and intramuscular administration).
Excretion
80-90 % with the urine (5- and 10-formyl-tetrahydrofolates inactive metabolites), 5-8 % with the faeces.
5.3 Preclinical safety data
Preclinical test results showed no risks not previously known from clinical experience (see other sections of the SmPC).
No mutagenic effects are expected at physiological dosages. Long-term studies on the tumorigenic potential of folinic acid as well as animal studies for clarification of reproductive toxicological properties are not available.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Trometamol
Hydrochloric acid, conc.
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in 6.6.
6.3 Shelf‑life
2 years.
Shelf-life after dilution
Chemical and physical in-use stability after dilution in 5 % glucose solution or 0.9 % sodium chloride solution has been demonstrated for 72 hours at +2 °C to +8 °C and at +25 °C, when protected from light.
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 °C to +8 °C, unless dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Store in a refrigerator (2 °C – 8 °C).
Keep the vial in the outer carton in order to protect from light.
6.5 Nature and content of container
Brown vials (type I glass) with chlorobutyl/butyl rubber stopper and aluminium overseal.
Clear vials (type I glass) with chlorobutyl/butyl rubber stopper and aluminium overseal.
Package sizes:
1 x 10 ml and 5 x 10 ml solution for injection
1 x 20 ml and 5 x 20 ml solution for injection
1 x 50 ml and 5 x 50 ml solution for injection
1 x 100 ml and 5 x 100 ml solution for injection
6.6 Special precautions for disposal
If necessary Kalciumfolinat STADA may be diluted with the following solutions for infusion: 5 % glucose solution or 0.9 % sodium chloride solution.
The medicinal product is for single use only. Any unused solution should be discarded.
The solution for injection should be inspected visually prior to use. Only clear solutions without particles should be used.
7. MARKETING AUTHORISATION HOLDER
STADA Arzneimittel AG
Stadastrasse 2-18
61118 Bad Vilbel
Germany
8. MARKETING AUTHORISATION NUMBER(S)
16728
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
2002-05-03/2007-05-03
10. DATE OF REVISION OF THE TEXT