Calcium Folinate Kalceks
Folinic acid (as calcium folinate hydrate) — 10 mg/ml solution for injection/infusion
Calcium folinate Kalceks contains folinic acid (also known as leucovorin), a reduced form of folic acid used primarily as rescue therapy to counteract the toxic effects of methotrexate and other folate antagonists, and in combination with fluorouracil to enhance its anti-cancer activity in colorectal cancer treatment. This prescription-only injectable medication is administered intravenously or intramuscularly under hospital supervision.
Quick Facts
Key Takeaways
- Calcium folinate (leucovorin) is a reduced form of folic acid used as essential rescue therapy after high-dose methotrexate chemotherapy to protect healthy cells from toxic damage.
- When combined with fluorouracil (5-FU), it enhances the cytotoxic effect against colorectal cancer cells by stabilising the binding of 5-FU metabolites to thymidylate synthase.
- This medication must never be injected intrathecally (into the spinal fluid) and is contraindicated in patients with vitamin B12 deficiency anaemia (pernicious anaemia).
- Side effects when used alone are generally mild; however, when used with fluorouracil, serious toxicities including life-threatening bone marrow suppression and severe gastrointestinal inflammation can occur.
- The drug requires refrigerated storage (2–8 °C) and must be protected from light; once opened, it should be used immediately.
What Is Calcium Folinate Kalceks and What Is It Used For?
Calcium folinate Kalceks is a sterile solution for injection and infusion containing 10 mg/ml of folinic acid in the form of calcium folinate hydrate. Folinic acid is a naturally occurring, biologically active form of folic acid that belongs to a pharmacological group known as detoxifying agents for antineoplastic treatment. Unlike synthetic folic acid, folinic acid does not require enzymatic reduction by dihydrofolate reductase to become metabolically active, which makes it uniquely valuable in clinical medicine.
The medication is approved for two primary clinical indications. First, it is used as calcium folinate rescue therapy in both adults and children to reduce the harmful effects of, and to treat overdosage with, certain anti-cancer drugs such as methotrexate and other folic acid antagonists. High-dose methotrexate is a cornerstone of treatment for several malignancies including osteosarcoma, acute lymphoblastic leukaemia, and certain lymphomas. During these treatments, calcium folinate rescue is essential to limit damage to healthy rapidly-dividing cells such as those lining the gastrointestinal tract and in the bone marrow.
Second, calcium folinate is used in combination with fluorouracil (5-FU) for the treatment of colorectal cancer. In this setting, folinic acid modulates the pharmacological activity of fluorouracil by enhancing the stability of the ternary complex formed between fluorodeoxyuridylate monophosphate (FdUMP), thymidylate synthase, and methylenetetrahydrofolate. This biochemical interaction results in more sustained inhibition of thymidylate synthase, thereby potentiating the cytotoxic effect of fluorouracil against cancer cells. This combination remains a fundamental component of modern colorectal cancer regimens including FOLFOX and FOLFIRI protocols endorsed by the European Society for Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN).
Calcium folinate Kalceks is manufactured by AS KALCEKS (Latvia) and is authorised throughout the European Economic Area under various trade names. The medication is listed on the World Health Organization (WHO) Model List of Essential Medicines, underscoring its critical importance in modern healthcare. Available in vial sizes ranging from 5 ml (50 mg) to 100 ml (1000 mg), it provides flexible dosing options for diverse clinical scenarios.
What Should You Know Before Receiving Calcium Folinate Kalceks?
Contraindications
Calcium folinate Kalceks must not be administered if you are allergic to calcium folinate or any of the other ingredients in the medication (sodium chloride, sodium hydroxide, water for injections). It is also strictly contraindicated in patients with pernicious anaemia or other anaemias caused by vitamin B12 deficiency. In these conditions, folinic acid may mask the haematological manifestations of B12 deficiency while allowing the neurological complications to progress, potentially causing irreversible nerve damage.
When calcium folinate is used in combination with certain anti-cancer drugs, it must not be given to patients who are pregnant or breastfeeding. Your treating oncologist will determine which specific drug combinations carry this restriction. Under no circumstances should calcium folinate be injected intrathecally (into the cerebrospinal fluid surrounding the spinal cord). Intrathecal administration can cause serious, life-threatening complications.
Warnings and Precautions
Before receiving calcium folinate, it is essential to inform your healthcare team about all pre-existing medical conditions. Patients with kidney disease (renal impairment) may require higher doses of calcium folinate or a longer duration of rescue therapy, because impaired renal function delays the clearance of methotrexate from the body. Serum methotrexate levels should be monitored to guide the appropriate duration and dosing of rescue therapy.
Patients with epilepsy require careful monitoring during calcium folinate treatment. Folinic acid may reduce the effectiveness of anti-epileptic medications (phenobarbital, phenytoin, primidone, and succinimides) by lowering their plasma concentrations, potentially increasing the frequency of seizures. Your neurologist and oncologist should coordinate care to manage this interaction.
When calcium folinate is given together with fluorouracil, the toxicity of fluorouracil is significantly enhanced. This is particularly critical in elderly patients and those with a history of gastrointestinal disease. Inform your doctor if you have had previous radiation therapy, gastrointestinal disease, mouth inflammation (stomatitis), or if you are feeling very weak. Regular blood tests and liver/kidney function monitoring are mandatory during combined treatment.
Pregnancy and Breastfeeding
Calcium folinate used as a single agent does not cause harmful effects during pregnancy. However, the combination of calcium folinate with fluorouracil must not be used during pregnancy or breastfeeding, as fluorouracil can cause serious harm to the developing foetus or nursing infant. If you are pregnant, think you might be pregnant, or are planning to become pregnant, inform your physician before treatment begins.
Calcium folinate may only be given together with methotrexate during pregnancy if your treating physician determines that the therapeutic benefit clearly outweighs the potential risks to the foetus. In all cases, the decision to use calcium folinate during pregnancy requires careful consideration of the individual clinical circumstances and should involve a multidisciplinary discussion between the oncology, obstetric, and neonatology teams.
Driving and Operating Machinery
There is no evidence that calcium folinate affects the ability to drive or operate machinery. However, patients should consider their overall health status and the effects of any concurrent medications when making this assessment. The underlying cancer treatment with methotrexate or fluorouracil may itself affect alertness and coordination.
Calcium folinate Kalceks contains 3.15 mg sodium per ml of solution, corresponding to 0.16% of the WHO-recommended maximum daily sodium intake for adults. This should be considered for patients on a controlled sodium diet, particularly when large volumes are administered.
How Does Calcium Folinate Interact with Other Drugs?
Drug interactions with calcium folinate are clinically significant and require careful management. It is essential to inform your healthcare team about all medications you are currently taking, have recently taken, or may take. The following interactions are of particular importance.
Major Interactions
| Drug | Effect | Clinical Significance |
|---|---|---|
| Fluorouracil (5-FU) | Calcium folinate enhances both the anti-cancer activity and the toxicity of fluorouracil | Increased risk of life-threatening bone marrow suppression, severe mucositis, and diarrhoea. Close monitoring mandatory. |
| Methotrexate | Calcium folinate counteracts the toxic effects of methotrexate (intended therapeutic use) | Timing is critical — rescue must begin within 24 hours of methotrexate. Serum levels guide dosing. |
| Trimethoprim / Sulfamethoxazole (Co-trimoxazole) | Calcium folinate may reduce or completely abolish the antimicrobial effectiveness | Avoid concurrent use. If co-administration unavoidable, monitor for treatment failure of infection. |
| Pyrimethamine | Calcium folinate may reduce the anti-parasitic effectiveness | Can compromise malaria or toxoplasmosis treatment. Consider alternative rescue strategies. |
Other Interactions
| Drug | Effect | Management |
|---|---|---|
| Phenobarbital | Reduced plasma levels of phenobarbital | Monitor drug levels; dose adjustment may be required to prevent seizures. |
| Phenytoin | Reduced plasma levels of phenytoin | Monitor drug levels; increase phenytoin dose if clinically indicated. |
| Primidone | Reduced plasma levels of primidone | Monitor drug levels and seizure frequency; adjust dosing accordingly. |
| Succinimides (e.g. ethosuximide) | Reduced plasma levels of the anti-epileptic | Monitor seizure control; therapeutic drug monitoring recommended. |
Pharmaceutical Incompatibilities
When preparing intravenous infusions, calcium folinate must not be mixed with certain drugs in the same solution. Documented incompatibilities include:
- Droperidol: Immediate precipitation when mixed directly with calcium folinate in a syringe or Y-site administration.
- Fluorouracil: Precipitation may occur when mixed in the same infusion bag. These drugs must be administered separately, despite being used together therapeutically.
- Foscarnet: Produces a cloudy yellow solution when combined with calcium folinate, indicating physicochemical incompatibility.
Calcium folinate may be diluted for intravenous infusion with 0.9% sodium chloride solution or 5% glucose solution only. Always follow institutional pharmacy guidelines for preparation and administration of these medications.
What Is the Correct Dosage of Calcium Folinate Kalceks?
Calcium folinate Kalceks is administered exclusively in a hospital setting under the supervision of an experienced physician. The dosage varies substantially depending on the clinical indication, the chemotherapy regimen employed, and individual patient factors. The following information provides a general overview; the actual dose will always be determined by the treating oncologist or haematologist.
Methotrexate Rescue Therapy
Adults and Children
Calcium folinate rescue should begin as soon as possible after methotrexate administration, typically within 24 hours. The dose depends on the methotrexate dose administered and the individual patient's serum methotrexate levels. Common rescue protocols include:
- Initial dose of 15 mg (approximately 10 mg/m²) given every 6 hours for 72 hours
- Dose adjustments based on serial serum methotrexate level monitoring
- In cases of delayed methotrexate excretion (e.g. due to renal impairment), higher doses and prolonged rescue may be necessary
Treatment is continued until serum methotrexate levels fall below 0.05 micromol/L. Patients with impaired renal function require especially vigilant monitoring and may need significantly higher and more prolonged rescue therapy.
Colorectal Cancer (with Fluorouracil)
Adults
When used with fluorouracil in colorectal cancer, various dosing regimens are employed according to institutional protocols and current oncology guidelines. The dose of calcium folinate depends on the specific fluorouracil protocol:
- Monthly regimen: Calcium folinate 200 mg/m² by slow intravenous injection, followed by fluorouracil
- Weekly regimen: Calcium folinate 20 mg/m² by intravenous bolus, or 200–500 mg/m² by intravenous infusion over 2 hours, followed by fluorouracil
- FOLFOX/FOLFIRI protocols: Calcium folinate (leucovorin) 400 mg/m² by 2-hour intravenous infusion as part of the standard biweekly regimen
The specific regimen is selected by the oncologist based on tumour characteristics, patient performance status, and treatment goals. Dose modifications are made according to haematological and gastrointestinal toxicity observed during prior cycles.
Overdose
As calcium folinate Kalceks is administered exclusively in a hospital setting under direct medical supervision, overdose is unlikely. There is no specific antidote for calcium folinate overdose. In the unlikely event of excessive administration, treatment is supportive. When used with fluorouracil, overdose may significantly exacerbate fluorouracil toxicity. If you experience any unexpected symptoms during or after treatment, inform your healthcare team immediately.
Calcium folinate Kalceks can be given as an intravenous injection, intravenous infusion (drip), or intramuscular injection. For intravenous infusion, it must first be diluted with a compatible solution. The intravenous infusion rate should generally not exceed 160 mg of calcium folinate per minute due to the calcium content of the solution.
What Are the Side Effects of Calcium Folinate Kalceks?
Like all medicines, calcium folinate can cause side effects, although not everybody experiences them. The side effects differ substantially depending on whether calcium folinate is used alone (e.g. for methotrexate rescue) or in combination with fluorouracil for cancer treatment. Understanding these differences is critical for appropriate monitoring and management.
Side Effects When Used Alone
Uncommon
May affect up to 1 in 100 people
- Fever
Rare
May affect up to 1 in 1,000 people
- Difficulty sleeping (insomnia)
- Agitation and depression (after high doses)
- Increased frequency of seizures in patients with epilepsy
- Gastrointestinal disturbances (after high doses)
Very Rare
May affect up to 1 in 10,000 people
- Severe allergic reactions (anaphylaxis) — sudden itchy rash, swelling of face/hands/throat, difficulty breathing, feeling faint
Not Known
Frequency cannot be estimated from available data
- Stevens-Johnson syndrome and toxic epidermal necrolysis — severe skin reactions with reddish target-like spots, blistering, peeling skin, sores around the mouth, throat, nose and genitals, often preceded by fever and flu-like symptoms
Sudden itchy rash (hives), swelling of hands, feet, ankles, face, lips, mouth or throat causing difficulty swallowing or breathing, or feeling faint. These may be signs of a severe allergic reaction. Also seek urgent care for reddish target-like skin spots, blistering, or skin peeling — possible signs of Stevens-Johnson syndrome.
Side Effects When Used with Fluorouracil
When calcium folinate is given in combination with fluorouracil, the toxicity profile changes significantly. The enhanced pharmacological activity of fluorouracil results in more frequent and more severe adverse effects. Close monitoring with regular blood counts and clinical assessment is essential.
Very Common
May affect more than 1 in 10 people
- Bone marrow suppression (myelosuppression) including potentially life-threatening neutropaenia, thrombocytopaenia, and anaemia
- Inflammation of the mucous membranes of the mouth and intestines (mucositis/stomatitis) — life-threatening cases have occurred
- Nausea, vomiting, and diarrhoea (with monthly dosing regimen)
- Severe diarrhoea and dehydration (with weekly dosing regimen)
Common
May affect up to 1 in 10 people
- Hand-foot syndrome (palmar-plantar erythrodysaesthesia) — redness, swelling, and peeling of the skin on the palms and soles
Not Known
Frequency cannot be estimated from available data
- Elevated blood ammonia levels (hyperammonaemia)
If you develop diarrhoea or inflammation of the mouth during treatment with calcium folinate and fluorouracil, inform your doctor immediately. The fluorouracil dose may need to be reduced or temporarily withheld until these symptoms have completely resolved. Diarrhoea in this context can be a sign of serious gastrointestinal toxicity and may signal the beginning of a rapid deterioration that can become life-threatening if not managed promptly.
Your doctor will also monitor blood calcium levels to ensure they do not fall too low during treatment, and regular complete blood count monitoring is essential to detect bone marrow suppression early. During combination therapy, patients are monitored closely until all toxicity symptoms have completely resolved before the next treatment cycle is administered.
How Should Calcium Folinate Kalceks Be Stored?
Proper storage of calcium folinate Kalceks is essential to maintain its effectiveness and safety. The medication must be stored in a refrigerator at 2–8 °C and kept in the original outer carton to protect it from light. Folinic acid is sensitive to photodegradation, and exposure to light can reduce the potency of the active substance.
The unopened vials should not be used after the expiry date printed on the vial label and outer carton (after "EXP"). The expiry date refers to the last day of the stated month. Once a vial has been opened, the medication should be used immediately. This is a single-use product; any remaining solution after use must be discarded according to local pharmaceutical waste regulations.
Stability After Dilution
After dilution with compatible infusion solutions, the chemical and physical stability depends on the diluent used:
- 0.9% Sodium chloride solution: Chemical and physical stability demonstrated for 4 days at 25 °C (protected from light) and at 2–8 °C
- 5% Glucose solution: Chemical and physical stability demonstrated for 24 hours at 2–8 °C
From a microbiological perspective, the diluted product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and should normally not exceed 24 hours at 2–8 °C, unless dilution has taken place under controlled and validated aseptic conditions. All diluted solutions should be inspected visually before administration — only clear, particle-free solutions should be used.
Medicines should not be disposed of via wastewater or household waste. As a hospital-administered medication, your healthcare facility will follow specific protocols for the safe disposal of cytotoxic waste and unused pharmaceutical products in accordance with environmental protection regulations.
What Does Calcium Folinate Kalceks Contain?
The active substance in Calcium folinate Kalceks is folinic acid, present in the form of calcium folinate hydrate. Each 1 mg of folinic acid corresponds to 1.08 mg of calcium folinate. The concentration is 10 mg of folinic acid per ml of solution.
| Vial Volume | Folinic Acid Content | Pack Sizes |
|---|---|---|
| 5 ml | 50 mg | 1, 5, or 10 vials |
| 10 ml | 100 mg | 1 or 10 vials |
| 20 ml | 200 mg | 1 or 10 vials |
| 30 ml | 300 mg | 1 or 10 vials |
| 50 ml | 500 mg | 1 or 10 vials |
| 100 ml | 1000 mg | 1 or 10 vials |
The other ingredients (excipients) are:
- Sodium chloride: Used to adjust the osmolality of the solution to make it compatible with body fluids
- Sodium hydroxide: Used for pH adjustment to ensure the solution is within the acceptable range for injection
- Water for injections: The solvent vehicle that meets pharmaceutical purity standards
The solution is a clear, colourless to slightly yellowish liquid, free from visible particles. The vials are made of clear glass, sealed with bromobutyl rubber stoppers and aluminium crimp caps. Not all pack sizes may be marketed in every country. The medication is authorised across the European Economic Area under various names, including Calcium folinate Kalceks (in the Nordic countries, Czech Republic, Estonia, Poland, Hungary, Latvia, and Lithuania), Folinsäure Kalceks (Austria, Germany), and Folinic acid Kalceks (Belgium, Bulgaria, Ireland, Netherlands, and others).
Frequently Asked Questions About Calcium Folinate Kalceks
Calcium folinate (also known as leucovorin or folinic acid) is used for two primary purposes: as rescue therapy to counteract the toxic effects of high-dose methotrexate chemotherapy and in combination with fluorouracil (5-FU) to enhance its anti-cancer effectiveness in colorectal cancer treatment. As rescue therapy, it provides healthy cells with a source of reduced folate that bypasses the metabolic block caused by methotrexate, protecting them from damage while the cancer cells remain affected.
No. Although calcium folinate (folinic acid) is chemically related to folic acid, they are distinct substances with different clinical applications. Folinic acid is a reduced, biologically active form of folic acid that does not require the enzyme dihydrofolate reductase for activation. This is clinically important because methotrexate works by blocking this very enzyme. Standard folic acid cannot bypass this block and therefore cannot be used as rescue therapy. Only folinic acid can provide the necessary rescue from methotrexate toxicity.
Calcium folinate Kalceks is an injectable medication that is typically administered in a hospital or clinic setting under the supervision of a healthcare professional experienced in chemotherapy administration. It requires intravenous or intramuscular injection, and the dosing depends on careful monitoring of blood tests and the patient's clinical status. In some cases, home infusion services may administer the medication under appropriate medical supervision, but this depends on local healthcare arrangements and the individual clinical situation.
Calcium folinate rescue should begin as early as possible after methotrexate administration, ideally within 24 hours. The timing is critical because the protective effect of folinic acid is most effective when given early, before methotrexate has caused irreversible damage to healthy cells. Serum methotrexate levels are monitored at regular intervals (typically every 24 hours), and rescue therapy continues until methotrexate levels fall below 0.05 micromol/L, which may take several days depending on renal function and the dose of methotrexate given.
Calcium folinate (leucovorin) is a racemic mixture containing both the active L-form and the inactive D-form of folinic acid. Levoleucovorin contains only the biologically active L-isomer. Because levoleucovorin is the pure active form, it is used at half the dose of racemic calcium folinate. Both are effective for methotrexate rescue and as a modulator of fluorouracil therapy. The choice between them depends on availability, institutional preference, and the specific treatment protocol being used.
Calcium folinate alone does not cause harmful effects during pregnancy. However, it must never be used in combination with fluorouracil during pregnancy or breastfeeding, as fluorouracil is teratogenic and can cause serious harm to the developing baby. When used as rescue therapy with methotrexate during pregnancy, it should only be given if the treating physician considers the benefit to the mother clearly outweighs the potential risk to the foetus. Always inform your doctor if you are or may be pregnant before any treatment.
References & Medical Sources
- European Medicines Agency (EMA). Summary of Product Characteristics: Calcium folinate Kalceks 10 mg/ml solution for injection/infusion. Last updated January 2024.
- World Health Organization (WHO). WHO Model List of Essential Medicines — 23rd List, 2023. Geneva: World Health Organization.
- British National Formulary (BNF). Folinic acid (calcium folinate). National Institute for Health and Care Excellence (NICE), 2024. Available at: bnf.nice.org.uk
- Cervantes A, Adam R, Rosello S, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Annals of Oncology. 2023;34(1):10–32. doi:10.1016/j.annonc.2022.10.003
- Howard SC, McCormick J, Pui CH, Buddington RK, Harvey RD. Preventing and managing toxicities of high-dose methotrexate. The Oncologist. 2016;21(12):1471–1482. doi:10.1634/theoncologist.2015-0164
- National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 1.2024.
- US Food and Drug Administration (FDA). Leucovorin Calcium Injection prescribing information. FDA Approved Drug Products.
- Groenland SL, Mathijssen RHJ, Beijnen JH, Huitema ADR, Steeghs N. Principles of anticancer drug dosing. British Journal of Clinical Pharmacology. 2019;85(12):2654–2663.
Medical Editorial Team
This article was written by the iMedic Medical Editorial Team, a multidisciplinary group of licensed physicians specialising in clinical pharmacology, oncology, and internal medicine. All content is reviewed according to international medical guidelines from the WHO, EMA, FDA, and ESMO.
Our editorial process follows the GRADE evidence framework and all medical claims are supported by peer-reviewed research at Evidence Level 1A. We maintain complete editorial independence with no pharmaceutical company sponsorship or commercial funding.
Last medical review: | Next scheduled review: