Natriumlevofolinat medac
Levofolinic acid – Folate rescue agent for cancer chemotherapy
Natriumlevofolinat medac contains levofolinic acid, the pharmacologically active isomer of folinic acid. It is used in cancer treatment as a rescue agent to reduce the toxic effects of high-dose methotrexate therapy, and in combination with 5-fluorouracil (5-FU) to enhance its anti-cancer effects. This medication is administered intravenously and must only be prepared and given by trained healthcare professionals in hospital settings.
Quick Facts
Key Takeaways
- Levofolinic acid is the active L-isomer of folinic acid, requiring half the dose of racemic folinic acid for the same therapeutic effect.
- Used as a rescue agent after high-dose methotrexate to prevent serious toxic effects on bone marrow, kidneys, and mucous membranes.
- When combined with 5-fluorouracil, it enhances the anti-cancer effect, particularly in advanced colorectal cancer treatment.
- Must never be administered intrathecally (into the spinal fluid) – severe adverse events including death have been reported.
- This medication is only given in hospital settings by trained healthcare professionals and requires careful monitoring of blood counts and organ function.
What Is Natriumlevofolinat medac and What Is It Used For?
Natriumlevofolinat medac belongs to a group of medicines known as antidotes. These are substances used during cancer chemotherapy to counteract the toxic effects of certain chemotherapy drugs. The active ingredient, levofolinic acid, is the pharmacologically active L-isomer of folinic acid (also known as leucovorin). Because it consists entirely of the active form, it requires only half the dose compared to racemic folinic acid to achieve equivalent therapeutic benefit.
Methotrexate Rescue Therapy
When used in combination with methotrexate, Natriumlevofolinat medac serves as a rescue agent. Methotrexate is a folic acid antagonist that blocks the body's ability to use folic acid, which is essential for cell division. While this mechanism makes methotrexate effective against cancer cells, it also damages healthy cells, particularly those in the bone marrow, gastrointestinal lining, and kidneys. Levofolinic acid provides an alternative source of reduced folate that bypasses the metabolic block caused by methotrexate, thereby protecting normal tissues from severe damage.
Rescue therapy with levofolinic acid is essential when methotrexate is administered at doses exceeding 500 mg/m² body surface area, and should be considered at doses of 100–500 mg/m². The timing of rescue therapy is critical – it must begin within 24 hours of starting methotrexate infusion and continue until plasma methotrexate levels fall below a safe threshold (0.05 µmol/L). This approach allows oncologists to use much higher doses of methotrexate than would otherwise be tolerable, significantly improving treatment outcomes for cancers such as osteosarcoma, lymphoma, and certain leukaemias.
In cases of accidental methotrexate overdose, Natriumlevofolinat medac is also used as an emergency antidote to prevent potentially life-threatening toxicity. Immediate administration is crucial in these situations, and higher doses may be required depending on the severity of the overdose.
Combination with 5-Fluorouracil
Natriumlevofolinat medac has been shown to enhance the anti-cancer effects of 5-fluorouracil (5-FU), a widely used chemotherapy agent. When levofolinic acid is administered before 5-FU, it increases intracellular levels of reduced folate. This stabilises the binding of the active metabolite of 5-FU (FdUMP) to the enzyme thymidylate synthase, forming a ternary complex that inhibits DNA synthesis more effectively. This biochemical enhancement translates into improved tumour response rates in clinical practice.
The combination of levofolinic acid and 5-FU is a cornerstone of chemotherapy regimens for advanced or metastatic colorectal cancer, including the widely used FOLFOX (with oxaliplatin) and FOLFIRI (with irinotecan) protocols. These regimens have been extensively validated in large randomised controlled trials and are recommended by major international guidelines including those of the European Society for Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN).
What Should You Know Before Taking Natriumlevofolinat medac?
Contraindications
There are several important situations where Natriumlevofolinat medac must not be used. Understanding these contraindications is essential for patient safety and for healthcare professionals who administer this medication.
- You are allergic to levofolinic acid or any of the other ingredients
- You have anaemia caused by vitamin B12 deficiency (pernicious anaemia)
- In combination with 5-fluorouracil if you are pregnant or breastfeeding
- In combination with 5-fluorouracil if you have severe diarrhoea
- In combination with 5-fluorouracil if there are medical reasons you cannot take 5-FU
The contraindication in vitamin B12 deficiency anaemia is particularly important because folate supplementation can mask the haematological signs of B12 deficiency while allowing neurological damage to progress unchecked. This can lead to irreversible nerve damage if the underlying B12 deficiency is not diagnosed and treated appropriately.
Warnings and Precautions
Natriumlevofolinat medac should only be used in combination with 5-fluorouracil or methotrexate under the direct supervision of a physician experienced in cancer treatment. Several important warnings apply to its use.
Levofolinic acid must never be administered intrathecally (into the spinal fluid). Severe adverse reactions, including deaths, have been reported with intrathecal administration of folinic acid products. This route of administration is absolutely contraindicated.
If you are taking certain anti-epileptic medications such as phenobarbital, phenytoin, or primidone, levofolinic acid may reduce their plasma concentrations, potentially increasing the risk of seizures. Your doctor will monitor blood levels of these medications during and after treatment with levofolinic acid, adjusting the dose as necessary.
Patients treated with cytotoxic agents such as hydroxycarbamide, cytarabine, mercaptopurine, or thioguanine may develop macrocytosis (enlarged red blood cells). This type of macrocytosis must not be treated with levofolinic acid, as it would not address the underlying cause and could mask important diagnostic information.
Precautions with Methotrexate
When used as rescue therapy after methotrexate, several specific precautions must be observed. Levofolinic acid should not be given simultaneously with methotrexate, as this would reduce the anti-tumour effectiveness of the treatment. The timing of rescue therapy is determined by the specific methotrexate protocol being used.
Excessively high doses of levofolinic acid should also be avoided, as they may impair the anti-tumour activity of methotrexate. However, in cases of accidental methotrexate overdose, immediate and adequate rescue therapy takes priority over concerns about anti-tumour efficacy.
Patients with impaired kidney function, dehydration, or those taking non-steroidal anti-inflammatory drugs (NSAIDs such as ibuprofen, diclofenac, or aspirin) may experience delayed methotrexate excretion. Fluid accumulation in body cavities (ascites or pleural effusion) can also slow methotrexate clearance. In these circumstances, higher doses of levofolinic acid or prolonged treatment may be necessary, and kidney function must be closely monitored.
Precautions with 5-Fluorouracil
When levofolinic acid is used together with 5-fluorouracil, the risk of toxic effects from 5-FU is increased. The most common dose-limiting toxicities include decreased white blood cell count (leucopenia), inflammation of the mucous membranes (mucositis), and diarrhoea. If watery stools occur more than twice daily or if mucositis develops, treatment should be interrupted and your doctor contacted immediately.
Elderly patients, frail patients, and those who have previously received radiotherapy are at particularly increased risk of 5-FU toxicity when combined with levofolinic acid. These patients require especially careful monitoring and may need dose reductions.
Gastrointestinal symptoms of any severity require immediate medical attention. Diarrhoea in particular can deteriorate rapidly and become life-threatening, requiring hospitalisation and intensive supportive care. Treatment with the combination must not be started or continued in the presence of any gastrointestinal adverse effects until symptoms have completely resolved.
Pregnancy and Breastfeeding
Levofolinic acid alone is not known to cause harmful effects during pregnancy. However, the combination of levofolinic acid with 5-fluorouracil must not be used during pregnancy, as 5-FU is known to cause birth defects and foetal harm.
If methotrexate must be given during pregnancy despite its known risks (which should only occur if the benefit clearly outweighs the risk to the unborn child), levofolinic acid can be used without restriction to reduce or counteract methotrexate toxicity.
Breastfeeding must be discontinued before starting treatment with methotrexate or 5-fluorouracil. Levofolinic acid alone can be used during breastfeeding when clinically necessary.
How Does Natriumlevofolinat medac Interact with Other Drugs?
Drug interactions involving levofolinic acid can have significant clinical consequences. It is essential that your healthcare team is aware of all medications you are taking, as the interactions can affect both the efficacy and safety of your treatment. The following table summarises the most important known drug interactions.
| Interacting Drug | Effect | Clinical Significance | Action Required |
|---|---|---|---|
| Methotrexate | Reduces methotrexate toxicity; may reduce anti-tumour effect if given simultaneously | Major | Precise timing of administration is critical; do not give simultaneously |
| 5-Fluorouracil | Enhances cytotoxic effects and increases side effects of 5-FU | Major | Close monitoring of blood counts and gastrointestinal symptoms |
| Phenobarbital | May decrease plasma levels of phenobarbital, increasing seizure risk | Moderate | Monitor drug levels; adjust dose if necessary |
| Phenytoin | May decrease plasma levels of phenytoin, increasing seizure risk | Moderate | Monitor drug levels; adjust dose if necessary |
| Primidone | May decrease plasma levels of primidone, increasing seizure risk | Moderate | Monitor drug levels; adjust dose if necessary |
| Co-trimoxazole | Reduces or neutralises the effect of the folate antagonist component | Major | Avoid concurrent use; inform treating physician |
| Pyrimethamine | Reduces or neutralises the anti-malarial/anti-parasitic effect | Major | Avoid concurrent use; inform treating physician |
| NSAIDs (ibuprofen, diclofenac, aspirin) | May delay methotrexate excretion, increasing its toxicity | Moderate | Use with caution during methotrexate therapy; may require higher levofolinic acid doses |
Interactions with Anti-Epileptic Drugs
The interaction between levofolinic acid and anti-epileptic medications (phenobarbital, phenytoin, and primidone) deserves particular attention. Levofolinic acid can accelerate the metabolism of these drugs, leading to decreased plasma concentrations. In patients with epilepsy, this reduction in drug levels can lower the seizure threshold and increase the frequency of seizures.
Healthcare providers should monitor anti-epileptic drug levels during treatment with levofolinic acid and for a period after treatment has ended. Dose adjustments of the anti-epileptic medication may be necessary to maintain adequate seizure control. Patients should be advised to report any increase in seizure frequency or unusual symptoms promptly.
Interactions with Folate Antagonists
When levofolinic acid is given together with folate antagonists used for purposes other than cancer treatment – such as co-trimoxazole (used for bacterial infections) or pyrimethamine (used for malaria and toxoplasmosis) – it can reduce or completely neutralise their therapeutic effects. This is because levofolinic acid provides the very folate that these drugs are designed to deplete. Healthcare professionals must weigh the need for folate rescue against the potential loss of antimicrobial efficacy when these drugs are used concurrently.
What Is the Correct Dosage of Natriumlevofolinat medac?
Natriumlevofolinat medac must only be prepared and administered by trained healthcare professionals. The solution can be given directly as an intravenous injection or as an intravenous infusion after dilution with sodium chloride 0.9% or glucose 5% solution. It must never be given intrathecally.
Methotrexate Rescue Therapy
The dosing regimen for rescue therapy depends on the methotrexate protocol being used. The methotrexate protocol determines the timing, dose, and duration of levofolinic acid rescue. The following are general guidelines:
Standard Rescue Protocol
- First dose: 7.5 mg levofolinic acid (approximately 3–6 mg/m²), given 12–24 hours after the start of methotrexate infusion (no later than 24 hours)
- Subsequent doses: Same dose every 6 hours for a total of 72 hours
- Route: Parenteral administration required for doses above 12.5–25 mg, or in patients with malabsorption
- Duration: Continue until plasma methotrexate level is below 0.05 µmol/L
If delayed methotrexate excretion is observed (e.g., due to renal impairment, fluid accumulation, or dehydration), higher doses may be required. The following table provides dose adjustments based on residual methotrexate levels at 48 hours:
| Residual Methotrexate Level | Levofolinic Acid Dose | Frequency |
|---|---|---|
| ≥ 0.5 µmol/L | 7.5 mg/m² | Every 6 hours for 48 hours or until MTX < 0.05 µmol/L |
| ≥ 1.0 µmol/L | 50 mg/m² | Every 6 hours for 48 hours or until MTX < 0.05 µmol/L |
| ≥ 2.0 µmol/L | 100 mg/m² | Every 6 hours for 48 hours or until MTX < 0.05 µmol/L |
In addition to levofolinic acid rescue, it is essential to: (a) alkalinise urine to maintain pH above 7.0 before starting methotrexate, (b) maintain urine output of 1,800–2,000 mL/m²/24 hours through increased fluid intake on days 2–4, and (c) measure plasma methotrexate, urea, and creatinine on days 2, 3, and 4 until methotrexate falls below 0.1 µmol/L.
Combination with 5-Fluorouracil
Several different regimens are used for the combination of levofolinic acid and 5-fluorouracil in the treatment of advanced or metastatic colorectal cancer. No single dosing regimen has been proven optimal, and the choice depends on the specific clinical protocol being followed. The following are commonly used regimens:
Biweekly Regimen (e.g., de Gramont / FOLFOX / FOLFIRI)
100 mg/m² levofolinic acid as a 2-hour IV infusion, followed by 400 mg/m² 5-FU bolus and then 600 mg/m² 5-FU as a 22-hour infusion, for 2 consecutive days, repeated every 2 weeks.
Weekly Regimen
10 mg/m² levofolinic acid as an IV bolus, or 100–250 mg/m² as a 2-hour IV infusion, followed by 500 mg/m² 5-FU as an IV bolus given during or after the levofolinic acid infusion.
Monthly Regimen
10 mg/m² levofolinic acid as an IV bolus, or 100–250 mg/m² as a 2-hour IV infusion, immediately followed by 370–425 mg/m² 5-FU as an IV bolus, for 5 consecutive days.
Children
Levofolinic acid is used in paediatric patients for methotrexate rescue therapy following the same general principles as in adults. Dosing is based on body surface area (mg/m²). No data are available on the use of the levofolinic acid/5-FU combination in children.
Elderly Patients
No specific dose adjustments are required based on age alone. However, elderly patients may be more susceptible to the toxic effects of the combination with 5-fluorouracil and may require dose reductions of 5-FU. Kidney function should be assessed before treatment, as age-related renal decline may affect methotrexate clearance.
Overdose
Very high doses of levofolinic acid can completely neutralise the effect of folic acid antagonists such as methotrexate, potentially rendering cancer treatment ineffective. If an overdose of the levofolinic acid/5-fluorouracil combination occurs, the management guidelines for 5-fluorouracil overdose should be followed, including supportive care and monitoring of blood counts and gastrointestinal function.
What Are the Side Effects of Natriumlevofolinat medac?
The side effect profile of Natriumlevofolinat medac depends significantly on whether it is used alone (for methotrexate rescue) or in combination with 5-fluorouracil. When used alone, the medication is generally well tolerated with few adverse effects. When used with 5-FU, the side effect profile is dominated by the enhanced toxicity of 5-fluorouracil.
Side Effects of Levofolinic Acid Alone
Uncommon
- Fever
Rare
- Insomnia, agitation, and depression (after high doses)
- Gastrointestinal disturbances (after high doses)
- Increased frequency of seizures in patients with epilepsy
Very Rare
- Severe allergic reaction (anaphylaxis) – sudden itchy rash, swelling of hands, feet, face, lips, mouth or throat, difficulty breathing, feeling faint
You experience signs of a severe allergic reaction including sudden itchy rash (hives), swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty swallowing or breathing), or feeling like you might faint. This is a medical emergency.
Side Effects When Combined with 5-Fluorouracil
When levofolinic acid is used in combination with 5-fluorouracil, the cytotoxic effects of 5-FU are enhanced. This leads to a higher incidence and greater severity of 5-FU side effects. The specific side effect profile also depends on the dosing schedule used.
Very Common (all regimens)
- Decreased blood cell counts (including potentially life-threatening states) – leucopenia, neutropenia, thrombocytopenia
- Inflammation of the mucous membranes in the mouth and gastrointestinal tract (mucositis/stomatitis) – life-threatening cases have occurred
Very Common (weekly regimen)
- Severe diarrhoea and dehydration – may require hospitalisation and has occasionally been fatal
Very Common (monthly regimen)
- Nausea and vomiting
Common
- Hand-foot syndrome (palmar-plantar erythrodysaesthesia) – redness, swelling, and peeling of the skin on palms and soles
Frequency Not Known
- Hyperammonaemia – elevated ammonia levels in the blood
The severity and pattern of side effects may vary depending on the specific chemotherapy regimen, the dose of 5-fluorouracil used, and individual patient factors. Patients who are elderly, debilitated, or who have previously received radiotherapy may be at increased risk of toxicity. Regular monitoring of blood counts, liver function, and kidney function is essential throughout treatment.
How Should You Store Natriumlevofolinat medac?
Proper storage of Natriumlevofolinat medac is essential to maintain its efficacy and safety. The following storage conditions must be observed:
- Temperature: Store in a refrigerator at 2–8°C
- Light protection: Keep the vial in the outer carton to protect from light
- Expiry date: Do not use after the expiry date stated on the label (EXP) and carton. The expiry date refers to the last day of that month
- Keep out of reach: Store out of the sight and reach of children
After Opening or Dilution
Once diluted with sodium chloride 0.9% or glucose 5% solution, or after mixing with 5-fluorouracil, the prepared solution is chemically and physically stable for up to 72 hours at 20–25°C. However, from a microbiological standpoint, the product should be used immediately. If not used immediately, storage should not normally exceed 24 hours at 2–8°C, unless preparation was performed under controlled and validated aseptic conditions.
The solution is for single use only. Any unused medicine or waste material should be disposed of in accordance with local requirements for cytotoxic waste. Only use the solution if it is clear and free from visible particles.
What Does Natriumlevofolinat medac Contain?
Understanding the composition of Natriumlevofolinat medac is important for healthcare professionals preparing and administering the medication, and for patients who may have allergies to specific ingredients.
Active Ingredient
The active substance is levofolinic acid, present as its disodium salt. Each millilitre of solution contains 54.65 mg disodium levofolinate, which is equivalent to 50 mg levofolinic acid.
| Vial Size | Disodium Levofolinate | Levofolinic Acid Equivalent |
|---|---|---|
| 1 ml | 54.65 mg | 50 mg |
| 4 ml | 218.6 mg | 200 mg |
| 9 ml | 491.85 mg | 450 mg |
Other Ingredients (Excipients)
- Sodium hydroxide (for pH adjustment)
- Hydrochloric acid (for pH adjustment)
- Water for injections
This medicine contains less than 1 mmol (23 mg) sodium per vial, which means it is essentially sodium-free. This is relevant for patients on sodium-restricted diets.
Appearance and Packaging
Natriumlevofolinat medac is a clear, colourless to slightly yellowish solution for injection/infusion. It is supplied in colourless Type I glass vials with bromobutyl rubber stoppers and aluminium flip-off caps. Available as packs of 1 or 5 vials in the 1 ml, 4 ml, or 9 ml sizes. Not all pack sizes may be marketed in all countries.
The product is compatible with 5-fluorouracil and can be diluted with sodium chloride 0.9% or glucose 5% solution. Preparation of the infusion solution must be performed under aseptic conditions.
Frequently Asked Questions
Folinic acid (leucovorin, calcium folinate) is a racemic mixture containing both the active L-isomer and the inactive D-isomer in equal proportions. Levofolinic acid contains only the pharmacologically active L-isomer. This means that levofolinic acid is twice as potent on a milligram basis – you need only half the dose of levofolinic acid compared to racemic folinic acid to achieve the same therapeutic effect. For example, 100 mg of levofolinic acid is equivalent to 200 mg of racemic folinic acid. Both are used for the same clinical purposes: methotrexate rescue and enhancing 5-FU efficacy.
The timing is critical for two reasons. First, rescue therapy must begin within 24 hours of starting methotrexate to prevent serious toxicity to the bone marrow, kidneys, and mucous membranes. Delayed rescue increases the risk of irreversible damage. Second, levofolinic acid must not be given at the same time as methotrexate, because it would counteract the anti-cancer effect. The methotrexate needs time to exert its cytotoxic effect on cancer cells before the rescue agent is introduced. The specific timing depends on the methotrexate protocol used.
Natriumlevofolinat medac is an intravenous medication that must be prepared and administered by trained healthcare professionals, typically in a hospital or specialised oncology clinic. It requires sterile preparation, precise dosing based on body surface area and clinical parameters, and is part of complex chemotherapy protocols that require close medical supervision and monitoring. It is not intended for self-administration at home.
Diarrhoea during treatment with the combination of levofolinic acid and 5-fluorouracil should be taken very seriously. If you experience watery stools more than twice a day, contact your healthcare team immediately. Do not wait for the next scheduled appointment. Diarrhoea can deteriorate rapidly and become life-threatening due to severe dehydration and electrolyte imbalances. Your doctor may need to interrupt or discontinue the combination therapy, provide intravenous fluids, and treat the diarrhoea aggressively. Treatment should not be resumed until all gastrointestinal symptoms have completely resolved.
Levofolinic acid itself is not expected to affect the ability to drive or operate machinery. However, since this medication is used as part of cancer chemotherapy regimens, your overall condition and the effects of other medications you are receiving are much more likely to influence your ability to drive. Side effects such as fatigue, nausea, and neurological symptoms from chemotherapy can impair driving ability. Always discuss with your healthcare team whether it is safe for you to drive during your treatment course.
No, they are different. Folic acid is a synthetic vitamin that must be converted by the body into its active reduced forms before it can be used. Levofolinic acid is already in its active reduced form, meaning it can immediately participate in cellular metabolism without requiring enzymatic conversion. This is especially important in the context of methotrexate rescue, where methotrexate blocks the enzyme (dihydrofolate reductase) needed to convert folic acid. Regular folic acid supplements cannot bypass this block, but levofolinic acid can. Do not substitute one for the other without medical advice.
References
- European Medicines Agency (EMA). Natriumlevofolinat medac – Summary of Product Characteristics. Available at: www.ema.europa.eu
- World Health Organization. WHO Model List of Essential Medicines – 23rd List (2023). Geneva: WHO; 2023.
- National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Colon Cancer. Version 1.2024. Available at: www.nccn.org
- European Society for Medical Oncology (ESMO). Clinical Practice Guidelines for diagnosis, treatment and follow-up of metastatic colorectal cancer. Annals of Oncology. 2023;34(1):10–32. doi:10.1016/j.annonc.2022.10.003
- de Gramont A, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000;18(16):2938–2947. doi:10.1200/JCO.2000.18.16.2938
- British National Formulary (BNF). Folinic acid (levofolinic acid). Available at: bnf.nice.org.uk
- Machover D, et al. Two consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines. Ann Oncol. 1996;7(1):95–98.
- Tournigand C, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol. 2004;22(2):229–237. doi:10.1200/JCO.2004.05.113
Editorial Team
This article has been medically reviewed by the iMedic Medical Review Board, an independent panel of board-certified oncologists and clinical pharmacologists with expertise in cancer chemotherapy and supportive care.
All content follows the GRADE evidence framework and is based on international guidelines from ESMO, NCCN, EMA, and WHO. Evidence Level 1A – based on systematic reviews and randomised controlled trials.
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