Calcium folinate (Leucovorin)

BRAND NAMES

Common brand names of calcium folinate (leucovorin) include Wellcovorin and Biovorin. Depending on the region, it may also be marketed under other names such as Lucal, Neovorin, Leucovorin Calcium (produced by various manufacturers), and international brands like Lederfolin or Folinico.

• Wellcovorin: One of the most widely used brand names in the United States.

• Biovorin: A well-recognized brand available in several global markets.

Other brands include:

• Lucal – by Celon Laboratories

• Neovorin – by Neon Laboratories

• Lederfolin– by Pfizer (Spain)

• Folinico – by Precimex (Mexico)

MECHANISM OF ACTION

Calcium folinate functions as a vital coenzyme in nucleic acid synthesis, a process essential for cell division and repair. Unlike folic acid, it bypasses the need for activation by the enzyme dihydrofolate reductase (DHFR). This distinctive property enables calcium folinate to exert different effects depending on how it is used in chemotherapy.

PHARMACOKINETICS:

Absorption

After oral administration, leucovorin is absorbed quickly. Its apparent bioavailability is approximately 97% at a 25 mg dose, 75% at 50 mg, and decreases to about 37% at a 100 mg dose.

Distribution

Calcium folinate, commonly known as leucovorin, is extensively distributed throughout the body after administration. As a formyl derivative of tetrahydrofolic acid and an active metabolite of folic acid, it tends to accumulate mainly in the liverand cerebrospinal fluid (CSF).

Metabolism

Leucovorin is mainly metabolized in the liver and intestinal mucosa to its active form, 5-methyltetrahydrofolate. It also converts to 5,10-methylenetetrahydrofolate, which enhances the inhibition of thymidylate synthase by stabilizing the binding of fluorodeoxyridylic acid.

Excretion

Calcium folinate (leucovorin) undergoes rapid metabolism in the liver and intestinal mucosa and is mainly excreted through the kidneys. Most of the drug is eliminated in the urine, while a smaller amount is excreted in the feces.

PHARMACODYNAMICS

Leucovorin is an active, chemically reduced form of folic acid that serves as an antidote to drugs acting as folic acid antagonists. It consists of a mixture of diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid (THF), with the biologically active component being the (-)-l-isomer, also known as citrovorum factor or (-)-folinic acid. Unlike folic acid, leucovorin does not require activation by dihydrofolate reductase to participate in folate-dependent “one-carbon” transfer reactions. Its administration helps reverse both the therapeutic and toxic effects of methotrexate and other folic acid antagonists, while also being used to enhance the efficacy of fluorouracil (5-FU) in chemotherapy.

ADMINISTRATION

The administration of calcium folinate (Leucovorin) depends on the specific medical condition and is given via intravenous (IV) injection or infusion, intramuscular (IM) injection, or oral tablets. The most critical administration warnings relate to its use in combination with certain other drugs and avoiding intrathecal injection. 

Key administration warnings

• Never administer intrathecally: Giving leucovorin into the spinal fluid (intrathecally) can be fatal and is strictly contraindicated.

• Do not mix with other drugs: Leucovorin is physically incompatible with several injectable medications. It should not be mixed in the same syringe or IV bag with 5-fluorouracil, methotrexate, or droperidol, as it may cause precipitation.

• Consider drug interactions: Leucovorin can interact with other medications, such as some anti-epileptic drugs, and may interfere with their effectiveness. This can increase the risk of seizures.

• Handle with care: This medication should be prepared and administered under the supervision of a clinician experienced in chemotherapy. 

DOSAGE AND STRENGTH

Calcium folinate, also known as leucovorin, is available in various strengths and is used in different dosage regimens depending on the condition being treated. The strengths come in oral tablets, capsules, and injectable solutions for intravenous (IV) or intramuscular (IM) administration. Dosages vary greatly and must be determined by a doctor based on the specific clinical situation. 

Common strengths

The available strengths of calcium folinate include: 

• Tablets: 5 mg, 10 mg, 15 mg, and 25 mg

• Capsules: 5 mg and 25 mg (available in some countries)

• Injections: Supplied in vials containing 10 mg/mL, 20 mg/mL, or higher concentrations after reconstitution. 

DRUG INTERACTIONS

Calcium folinate (leucovorin) can interact with various drugs, particularly chemotherapy agents, certain antibiotics, and some antiepileptics. It acts as a rescue agent for methotrexate, but if given too soon or in high doses, it can reduce methotrexate’s therapeutic effect. Leucovorin also enhances the efficacy and toxicity of fluorouracil (5-FU) and capecitabine, and can counteract other folic acid antagonists like trimetrexate, aminopterin, pralatrexate, and raltitrexed. With antibiotics such as trimethoprim-sulfamethoxazole or other antifolic drugs, leucovorin may reduce antibacterial effectiveness. Additionally, high doses can lower plasma levels of antiepileptic drugs like phenytoin, phenobarbital, and primidone, potentially increasing seizure risk.

FOOD INTERACTIONS

Calcium folinate is generally well absorbed and does not have significant food interactions, meaning it can be taken with or without food. However, high intake of folate-rich foods or supplements may theoretically influence its effectiveness in certain treatments, especially when used with folate antagonists like methotrexate. 

CONTRAINDICATIONS

Contraindications of Calcium Folinate (Leucovorin):

Calcium folinate (leucovorin) should not be used in patients with:

• Known hypersensitivity to leucovorin, folinic acid, or any component of the formulation.

• Vitamin B12 deficiency without concurrent B12 therapy, as leucovorin can correct the anemia without addressing the underlying neurological damage.

• Caution in patients receiving high-dose folate antagonists if timing is incorrect, as it may reduce therapeutic efficacy.

SIDE EFFECTS

Calcium folinate, or leucovorin, is generally well tolerated and usually causes minimal side effects when used alone. It is primarily administered to reduce the toxic effects of chemotherapy drugs like methotrexate. However, some side effects may occur, especially when combined with other medications.

Common side effects are usually mild and often do not require medical intervention, and may include:

• Nausea

• Vomiting

• Diarrhea

• Mouth inflammation or soreness (stomatitis)

• Fatigue or weakness

• Rash or itching

• Reduced appetite

OVER DOSE

An overdose of calcium folinate (leucovorin) is generally not life-threatening when taken alone, but it can reduce the effectiveness of certain medications and may lead to side effects, particularly if administered incorrectly. The greatest risks arise when it interferes with chemotherapy or when high intravenous doses result in hypercalcemia.

Symptoms of overdose may include:

• Allergic reactions: Hives, rash, itching, or swelling of the face, tongue, or throat.

• Gastrointestinal issues: Nausea, vomiting, diarrhea, indigestion, and mouth or lip inflammation (stomatitis).

• Neurological symptoms: Rarely, high doses can cause seizures, agitation, depression, or insomnia.

• Hypercalcemia: Very high or repeated IV doses may lead to dangerously elevated calcium levels in the blood.

TOXICITY

Calcium folinate, or leucovorin, has low toxicity when used alone, but its toxic effects are greatly dependent on how and with what other medications it is administered. Leucovorin is a rescue agent that counteracts the adverse effects of certain cancer drugs, but can also amplify the toxicity of others.