Folinic Acid

V03A - All other therapeutic products ATC V03AF03 Small molecule Prodrug First-in-class Natural product Orphan

JFDA label: CALCIUM FOLINAT "EBEWE"

Mechanism of Action

Leucovorin calcium is a reduced form of folic acid, leucovorin supplies the necessary cofactor blocked by methotrexate. Leucovorin actively competes with methotrexate for transport sites, displaces methotrexate from intracellular binding sites, and restores active folate stores required for DNA/RNA synthesis. Stabilizes the binding of 5-dUMP and thymidylate synthetase, enhancing the activity of fluorouracil. When administered with pyrimethamine for the treatment of opportunistic infections, leucovorin reduces the risk for hematologic toxicity (HHS [OI adult 2015]). Methanol toxicity treatment: Formic acid (methanol’s toxic metabolite) is normally metabolized to carbon dioxide and water by 10-formyltetrahydrofolate dehydrogenase after being bound to tetrahydrofolate. Administering a sourc

Indications

Approved

Colorectal cancer, advanced
Injection
Megaloblastic anemia
Methotrexate toxicity
Oral

Off-label

Adjunctive cofactor therapy in methanol toxicity
Bladder cancer (neoadjuvant treatment)
Esophageal cancer (advanced or metastatic)
Gastric cancer (advanced or metastatic)
Pancreatic cancer (metastatic)
Prevention of pyrimethamine hematologic toxicity in HIV-exposed/-positive patients (children)
Prevention of pyrimethamine hematologic toxicity in HIV-infected patients (adolescents and adults)

Contraindications

Source: Lexicomp

Pernicious anemia and other megaloblastic anemias secondary to vitamin B12-deficiency Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Blood and lymphatic system disorders (1)

Not Known Thrombocythemia

Immune system disorders (2)

Not Known Anaphylactoid reaction · hypersensitivity reaction

Skin and subcutaneous tissue disorders (4)

Not Known Erythema · pruritus · skin rash · urticaria

Respiratory, thoracic and mediastinal disorders (1)

Not Known Wheezing

Dosing

Source: Lexicomp

Note: Because oral absorption is saturable at doses >25 mg, administering single oral doses >25 mg is not recommended (convert to parenteral therapy). Colorectal cancer, advanced: IV: 200 mg/m2/day over at least 3 minutes for 5 days every 4 weeks for 2 cycles, then every 4 to 5 weeks (in combination with fluorouracil) or 20 mg/m2/day for 5 days every 4 weeks for 2 cycles, then every 4 to 5 weeks (in combination with fluorouracil). Note: Multiple leucovorin-containing regimens are available for the treatment of colorectal cancer. Refer to appropriate literature/guidelines for additional details. Folic acid antagonist (eg, trimethoprim, pyrimethamine) overdose: Oral: 5 to 15 mg once daily Folate-deficient megaloblastic anemia: IM, IV: ≤1 mg once daily High-dose methotrexate-rescue: Initial: Oral, IM, IV: 15 mg (~10 mg/m2); start 24 hours after beginning methotrexate infusion; continue every 6 hours for 10 doses, until methotrexate level is Normal methotrexate elimination (serum methotrexate level ~10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and Oral, IM, IV: 15 mg every 6 hours for 60 hours (10 doses) beginning 24 hours after the start of methotrexate infusion Delayed late methotrexate elimination (serum methotrexate level remaining >0.2 micromolar at 72 hours and >0.05 micromolar at 96 hours after administration): Continue leucovorin calcium 15 mg (oral, IM or IV) every 6 hours until methotrexate level is Delayed early methotrexate elimination and/or acute renal injury (serum methotrexate level ≥50 micromolar at 24 hours, or ≥5 micromolar at 48 hours, or a doubling of serum creatinine level at 24 hours after methotrexate administration): IV: 150 mg every 3 hours until methotrexate level is High-dose methotrexate overexposure: Leucovorin nomogram dosing for high-dose methotrexate overexposure (off-label dosing; generalized dosing derived from reference nomogram figures, refer to each reference [Bleyer 1978; Bleyer 1981; Widemann 2006] or institution-specific nomogram for details): At 24 hours: For methotrexate levels of ≥100 micromolar at ~24 hours, leucovorin is initially dosed at 1,000 mg/m2 IV every 6 hours For methotrexate levels of ≥10 to 2 IV every 3 or 6 hours For methotrexate levels of ~1 to 10 micromolar at 24 hours, leucovorin is initially dosed at 10 mg/m2 IV or orally every 3 or 6 hours At 48 hours: For methotrexate levels of ≥100 micromolar at 48 hours, leucovorin is dosed at 1,000 mg/m2 IV every 6 hours For methotrexate levels of ≥10 to 2 IV every 3 hours For methotrexate levels of ~1 to 10 micromolar at 48 hours, leucovorin is dosed at 100 mg/m2 IV every 6 hours or 10 mg/m2 IV or orally to 100 mg/m2 IV every 3 hours At 72 hours: For methotrexate levels of ≥10 micromolar at 72 hours, leucovorin is dosed at 100 to 1,000 mg/m2 IV every 3 to 6 hours For methotrexate levels of ~1 to 10 micromolar at 72 hours, leucovorin is dosed at 10 mg/m2 IV or orally to 100 mg/m2 IV every 3 hours For methotrexate levels of

(For additional information see "Leucovorin: Pediatric drug information") Note: Because oral absorption is saturable at doses >25 mg, administering single oral doses >25 mg is not recommended (convert to parenteral therapy). Folic acid antagonist (eg, trimethoprim, pyrimethamine) overdose: Refer to adult dosing. Folate-deficient megaloblastic anemia: Refer to adult dosing. High-dose methotrexate-rescue: Refer to adult dosing. Cofactor therapy in methanol toxicity (off-label use): Refer to adult dosing. Prevention of pyrimethamine hematologic toxicity in HIV-exposed/-positive patients (off-label uses; CDC 2009): Infants and Children >1 month of age: Note: Leucovorin should continue for 1 week after pyrimethamine is discontinued. Toxoplasmosis (Toxoplasma gondii): Primary prophylaxis: Oral: 5 mg once every 3 days (in combination with pyrimethamine [with either dapsone or atovaquone]) Secondary prophylaxis: Oral: 5 mg once every 3 days (in combination with pyrimethamine [with either sulfadiazine, atovaquone, or clindamycin]) Treatment (congenital): Oral or IM: 10 mg with every pyrimethamine dose (in combination with either sulfadiazine or clindamycin); treatment duration: 12 months Treatment (acquired): Oral: Acute induction: 10 to 25 mg once daily (in combination with pyrimethamine [with either sulfadiazine, clindamycin, or atovaquone]) for ≥6 weeks Adolescents: Refer to adult dosing

Refer to adult dosing.

There are no dosage adjustments provided in the manufacturer’s labeling.

Warnings & Precautions

Source: Lexicomp

Hypersensitivity

Hypersensitivity, including allergic reactions, anaphylactoid reactions, and urticaria have been reported with leucovorin. Because leucovorin is typically administered in combination with other chemotherapy agents, it may be difficult to determine the causative agent for hypersensitivity reactions. In a series of 44 patients with hypersensitivity to leucovorin-containing regimens, hypersensitivity/infusion reaction to leucovorin was confirmed in 5 patients; reactions also occurred with subsequent rechallenge with LEVOleucovorin (Ureña-Tavera 2015).

Seizures

Seizures or syncope have been reported (rarely) in patients with cancer receiving leucovorin, usually in association with fluoropyrimidine administration, and most commonly in patients with CNS metastases or other predisposing factors; a causal relationship has not been established. Disease-related concerns:

Anemias

Leucovorin is inappropriate treatment for pernicious anemia and other megaloblastic anemias secondary to a lack of vitamin B12; a hematologic remission may occur while neurologic manifestations progress.

Renal impairment

Leucovorin is excreted renally; the risk for toxicities may be increased in patients with renal impairment. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Fluorouracil

Leucovorin may increase the toxicity of 5-fluorouracil; deaths from severe enterocolitis, diarrhea, and dehydration have been reported (in elderly patients); granulocytopenia and fever have also been reported.

Sulfamethoxazole-trimethoprim

Combination of leucovorin and sulfamethoxazole-trimethoprim for the acute treatment of PCP in patients with HIV infection has been reported to cause increased rates of treatment failure. Dosage form specific issues:

Administration route

Parenteral administration may be preferred to oral if vomiting or malabsorption is likely. Because oral absorption is saturable at doses above 25 mg, administering oral doses greater than 25 mg is not recommended (convert to parenteral therapy).

Benzyl alcohol and derivatives

When doses >10 mg/m2 are required using the powder for injection, reconstitute using sterile water for injection, not a solution containing benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

Injection

Due to calcium content, do not administer IV solutions at a rate >160 mg/minute. Not intended for intrathecal use. Other warnings and precautions:

Folic acid antagonist overdose

When used for the treatment of accidental folic acid antagonist overdose, administer as soon as possible.

Methotrexate overdose

When used for the treatment of a methotrexate overdose, administer IV leucovorin as soon as possible. Monitoring of the serum methotrexate concentration is essential to determine the optimal dose/duration of leucovorin; however, do not wait for the results of a methotrexate level before initiating leucovorin. It is important to adjust the leucovorin dose once a methotrexate level is known. The dose may need to be increased or administration prolonged in situations in which methotrexate excretion may be delayed (eg, ascites, pleural effusion, renal insufficiency, inadequate hydration). Never administer leucovorin intrathecally.

Methotrexate rescue therapy

Methotrexate serum concentrations should be monitored to determine dose and duration of leucovorin therapy. Dose may need increased or administration prolonged in situations where methotrexate excretion may be delayed (eg, ascites, pleural effusion, renal insufficiency, inadequate hydration). Never administer leucovorin intrathecally.

Pregnancy & Lactation

Pregnancy

FDA category C

Animal reproduction studies have not been conducted. Leucovorin is a biologically active form of folic acid. Adequate amounts of folic acid are recommended during pregnancy. Refer to Folic Acid monograph.

Lactation

Leucovorin is a biologically active form of folic acid. Adequate amounts of folic acid are recommended in breast-feeding women. Refer to Folic Acid monograph.

Monitoring

Clinical pearl	High-dose methotrexate therapy: Plasma methotrexate concentration; leucovorin is continued until the plasma methotrexate level Fluorouracil therapy: CBC with differential and platelets, liver function tests, electrolytes

Chemistry & Properties

Formula	C20H23N7O7
Molecular weight	473.45 g/mol
CAS	58-05-9
PubChem CID	135403648
InChIKey	`VVIAGPKUTFNRDU-OLZOCXBDSA-N`
logP	-0.73
Polar surface area	219.84 Å²
H-bond acceptors / donors	9 / 7
Drug-likeness (QED)	0.21
Lipinski violations	1

SMILES

Nc1nc(=O)c2c([nH]1)NC[C@@H](CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)N2C=O

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	10.0%
Half-life	1.122 h
Volume of distribution	0.225 L/kg
Protein binding	69.3%
BBB penetrant	No

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
CALCIUM FOLINAT "EBEWE"	Ampoule (as Calcium Folinate) 10 mg/ml	5 amp	Sabbagh Drug Store	—