(6R,S)-5-Formyl-5,6,7,8-tetrahydrofolsaeure

473.4

473.166

200-361-6

DTXSID10224654

Crystals from water with 3 mol of water of crystallization.

219.84

1.1529

245 °C (decomp)

Sparingly soluble in water

2.3X10-21 mm Hg at 25 °C at 25 °C /Estimated/

Henry's Law constant = 4.4X10-27 atm-cu m/mole at 25 °C /Estimated/

pKa1= 3.1; pKa2= 4.8; pKa3= 10.4

Crystals; decompose 240-250 °C; sparingly soluble in water. /dl-Folinic acid/|Hydroxyl radical reaction rate constant = 2.7X10-10 cu cm/molec-sec at 25 °C /Estimated/

Leucovorin calcium injection, powder for injection, and tablets should be stored at 15-30 °C and protected from light. /Leucovorin calcium/|When leucovorin calcium powder for injection is reconstituted as directed, resultant solutions should be used immediately when reconstituted with sterile water for injection or within 7 days when reconstituted with bacteriostatic water for injection containing benzyl alcohol. /Leucovorin calcium/|Leucovorin calcium solutions that have been admixed with 10% dextrose injection, 10% dextrose and 0.9% sodium chloride injection, Ringer's injection, or lactated Ringer's injection are stable for 24 hr when stored at room temperature protected from light. Although some former manufacturers of leucovorin calcium powder for injection have recommended that reconstituted solutions of the drug be protected from light, there is evidence that solutions of the drug are not adversely affected by exposure to room light. Reconstituted solutions of leucovorin calcium that have been further diluted with 50 mL of 5% dextrose injection and stored in Viaflex (R) or glass containers unprotected from light retain at least 90% potency for 24 hr at room temperature. /Leucovorin calcium/|pH of saturated aqueous solution 2.8-3.0 at which pH partial decomposition takes place. More stable at neutral or mildly alkaline pH.

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl leucovorin calcium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Leucovorin Calcium/

Neither normal nor excessively high intakes of folate are associated with liver injury or liver test abnormalities. In long term clinical trials, serum enzyme and bilirubin elevations were no more frequent with folic acid therapy than with placebo. Use of high doses of folic acid (up to 15 mg daily) has not been associated with appreciable adverse reactions, ALT elevations or hepatotoxicity.

Concurrent use of leucovorin /with fluorouracil/ may increase the therapeutic and toxic effects of fluorouracil; although the two medications may be used together for therapeutic advantage, caution is necessary.|Exposure of tumor cells to reduced folates /like leucovorin/ before or with the fluoropyrimidines, 5-fluorouracil or 5-fluoro-2'deoxyuridine, results in a substantial increase in the activity of these drugs. Available evidence suggests that the mechanism of this synergism is a kinetic stabilization of complex formed between thymidylate synthase and fluorodeoxyuridylate that also involves a mole of the cofactor for the thymidylate synthase reaction, 5,10-methylenetetrahydrofolate. This effect results in an extended time of depletion of thymidine nucleotides with a resultant increased level of cell death.|Large dose of leucovorin may counteract the anticonvulsant effects of these medications: /barbiturate anticonvulsants, hydantoin anticonvulsants, primidone/.|The Sprague Dawley rat was used to demonstrate the effect of nitrous oxide, with and without folinic pretreatment, on reproductive indices and fetal development. ... Groups of animals were exposed to 70-75% nitrous oxide on day 9 of pregnancy with or without folinic acid 0.1 mg ip 12 hr before, and immediately before, exposure. Subsequent fetal development was compared with that of various control groups. There were no significant differences in fetal survival, but fetal wt were reduced in both groups exposed to nitrous oxide. Of the indices of skeletal maturity, the number of ossified sternebrae was reduced only in the nitrous oxide group not receiving folinic acid. The incidence of major skeletal abnormalities in the untreated nitrous oxide group was significantly increased to five times that of the control groups, whereas the incidence in the nitrous oxide group receiving folinic acid was not significantly different from control. It is concluded that pretreatment with folinic acid can at least partially reduce the teratogenic effects of nitrous oxide in the rat.

Leucovorin is a metabolite of folic acid. Folic acid is considered a member of the vitamin B complex and it is a natural component of liver, kidney, mushrooms, spinach, fresh fruit, yeast, green leaves and grasses(1).

Leucovorin's production and use as a vitamin and an antianemic drug(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1,500(SRC), determined from a structure estimation method(2), indicates that leucovorin is expected to have low mobility in soil(SRC). The pKa values of leucovorin are 3.5 and 4.5 for the carboxylic acids moieties and 10.3 for the amino group(3), indicating that this compound will primarily exist as two anions and one cation in the environment and charged species do not volatilize from moist soil surfaces. Leucovorin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.3X10-21 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2005).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1,500(SRC), determined from a structure estimation method(2), indicates that leucovorin is expected to adsorb to suspended solids and sediment(SRC). The pKa values of leucovorin are 3.1, 4.8 for the carboxylic acid moieties and 10.3 for the amine(3), indicating that this compound will primarily exist as two anions and one cation in the environment and charged species do not volatilize from water surfaces. According to a classification scheme(4), an estimated BCF of 3.2(SRC), from an estimated log Kow of -4.5(5) and a regression derived equation(6) suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2005).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), leucovorin, which has an estimated vapor pressure of 2.3X10-21 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase leucovorin may be removed from the air by wet and dry deposition(SRC). Leucovorin does not absorb UV light >290 nm(3); therefore leucovorin should not be susceptible to photolysis(SRC).

Leucovorin does not absorb light at wavelengths greater than 290 nm(1) and therefore, should not be susceptible to phololysis.

An estimated BCF of 3.2 was calculated for leucovorin(SRC), using an estimated log Kow of -4.5(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc for leucovorin can be estimated to be 1,500(SRC). According to a classification scheme(2), this estimated Koc value suggests that leucovorin is expected to have low mobility in soil. The pKa values of leucovorin are 3.5 and 4.5 for the carboxylic acids moieties and 10.3 for the amino group(3), indicating that this compound will primarily exist as two anions and a cation in the environment.

The pKa values of leucovorin are 3.1, 4.8 for the carboxylic acid moieties and 10.3 for the amine(1), indicating that this compound will primarily exist as two anions and one cation in the environment and charged species do not volatilize from moist soil or water surfaces. Leucovorin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.3X10-21 mm Hg(SRC), determined from a fragment constant method(2).

Leucovorin is a metabolite of folic acid. Folic acid is considered a member of the vitamin B complex and it is a natural component of liver, mushrooms, spinach, fresh fruit, and yeast(1).

It is not known whether leucovorin is distributed into breast milk.

Occupational exposure to leucovorin may occur through inhalation and dermal contact with this compound at workplaces where leucovorin is produced or used. The general population may be exposed to leucovorin via ingestion of foods which contain folic acid as a natural component and through oral consumption of the vitamin B complex. Additional exposure to the drug among the general population may also ocurr to those administered leucovorin (an antianemic). (SRC)

It is not known whether leucovorin is distributed into breast milk.

Folic acid is a water soluble vitamin found in many foods and particularly in leafy green vegetables that is essential for the critical biosynthetic pathways involving transfer of methyl groups to organic compounds. There is no evidence that folic acid, in physiologic or even super-physiologic, high doses, causes liver injury or jaundice.

Vitamins

Leucovorin is indicated for use in combination with agents such as fluorouracil or high-dose methotrexate, as second-line treatment of squamous cell head and neck carcinoma. /NOT included in US product labeling/|Antidotes|Leucovorin is indicated as a antidote to the toxic effects of folic acid antagonists such as methotrexate, pyrimethamine, or trimethoprim. Leucovorin also is indicated as a rescue after high-dose methotrexate therapy in osteosarcoma and as a part of chemotherapeutic treatment programs in the management of several forms of cancer. /Included in US product labeling/|Leucovorin is indicated to treat megaloblastic anemias associated with sprue, nutritional deficiency, pregnancy, and infancy when oral folic acid therapy is not feasible. Leucovorin is not recommended for use in the treatment of pernicious anemia or other megaloblastic anemias secondary to lack of vitamin B12, since it may produce a hematologic remission while neurologic manifestations continue to progress. /Included in US product labeling/|For more Therapeutic Uses (Complete) data for LEUCOVORIN (7 total), please visit the HSDB record page.

Since allergic reactions have been reported following oral and parenteral administration of folic acid, the possibility of allergic reactions to leucovorin should be considered.|There is a potential danger in administering leucovorin to patients with undiagnosed anemia, as leucovorin may obscure the diagnosis of pernicious anemia by alleviating hematologic manifestations of the disease while allowing neurologic complications to progress. This may result in severe nervous system damage before the correct diagnosis is made. Adequate doses of Vitamin Bl2 may prevent, halt, or improve neurologic changes caused by pernicious anemia.|When leucovorin rescue is used in conjunction with high dose methotrexate therapy, the drugs should be administered only by physicians experienced in cancer chemotherapy, in centers where facilities for measuring blood methotrexate concentrations are available. Leucovorin is usually effective in counteracting severe methotrexate toxicity in these regimens, but toxic reactions to methotrexate may occur despite leucovorin therapy, especially when the half-life of methotrexate is increased (eg, renal dysfunction). Therefore, it is extremely important that leucovorin be administered until the blood concentration of methotrexate declines to nontoxic concentrations.|Since leucovorin calcium enhances the toxicity of fluorouracil, adjunctive therapy with leucovorin calcium and fluorouracil should be given only by, or under the supervision of, physicians experienced in cancer chemotherapy and in the use of antimetabolites. /Leucovorin calcium/|For more Drug Warnings (Complete) data for LEUCOVORIN (10 total), please visit the HSDB record page.

Duration of action: All routes: 3 to 6 hours.|Onset of action: Oral: 20 to 30 minutes. Intramuscular: 10 to 20 minutes. Intravenous: Less than 5 minutes.|Crosses blood-brain barrier in moderate amounts; largely concentrated in liver.|Elimination: Renal: 80-90%. Fecal: 5-8%.|For more Absorption, Distribution and Excretion (Complete) data for LEUCOVORIN (10 total), please visit the HSDB record page.

In vivo, leucovorin calcium is rapidly and extensively converted to other tetrahydrofolic acid derivatives including 5-methyl tetrahydrofolate, which is the major transport and storage form of folate in the body. /Leucovorin calcium/|Hepatic and intestinal mucosal, mainly to 5-methyltetrahydrofolate (active). After oral administration, leucovorin is substantially (greater than 90%) and rapidly (within 30 minutes) metabolized. Metabolism is less extensive (about 66% after intravenous and 72% after intramuscular administration) and slower with parenteral administration.

Terminal half-life for total reduced folates: 6.2 hours.

Leucovorin is a derivative of tetrahydrofolic acid, the reduced form of folic acid, which is involved as a cofactor for 1-carbon transfer reactions in the biosynthesis of purines and pyrimidines of nucleic acids. Impairment of thymidylate synthesis in patients with folic acid deficiency is thought to account for the defective DNA synthesis that leads to megaloblast formation and megaloblastic and macrocytic anemias. Because of its ready conversion to other tetrahydrofolic acid derivatives, leucovorin is a potent antidote for both the hematopoietic and reticuloendothelial toxic effects of folic acid antagonists (eg, methotrexate, pyrimethamine, trimethoprim). It is postulated that in some cancers leucovorin enters and rescues normal cells from the toxic effects of folic acid antagonists, in preference to tumor cells, because of a difference in membrane transport mechanisms; this principle is the basis of high dose methotrexate therapy with leucovorin rescue.

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

/HUMAN EXPOSURE STUDIES/ The ... regimen of leucovorin 20 mg/m followed immediately by 5-fluorouracil 425 mg/m administered for 5 consecutive days every 4 weeks is commonly used in the treatment of colorectal cancer. This study was aimed at prospectively determining the incidence and pattern of severe toxicity associated with this regimen... /in/ ... 243 patients with colorectal cancer ... for the incidence of severe toxicity (defined as toxicity requiring hospitalization). Of the 243 patients, 32 (13%) were hospitalized for chemotherapy-related toxicity. Major toxicities included neutropenic fever in 21 (9%), grade III/IV mucositis in 25 (10%) and grade III/IV diarrhea in 20 (8%). There were five (2%) treatment-related deaths. Female patients exhibited a higher incidence of severe toxicity (18%) and toxic death (4/105) than did male patients (9% and 1/138, respectively). Elderly patients (> or =70 years) had a higher incidence of severe toxicity than younger patients did (24% versus 7%, < 0.001). Toxic death occurred in 4 of 89 patients aged 70 years or more compared to 1 of 154 in younger patients. Most episodes of severe toxicity (56%) and toxic deaths (4/5) were observed after the first cycle. /This/ ... regimen can be associated with severe toxicity, usually occurring after the first cycle. Female gender and advanced age predict severe toxicity; therefore, dose reduction in high-risk patients should be considered, especially during the first cycle.|/SIGNS AND SYMPTOMS/ It has been suggested that seizures are associated with high-dose leucovorin and fluorouracil therapy in cancer patients, especially in patients with central nervous system metastases or other predisposing factors.

Tablets, 5, 10, 15, and 25 mg. Powder for oral solution, 1 mg, following reconstitution. Ampules, 3 mg/ml and 5 mg/ml. Vials, 50, 100, and 350 mg. /Leucovorin calcium/|Oral Tablets, 5 mg (of leucovorin), Wellcovorin (with povidone; scored), Burroughs Wellcome; 10 mg (of leucovorin), Leucovorin Calcium Tablets (scored), Lederle; 15 mg (of leucovorin), Leucovorin Calcium Tablets (scored), Lederle; 25 mg (of leucovorin), Wellcovorin (with povidone; scored), Burroughs Wellcome; Parenteral For Injection, 50 mg (of leucovorin), Leucovorin Calcium for Injection, Cetus, Elkins-Sinn, Lederle; 100 mg (of leucovorin), Leucovorin Calcium for Injection, Cetus, Lederle; Wellcovorin, Burroughs Wellcome; 350 mg (of leucovorin), Leucovorin Calcium for Injection, Lederle; Injection, 3 mg (of leucovorin) per ml, Leucovorin Calcium Injection (with benzyl alcohol 0.9%), Lederle. /Leucovorin calcium/

A member of the folic acid group of vitamins and a growth factor for the bacterium leuconostoc citroforum. Folinic acid is an important metabolite of folic acid and may be the active form in cellular metabolism.|Intermediate product of the metabolism of folic acid; the active form into which that acid is converted in the body, ascorbic acid being a necessary factor in the conversion process.|Information available in 2005 indicated that Leucovorin (folinic acid) was used in the manufacture of pharmaceutical preparations in the following countries: Belgium (1)|Information available in 2005 indicated that Calcium folinate was used in the manufacture of pharmaceutical preparations in the following countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Croatia, Czech Republic, Denmark, Finland, France, Germany, Greece, Hong Kong, Hungary, India, Indonesia, Ireland, Israel, Italy, Luxembourg, Malaysia, Mexico, Netherlands, New Zealand, Norway, Poland, Portugal, Romania, Russian Federation, Singapore, Slovenia, South Africa, Spain, Sweden, Switzerland, Thailand, Turkey, United Kingdom, United States, Yugoslavia (1,2)|For more General Manufacturing Information (Complete) data for LEUCOVORIN (6 total), please visit the HSDB record page.

Analyte: leucovorin calcium; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards /leucovorin calcium/|Analyte: leucovorin calcium; matrix: chemical purity; procedure: liquid chromatography with detection at 254 nm and comparison to standards /leucovorin calcium/|Analyte: leucovorin calcium; matrix: pharmaceutical preparation (injection solution); procedure: infrared absorption spectrophotometry with comparison to standards (chemical identification) /leucovorin calcium/|Analyte: leucovorin calcium; matrix: pharmaceutical preparation (injection solution); procedure: liquid chromatography with detection at 254 nm and comparison to standards (chemical purity) /leucovorin calcium/|For more Analytic Laboratory Methods (Complete) data for LEUCOVORIN (7 total), please visit the HSDB record page.