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LEUCOVORIN AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Leucovorin calcium (also known as folinic acid) is the 5-formyl derivative of tetrahydrofolic acid, the active form of folic acid. Levoleucovorin calcium, the levo isomeric form of racemic d,l-leucovorin, is the pharmacologically active isomer of leucovorin [(6-S)-leucovorin].

Specific Substances

    A) LEUCOVORIN
    1) Folinic acid
    2) Citrovorum factor
    3) Calcium folinate
    4) Leucovorin calcium
    5) NSC-3590
    6) 5-Formyltetrahydropteroylglutamic acid
    7) N-[4-(2-Amino-5-formyl-5ylmethylamino-benzoyl]-L(+)-glutamic acid
    8) CAS 58-05-9
    9) CAS 1492-18-8 (anhydrous calcium folinate)
    10) CAS 41927-89-3 (calcium folinate pentahydrate)
    LEVOLEUCOVORIN
    1) d,l-leucovorin
    2) Racemic d,l-leucovorin
    3) Levoleucovorin calcium
    4) (6S)-N-[4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl-L-glutamate pentahydrate

    1.2.1) MOLECULAR FORMULA
    1) C20-H21-Ca-N7-O7 (Prod Info leucovorin calcium oral tablets, 2005; Prod Info leucovorin calcium injection, 2005; Prod Info leucovorin calcium injection, 2000)
    2) C20-H21-Ca-N7-O7-5H2O (Prod Info levoleucovorin solution for IV injection, 2008)

Available Forms Sources

    A) FORMS
    1) LEUCOVORIN CALCIUM is available as injection powder for solution (50 mg, 100 mg, 200 mg, and 350 mg), injection solution (10 mg/mL), and oral tablets (5 mg, 10 mg, 15 mg, and 25 mg) (Prod Info leucovorin calcium oral tablets, 2005; Prod Info leucovorin calcium injection, 2005; Prod Info leucovorin calcium injection, 2000).
    2) Certain diluents used in leucovorin calcium for injection may contain benzyl alcohol (Prod Info leucovorin calcium injection, 2005).
    3) LEVOLEUCOVORIN is available as a 50-mg single-use vial for injection, containing a sterile lyophilized powder of 64 mg of levoleucovorin calcium pentahydrate (equivalent to 50 mg levoleucovorin) and 50 mg mannitol (Prod Info levoleucovorin solution for IV injection, 2008).
    B) USES
    1) LEUCOVORIN
    a) FDA APPROVED INDICATIONS - Leucovorin calcium is used:
    1) For rescue therapy after high-dose methotrexate in patients with osteosarcoma (Prod Info leucovorin calcium injection, 2005; Prod Info leucovorin calcium injection, 2000).
    2) To reduce the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists (Prod Info leucovorin calcium oral tablets, 2005; Prod Info leucovorin calcium injection, 2005; Prod Info leucovorin calcium injection, 2000).
    3) To treat megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible (Prod Info leucovorin calcium injection, 2005; Prod Info leucovorin calcium injection, 2000) (not effective for treatment of pernicious anemia or megaloblastic anemias secondary to vitamin B12 (cobalamin) deficiency).
    4) In combination with fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer (Prod Info leucovorin calcium injection, 2005; Prod Info leucovorin calcium injection, 2000).
    b) NON-FDA APPROVED INDICATION - May be used to treat methanol toxicity. Leucovorin and folic acid enhance the metabolism of formic acid (formate) in primates (Noker et al, 1980; Anon, 1979) and probably other nonprimate animals (Makar & Tephly, 1976) to carbon dioxide and water. Folic acid is more commonly used for this indication than is leucovorin.
    2) LEVOLEUCOVORIN
    a) Levoleucovorin is used as rescue therapy following high-dose methotrexate therapy in patients with osteosarcoma. It is also used to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdose of folic acid antagonists (Prod Info levoleucovorin solution for IV injection, 2008).
    3) FOLINIC ACID VS FOLIC ACID USE AFTER METHOTREXATE - Methotrexate is a chemotherapeutic agent that is a folic acid antagonist. It is structurally similar to folic acid and acts by reversibly inhibiting dihydrofolate reductase, the enzyme that reduces folic acid to tetrahydrofolic acid. This inhibition ultimately interferes with the synthesis of DNA and cell reproduction. Large doses of folic acid given simultaneously have no effect on methotrexate due to greater methotrexate affinity for the enzyme than folic acid itself. However, leucovorin calcium, a tetrahydrofolic acid derivative, can block the effects of methotrexate, particularly if given shortly after methotrexate administration. This combination of high dose methotrexate therapy and folinic acid rescue with leucovorin calcium is frequently employed in an effort to reduce exposure of sensitive cells to methotrexate (Prod Info Methotrexate injection, , 2003.).
    4) In some cases, clinicians have prescribed leucovorin calcium using the name folinic acid, and folic acid was dispensed or administered to the cancer patient by mistake (Institute for Safe Medication Practices, 2000).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Leucovorin calcium is used for the following indications: (1) For rescue therapy after high-dose methotrexate in patients with osteosarcoma; (2) To reduce the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists; (3) To treat megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible (not effective for treatment of pernicious anemia or megaloblastic anemias secondary to vitamin B12 (cobalamin) deficiency); (4) In combination with fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer. Levoleucovorin is used as rescue therapy following high-dose methotrexate therapy in patients with osteosarcoma. It is also used to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdose of folic acid antagonists.
    B) PHARMACOLOGY: LEUCOVORIN: Leucovorin calcium, a reduced folic acid derivative, inhibits dihydrofolate reductase, thus it is used to counteract the therapeutic and toxic effects of folic acid antagonists. It also stabilizes the binding of fluorodeoxyuridylic acid to thymidylate synthase resulting in the inhibition of this enzyme. LEVOLEUCOVORIN: As rescue from methotrexate toxicity, leucovorin competes with methotrexate for binding to dihydrofolate reductase and active transport into cells, and for folylpolyglutamate synthetase. Levoleucovorin does not require reduction by dihydrofolate reductase in order to be used in reactions using folates as a source of "one-carbon moieties".
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) LEUCOVORIN: Most adverse effects reported with leucovorin calcium are in combination use with 5-flourouracil (leucovorin calcium appears to enhance the toxicity of 5FU). The most commonly reported effects are leukopenia, nausea, vomiting, diarrhea, stomatitis, and alopecia. Dermatitis, constipation, anorexia, thrombocytopenia, lethargy, malaise, and fatigue have also been reported in patients receiving leucovorin calcium in combination with 5FU. Allergic sensitization, anaphylactoid reactions, and urticaria have been reported. LEVOLEUCOVORIN: The most commonly reported adverse effects following levoleucovorin therapy are vomiting, stomatitis, nausea, and diarrhea. Other effects include loss of appetite, taste sense altered, dyspepsia, abdominal pain, typhlitis, dyspnea, asthenia, neuropathy, confusion, lethargy/malaise/fatigue, allergic reactions, abnormal renal function, dermatitis, and alopecia.
    E) WITH POISONING/EXPOSURE
    1) Limited overdose data available. Overdose effects are expected to be an extension of adverse effects reported with therapeutic use. Overdose may nullify the desired chemotherapeutic effects of concomitantly administered folic acid antagonists. Intrathecal administration of leucovorin calcium has been associated with seizures, severe neurotoxicity and death.
    0.2.20) REPRODUCTIVE
    A) Leucovorin calcium and levoleucovorin are classified as FDA pregnancy category C.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status following significant overdose.
    C) Monitor CBC with differential and platelet count, serum calcium, and renal function in symptomatic patients.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Refer to PARENTERAL SECTION for information on specific treatment.
    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage nausea and vomiting with antiemetics. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. For severe neutropenia, administer colony stimulating factor (eg, filgrastim, sargramostim). Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or hemorrhage. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    C) INTRATHECAL INJECTION
    1) Leucovorin and levoleucovorin may be harmful or fatal if given intrathecally. Keep patient upright if possible. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free 0.9% saline). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 18 to 24 hr). FFP (25 ml FFP/liter NS) or albumin 5% have also been used for perfusion. Dexamethasone 4 mg IV every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for persistent seizures and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    E) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with persistent seizures or severe allergic reactions.
    F) ANTIDOTE
    1) None.
    G) MYELOSUPPRESSION
    1) For severe neutropenia, administer colony stimulating factor. Filgrastim 5 mcg/kg/day IV or SubQ or sargramostim 250 mcg/m(2)/day IV infused over 4 hours. Monitor serial CBC with differential. Transfusions may be required for severe thrombocytopenia or bleeding.
    H) ENHANCED ELIMINATION
    1) It is unknown if hemodialysis would be effective in overdose.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    J) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    K) PHARMACOKINETICS
    1) LEUCOVORIN: Tmax: IM: 52 min; IV: 10 min; ORAL: 1.72 hours. Absorption: Rapidly absorbed after oral administration; saturation of absorption is reached at doses greater than 25 mg. Bioavailability is approximately 97% for a 25-mg dose, 75% for a 50-mg dose, and 37% for a 100-mg dose. Excretion: Renal: 80% to 90%. Elimination half-life: Total reduced folates: (IM and IV) 6.2 hours. ORAL: 3.5 hours. LEVOLEUCOVORIN: Tmax: 0.9 hours. Absorption: The absolute bioavailability of oral leucovorin tablets was similar (65%) when given at twice the dose of levoleucovorin. Excretion: Levoleucovorin is excreted renally, primarily as active folate metabolites. Elimination half-life: 5 hours to 7 hours.
    L) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause abnormal renal function, leukopenia, or thrombocytopenia.

Range Of Toxicity

    A) TOXICITY: Toxic dose is not known. An 11-year-old boy died after receiving 150 mg of leucovorin intrathecally in 3 divided doses over 24 hours. Therapeutic dose varies by indication.

Clinical Effects

Summary Of Exposure

    A) USES: Leucovorin calcium is used for the following indications: (1) For rescue therapy after high-dose methotrexate in patients with osteosarcoma; (2) To reduce the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists; (3) To treat megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible (not effective for treatment of pernicious anemia or megaloblastic anemias secondary to vitamin B12 (cobalamin) deficiency); (4) In combination with fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer. Levoleucovorin is used as rescue therapy following high-dose methotrexate therapy in patients with osteosarcoma. It is also used to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdose of folic acid antagonists.
    B) PHARMACOLOGY: LEUCOVORIN: Leucovorin calcium, a reduced folic acid derivative, inhibits dihydrofolate reductase, thus it is used to counteract the therapeutic and toxic effects of folic acid antagonists. It also stabilizes the binding of fluorodeoxyuridylic acid to thymidylate synthase resulting in the inhibition of this enzyme. LEVOLEUCOVORIN: As rescue from methotrexate toxicity, leucovorin competes with methotrexate for binding to dihydrofolate reductase and active transport into cells, and for folylpolyglutamate synthetase. Levoleucovorin does not require reduction by dihydrofolate reductase in order to be used in reactions using folates as a source of "one-carbon moieties".
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) LEUCOVORIN: Most adverse effects reported with leucovorin calcium are in combination use with 5-flourouracil (leucovorin calcium appears to enhance the toxicity of 5FU). The most commonly reported effects are leukopenia, nausea, vomiting, diarrhea, stomatitis, and alopecia. Dermatitis, constipation, anorexia, thrombocytopenia, lethargy, malaise, and fatigue have also been reported in patients receiving leucovorin calcium in combination with 5FU. Allergic sensitization, anaphylactoid reactions, and urticaria have been reported. LEVOLEUCOVORIN: The most commonly reported adverse effects following levoleucovorin therapy are vomiting, stomatitis, nausea, and diarrhea. Other effects include loss of appetite, taste sense altered, dyspepsia, abdominal pain, typhlitis, dyspnea, asthenia, neuropathy, confusion, lethargy/malaise/fatigue, allergic reactions, abnormal renal function, dermatitis, and alopecia.
    E) WITH POISONING/EXPOSURE
    1) Limited overdose data available. Overdose effects are expected to be an extension of adverse effects reported with therapeutic use. Overdose may nullify the desired chemotherapeutic effects of concomitantly administered folic acid antagonists. Intrathecal administration of leucovorin calcium has been associated with seizures, severe neurotoxicity and death.

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) LEVOLEUCOVORIN: In studies evaluating levoleucovorin rescue following high-dose methotrexate therapy in patients (ages 6 to 21 years) with osteogenic sarcoma, dyspnea occurred in 6.3% of patients (1 of 16) (Prod Info Fusilev(R) intravenous injection , 2011).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) LEUCOVORIN: Although a causal relationship has not been established, seizures and/or syncope have occurred rarely in cancer patients receiving leucovorin calcium, usually in association with fluoropyrimidine administration (Prod Info LEUCOVORIN CALCIUM powder for intramuscular, intravenous injection, 2013; Prod Info LEUCOVORIN CALCIUM oral tablets, 2014).
    2) WITH POISONING/EXPOSURE
    a) LEUCOVORIN: Intrathecal administration of leucovorin calcium has been associated with seizures, severe neurotoxicity and death (Jardine et al, 1996; Spiegel et al, 1984).
    b) CASE REPORT: An 11-year-old boy with a history of acute lymphocytic leukemia received an overdose of 20 mg of intrathecal methotrexate (intended dose 12 mg), and was then treated with intrathecal and intravenous leucovorin calcium. Following the overdose, 10 mL of CSF was removed and then 50 mg of leucovorin calcium in saline was given intrathecally followed by 100 mg intravenously every 4 hours; 2 additional doses of 50 mg leucovorin calcium were administered intrathecally over the next 24 hours. Seizure activity began shortly after the infusions were completed with an EEG showing epileptiform activity. Progressive multi-system organ failure developed, including diffuse cerebral edema with herniation, and EEG was consistent with brain death; he was removed from life support 5 days after exposure . (Jardine et al, 1996). The 20 mg intrathecal dose of methotrexate in this case would NOT be expected to cause significant neurotoxicity; the effects in this case were attributed to the intrathecal leucovorin.
    B) LETHARGY
    1) WITH THERAPEUTIC USE
    a) LEUCOVORIN: Lethargy/malaise/fatigue have been reported in patients receiving leucovorin calcium in combination with 5-flourouracil (Prod Info LEUCOVORIN CALCIUM powder for intramuscular, intravenous injection, 2013).
    b) LEVOLEUCOVORIN: Lethargy/malaise/fatigue have been reported in patients receiving levoleucovorin calcium in combination with 5-fluorouracil (Prod Info Fusilev(R) intravenous injection , 2011).
    C) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) LEVOLEUCOVORIN: In studies evaluating levoleucovorin rescue following high-dose methotrexate therapy in patients (ages 6 to 21 years) with osteogenic sarcoma, confusion occurred in 6.3% of patients (1 of 16) (Prod Info Fusilev(R) intravenous injection , 2011).
    D) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) LEVOLEUCOVORIN: In studies evaluating levoleucovorin rescue following high-dose methotrexate therapy in patients (ages 6 to 21 years) with osteogenic sarcoma, neuropathy occurred in 6.3% of patients (1 of 16) (Prod Info Fusilev(R) intravenous injection , 2011).
    E) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) LEVOLEUCOVORIN: Asthenia has been reported in patients receiving levoleucovorin calcium in combination with 5-fluorouracil (Prod Info Fusilev(R) intravenous injection , 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) LEUCOVORIN: When leucovorin calcium and 5-fluorouracil (5-FU) were given concurrently as palliative therapy for advanced colorectal cancer, gastrointestinal toxicities, such as stomatitis, diarrhea, nausea and vomiting, constipation, and anorexia, were more common than those observed in patients treated with 5-FU alone. Gastrointestinal toxicities may be more severe and of prolonged duration with the combination (Prod Info LEUCOVORIN CALCIUM powder for intramuscular, intravenous injection, 2013).
    B) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) LEVOLEUCOVORIN: In studies evaluating levoleucovorin rescue following high-dose methotrexate therapy in patients (ages 6 to 21 years) with osteogenic sarcoma, stomatitis (all-grade) occurred in 37.5% of patients (n=6 of 16); stomatitis (grade 3 or greater) occurred in 6.3% of patients (n=1 of 16) (Prod Info Fusilev(R) intravenous injection , 2011).
    b) LEVOLEUCOVORIN: Stomatitis has been reported in patients receiving levoleucovorin calcium in combination with 5-fluorouracil (Prod Info Fusilev(R) intravenous injection , 2011).
    C) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) LEUCOVORIN: Anorexia has been reported in patients receiving leucovorin calcium in combination with 5-fluorouracil (Prod Info LEUCOVORIN CALCIUM powder for intramuscular, intravenous injection, 2013).
    b) LEVOLEUCOVORIN: Anorexia/decreased appetite has been reported in patients receiving levoleucovorin calcium in combination with 5-fluorouracil (Prod Info Fusilev(R) intravenous injection , 2011).
    D) NAUSEA
    1) WITH THERAPEUTIC USE
    a) LEUCOVORIN: Nausea has been reported in patients receiving leucovorin calcium in combination with 5-fluorouracil (Prod Info LEUCOVORIN CALCIUM powder for intramuscular, intravenous injection, 2013).
    b) LEVOLEUCOVORIN: One of the most prevalent adverse effects of levoleucovorin combined with 5-fluorouracil is nausea; the incidence and severity of this effect appears similar to those of racemic leucovorin plus 5-fluorouracil based on indirect comparison (Prod Info Fusilev(R) intravenous injection , 2011; Erlichman et al, 1993; Papadimitrakopoulou et al, 1997a; Valone et al, 1993a).
    E) VOMITING
    1) WITH THERAPEUTIC USE
    a) LEUCOVORIN: Vomiting has been reported in patients receiving leucovorin calcium in combination with 5-fluorouracil (Prod Info LEUCOVORIN CALCIUM powder for intramuscular, intravenous injection, 2013).
    b) LEVOLEUCOVORIN: One of the most prevalent adverse effects of levoleucovorin combined with 5-fluorouracil is vomiting; the incidence and severity of this effect appears similar to those of racemic leucovorin plus 5-fluorouracil based on indirect comparison (Prod Info Fusilev(R) intravenous injection , 2011; Erlichman et al, 1993; Papadimitrakopoulou et al, 1997a; Valone et al, 1993a).
    F) TYPHLITIS
    1) WITH THERAPEUTIC USE
    a) LEVOLEUCOVORIN: In studies evaluating levoleucovorin rescue following high-dose methotrexate therapy in patients (ages 6 to 21 years) with osteogenic sarcoma, typhlitis (grade 3 or greater) occurred in 6.3% of patients (1 of 16) (Prod Info Fusilev(R) intravenous injection , 2011).
    G) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) LEUCOVORIN: Diarrhea has been reported in patients receiving leucovorin calcium in combination with 5-fluorouracil (Prod Info LEUCOVORIN CALCIUM powder for intramuscular, intravenous injection, 2013).
    b) LEVOLEUCOVORIN: Diarrhea has been reported in patients receiving levoleucovorin calcium in combination with 5-fluorouracil (Prod Info Fusilev(R) intravenous injection , 2011).
    H) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) LEVOLEUCOVORIN: Abdominal pain has been reported in patients receiving levoleucovorin calcium in combination with 5-fluorouracil (Prod Info Fusilev(R) intravenous injection , 2011).
    I) INDIGESTION
    1) WITH THERAPEUTIC USE
    a) LEVOLEUCOVORIN: In studies evaluating levoleucovorin rescue following high-dose methotrexate therapy in patients (ages 6 to 21 years) with osteogenic sarcoma, dyspepsia occurred in 6.3% of patients (1 of 16) (Prod Info Fusilev(R) intravenous injection , 2011).
    J) TASTE SENSE ALTERED
    1) WITH THERAPEUTIC USE
    a) LEVOLEUCOVORIN: In studies evaluating levoleucovorin rescue following high-dose methotrexate therapy in patients (ages 6 to 21 years) with osteogenic sarcoma, taste perversion occurred in 6.3% of patients (1 of 16) (Prod Info Fusilev(R) intravenous injection , 2011).
    K) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE
    1) WITH THERAPEUTIC USE
    a) LEVOLEUCOVORIN: One of the most prevalent adverse effects of levoleucovorin combined with 5-fluorouracil is mucositis; the incidence and severity of this effect appears similar to those of racemic leucovorin plus 5-fluorouracil based on indirect comparison (Erlichman et al, 1993; Papadimitrakopoulou et al, 1997a; Valone et al, 1993a).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) LEVOLEUCOVORIN: In studies evaluating levoleucovorin rescue following high-dose methotrexate therapy in patients (ages 6 to 21 years) with osteogenic sarcoma, abnormal renal function occurred in 6.3% of patients (1 of 16) (Prod Info Fusilev(R) intravenous injection , 2011).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) LEUCOVORIN: Leukopenia has been reported in patients receiving leucovorin calcium in combination with 5-flourouracil (Prod Info LEUCOVORIN CALCIUM powder for intramuscular, intravenous injection, 2013).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) LEUCOVORIN: Thrombocytopenia has been reported in patients receiving leucovorin calcium in combination with 5-flourouracil (Prod Info LEUCOVORIN CALCIUM powder for intramuscular, intravenous injection, 2013).
    C) EOSINOPHILIC DISORDER
    1) WITH THERAPEUTIC USE
    a) LEUCOVORIN: CASE REPORT: A 78-year-old woman developed hypereosinophilia after treatment with calcium folinate (leucovorin calcium), cyanocobalamin, and ferrous gluconate for microcytic anemia. Withdrawal of all treatment except ferrous gluconate resulted in normalization of her eosinophil count. Cyanocobalamin alone did not affect the eosinophil count, whereas, reinstitution of leucovorin calcium again precipitated hypereosinophilia. As the woman had been treated on two previous occasions with the triple regimen without effect on eosinophils, it was presumed that the development of this adverse effect was due to an immunological mechanism (Gallerani et al, 1996).
    D) GRANULOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) LEVOLEUCOVORIN: One of the most prevalent adverse effects of levoleucovorin combined with 5-fluorouracil is granulocytopenia; the incidence and severity of this effect appears similar to those of racemic leucovorin plus 5-fluorouracil based on indirect comparison (Erlichman et al, 1993; Papadimitrakopoulou et al, 1997a; Valone et al, 1993a).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) LEUCOVORIN: Alopecia has been reported in patients receiving leucovorin calcium in combination with 5-fluorouracil (Prod Info LEUCOVORIN CALCIUM powder for intramuscular, intravenous injection, 2013).
    b) LEVOLEUCOVORIN: Alopecia has been reported in patients receiving levoleucovorin calcium in combination with 5-fluorouracil (Prod Info Fusilev(R) intravenous injection , 2011).
    B) DERMATITIS
    1) WITH THERAPEUTIC USE
    a) LEUCOVORIN: Dermatitis has been reported in patients receiving leucovorin calcium in combination with 5-fluorouracil (Prod Info LEUCOVORIN CALCIUM powder for intramuscular, intravenous injection, 2013).
    b) LEVOLEUCOVORIN: Dermatitis has been reported in patients receiving levoleucovorin calcium in combination with 5-fluorouracil (Prod Info Fusilev(R) intravenous injection , 2011).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) LEUCOVORIN: Allergic sensitization, anaphylactoid reactions, and urticaria have been reported following both oral and parenteral administration of leucovorin calcium. Anaphylactic reactions including shock have also been reported (Prod Info LEUCOVORIN CALCIUM powder for intramuscular, intravenous injection, 2013).
    b) LEVOLEUCOVORIN: During postmarketing surveillance, of the 217 adverse reactions (108 reports) in which levoleucovorin may have contributed to, there were 40 cases of possible allergic reactions reported. There were 47 cases of possible allergic reactions (67 events) in an analysis of patients in which levoleucovorin was reported as the primary suspected cause and 5-fluorouracil was given concurrently (Prod Info Fusilev(R) intravenous injection , 2011).
    c) CASE REPORT: Anaphylaxis secondary to intravenous administration of leucovorin calcium occurred in an 80-year-old patient with colon cancer who was receiving second-line chemotherapy with irinotecan, 5- fluorouracil, and leucovorin calcium. During the first course, the patient developed a nettle rash following the administration of intravenous leucovorin calcium (200 mg/m(2)), ondansetron, and atropine. The patient received leucovorin calcium, metoclopramide, and prednisone for the second course and developed another rash and profound hypotension requiring intravenous epinephrine. Leucovorin calcium was discontinued and subsequent courses were uneventful (Benchalal et al, 2002).

Reproductive

    3.20.1) SUMMARY
    A) Leucovorin calcium and levoleucovorin are classified as FDA pregnancy category C.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified leucovorin calcium and levoleucovorin as FDA pregnancy category C (Prod Info levoleucovorin solution for IV injection, 2008; Prod Info leucovorin calcium oral tablets, 2005; Prod Info leucovorin calcium injection, 2005; Prod Info leucovorin calcium injection, 2000).
    2) Leucovorin calcium, an active metabolite of folic acid, has been used for the treatment of megaloblastic anemia in pregnancy, although its general safety for use during pregnancy cannot be confirmed. Until more data are available, caution is recommended when considering the use of leucovorin calcium and levoleucovorin in pregnant women.
    3) No human studies of pregnancy outcomes after exposure to levoleucovorin have been published, and there have been no reports of outcomes after inadvertent exposure during pregnancy (Prod Info levoleucovorin solution for IV injection, 2008).
    B) LACK OF EFFECT
    1) Twin neonates exposed to 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) from week 13 of gestation through delivery were born with no evidence of teratogenicity or intrauterine growth retardation and remained developmentally normal at their 2-year follow up. A 26-year-old woman diagnosed with metastatic colorectal cancer in week 10 of pregnancy received 10 courses of a full-dose biweekly modified FOLFOX-6 regimen (oxaliplatin 85 mg/m(2) 2-hour infusion with leucovorin 400 mg/m(2), then 5-FU 400 mg/m(2) bolus and 5-FU 2400 mg/m(2) 46-hour infusion). The last FOLFOX exposure occurred 15 days before delivery at 33 weeks via cesarean section; the fraternal twins both had birth weights of about 2200 g and had one-minute Apgar scores of 10 (Jeppesen & Osterlind, 2011).
    C) ANIMAL STUDIES
    1) No animal reproduction studies have been performed with leucovorin calcium (Prod Info leucovorin calcium oral tablets, 2005; Prod Info leucovorin calcium injection, 2005; Prod Info leucovorin calcium injection, 2000) or levoleucovorin (Prod Info levoleucovorin solution for IV injection, 2008).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known whether leucovorin calcium or levoleucovorin are excreted into human breast milk and the potential for adverse effects in the nursing infant from exposure to the drugs are unknown (Prod Info levoleucovorin solution for IV injection, 2008; Prod Info leucovorin calcium oral tablets, 2005; Prod Info leucovorin calcium injection, 2005; Prod Info leucovorin calcium injection, 2000).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status following significant overdose.
    C) Monitor CBC with differential and platelet count, serum calcium, and renal function in symptomatic patients.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status following significant overdose.
    C) Monitor CBC with differential and platelet count, serum calcium, and renal function in symptomatic patients.
    D) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is generally not recommended because of the potential for persistent seizures and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Refer to PARENTERAL SECTION for information on specific treatment.

Range Of Toxicity

Summary

    A) TOXICITY: Toxic dose is not known. An 11-year-old boy died after receiving 150 mg of leucovorin intrathecally in 3 divided doses over 24 hours. Therapeutic dose varies by indication.

Therapeutic Dose

    7.2.1) ADULT
    A) LEUCOVORIN
    1) LEUCOVORIN RESCUE AFTER HIGH-DOSE METHOTREXATE THERAPY
    a) Leucovorin 15 milligrams (10 milligrams/meter(2) (mg/m(2)) by intramuscular/intravenous/oral routes every 6 hours until serum methotrexate level is below 0.01 micromole/liter (mcmol/L); if 24 hour serum creatinine 50% above baseline, 24 hour methotrexate level above 5 mcmol/L, OR 48 hour methotrexate level above 0.9 mcmol/L, increase dose to 100 mg/m(2) IV every 3 hour until serum methotrexate less than 0.01 mcmol/L (Prod Info leucovorin calcium oral tablets, 2005; Prod Info leucovorin calcium injection, 2005; Prod Info leucovorin calcium injection, 2000).
    2) METHOTREXATE OVERDOSE
    a) DOSE: Dosage determination is highly controversial. It is generally recommended that doses of leucovorin equal to or greater than, the ingested dose of methotrexate be given (Howland, 2006). Lower doses are used during therapy with methotrexate in an attempt to protect normal body cells but not tumor cells.
    b) 100 mg/m(2) IV infused over 15 to 30 minutes every 3 to 6 hours for several days until methotrexate concentration is less than 0.01 mcmol/L (1 x 10(-8) M). In adults the rate should not exceed 160 mg/minute. If methotrexate levels are unavailable, leucovorin should be continued for 12 to 24 doses (3 days) or longer (Howland, 2006). For patients with cancer, leucovorin is continued until the methotrexate level is less than 0.1 mcmol/L (1 x 10(-7) M).
    c) Leucovorin should be administered intravenously as soon as possible after overdose, ideally within the first hour (do not wait for blood levels) (Howland, 2006).
    3) COLORECTAL CANCER, ADVANCED, IN COMBINATION WITH 5-FLUOROURACIL (PALLIATIVE TREATMENT)
    a) Either of the following 2 regimens is recommended:
    b) Leucovorin 200 milligrams/meter(2) (mg/m(2)) intravenously (IV) over a minimum of 3 min, followed by 5-fluorouracil 370 mg/m(2) IV daily for 5 days; may repeat in 4-week intervals for 2 courses, then 4- to 5-week intervals; adjust based on patient tolerance.
    c) Leucovorin 20 milligrams/meter(2) (mg/m(2)) intravenously (IV) followed by 5-fluorouracil 425 mg/m(2) IV daily for 5 days; may repeat in 4-week intervals for 2 courses, then 4- to 5-week intervals; adjust based on patient tolerance (Prod Info leucovorin calcium injection, 2005; Prod Info leucovorin calcium injection, 2000).
    4) MEGALOBLASTIC ANEMIA DUE TO FOLATE DEFICIENCY, WHEN ORAL THERAPY IS NOT FEASIBLE:
    a) Up to 1 mg by intramuscular or intravenous routes (IM/IV) daily (Prod Info leucovorin calcium injection, 2005; Prod Info leucovorin calcium injection, 2000).
    5) METHANOL TOXICITY
    a) Leucovorin and folic acid enhance the metabolism of formic acid (formate) in primates (Noker et al, 1980; Anon, 1979) and probably other nonprimate animals (Makar & Tephly, 1976) to carbon dioxide and water. DOSE (Modified from the work of (Noker et al, 1980; Howland, 2006a):
    1) In a symptomatic patient (metabolic acidosis, visual disturbances), initially administer intravenously leucovorin 1 milligram/kilogram (mg/kg) (up to 50 mg/dose), alternatively, give intravenous folic acid 1 mg/kg (up to 50 mg/dose). Repeat folic acid every 4 to 6 hours until methanol is eliminated and acidosis resolves. If hemodialysis has been used, give a dose of folic acid at the completion of dialysis.
    2) Asymptomatic patients with known or suspected toxic blood methanol concentration, administer intravenous folic acid instead of leucovorin since the body should have adequate time to convert folic acid to active leucovorin. Give 50 mg folic acid IV every 4 hours for the first 24 hours until methanol is eliminated.
    3) Doses should be increased during dialysis or when treating chronic alcoholics.
    6) Because of the calcium content, do not administer the intravenous leucovorin calcium faster than 160 mg/min (16 mL of a 10 mg/mL, or 8 mL of a 20 mg/mL solution per minute) in adults (Prod Info leucovorin calcium injection, 2005).
    B) LEVOLEUCOVORIN
    1) The recommended dose of levoleucovorin rescue is 7.5 milligrams (mg) (approximately 5 mg/square meter (mg/m(2))) given intravenously every 6 hours for 10 doses starting 24 hours after the beginning of methotrexate infusion (12 grams/m(2) intravenous infusion over 4 hours), followed by dosing adjustment according to serum methotrexate levels and renal function. Continue levoleucovorin until methotrexate level is less than 5 x 10(-8) M (0.05 micromolar). Hydration and urinary alkalinization (pH 7 or higher) are suggested. Dose adjustment may be required (Prod Info levoleucovorin solution for IV injection, 2008).

Minimum Lethal Exposure

    A) Toxic dose is not known. An 11-year-old boy developed severe neurotoxicity and died after receiving 150 mg of leucovorin intrathecally in 3 divided doses over 24 hours (Jardine et al, 1996).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) LEUCOVORIN - Leucovorin calcium, a reduced folic acid derivative, inhibits dihydrofolate reductase thus it is used to counteract the therapeutic and toxic effects of folic acid antagonists. It also stabilizes the binding of fluorodeoxyuridylic acid to thymidylate synthase resulting in the inhibition of this enzyme (Prod Info leucovorin calcium intravenous solution, intramuscular solution, 2000; Prod Info leucovorin calcium oral tablet, 1999).
    B) LEVOLEUCOVORIN - As rescue from methotrexate toxicity, leucovorin competes with methotrexate for binding to dihydrofolate reductase and active transport into cells, and for folylpolyglutamate synthetase. Levoleucovorin does not require reduction by dihydrofolate reductase in order to be used in reactions using folates as a source of "one-carbon moieties" (Prod Info levoleucovorin solution for IV injection, 2008; Koizumi et al, 1990; Zittoun et al, 1993).
    C) Levoleucovorin has been used mainly to enhance the antitumor efficacy of 5-fluorouracil. It was speculated that absence of the potentially opposing effects of the d-diastereoisomer would enable levoleucovorin to increase 5-fluorouracil efficacy to a greater extent (without greater toxicity) than that afforded by racemic leucovorin (Papadimitrakopoulou et al, 1997; Valone et al, 1993).
    D) FOLINIC ACID VS FOLIC ACID USE AFTER METHOTREXATE - Methotrexate is a chemotherapeutic agent that is a folic acid antagonist. It is structurally similar to folic acid and acts by reversibly inhibiting dihydrofolate reductase, the enzyme that reduces folic acid to tetrahydrofolic acid. This inhibition ultimately interferes with the synthesis of DNA and cell reproduction. Large doses of folic acid given simultaneously have no effect on methotrexate due to greater methotrexate affinity for the enzyme than folic acid itself. However, leucovorin calcium, a tetrahydrofolic acid derivative, can block the effects of methotrexate, particularly if given shortly after methotrexate administration. This combination of high dose methotrexate therapy and folinic acid rescue with leucovorin calcium is frequently employed in an effort to reduce exposure of sensitive cells to methotrexate (Prod Info Methotrexate injection, , 2003.).
    E) TREATMENT OF METHANOL TOXICITY: Leucovorin and folic acid enhance the metabolism of formic acid (formate) in primates (Noker et al, 1980; Anon, 1979) and probably other nonprimate animals (Makar & Tephly, 1976) to carbon dioxide and water.

Physicochemical

Physical Characteristics

    A) A water-soluble form of reduced folate in the folate group (Prod Info leucovorin calcium oral tablets, 2005).

Molecular Weight

    A) 511.51 (Prod Info leucovorin calcium oral tablets, 2005; Prod Info leucovorin calcium injection, 2005; Prod Info leucovorin calcium injection, 2000)
    B) 601.6 (Prod Info levoleucovorin solution for IV injection, 2008)

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