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Leucovorin is a derivative of folic acid with chemoprotection, antidote, and synergistic activity. Leucovorin does not require metabolism by dihydrofolate reductase, the molecular target of folate antagonist-type chemotherapeutic drugs, and is converted to a tetrahydrofolate, which is the necessary folate for purine and pyrimidine synthesis. As this agent allows for some purine/pyrimidine synthesis to occur, the toxic effects of folic acid antagonist-type chemotherapeutic drugs are counteracted while still permitting the antitumor activity of the folic acid antagonist through dihydrofolate reductase inhibition. This agent also potentiates the effects of 5-fluorouracil and its derivatives by stabilizing the binding of 5-fluorouracil’s converted form fluorodeoxyuridylic acid to its target enzyme thymidylate synthase, thus prolonging drug activity.

Folinic Acid (also known as 5-formyl tetrahydrofolic acid or leucovorin) is the 5-formyl derivative of tetrahydrofolic acid, a necessary co-factor in the body. Commercially available leucovorin is composed of a 1:1 racemic mixture of the dextrorotary and levorotary isomers, while levoleucovorin contains only the pharmacologically active levo-isomer. In vitro, the levo-isomer has been shown to be rapidly converted to the biologically available methyl-tetrahydrofolate form while the dextro form is slowly excreted by the kidneys. Despite this difference in activity, the two commercially available forms have been shown to be pharmacokinetically identical and may be used interchangeably with limited differences in efficacy or side effects (Kovoor et al, 2009). As folate analogs, leucovorin and levoleucovorin are both used to counteract the toxic effects of folic acid antagonists, such as methotrexate, which act by inhibiting the enzyme dihydrofolate reductase (DHFR). They are indicated for use as rescue therapy following use of high-dose methotrexate in the treatment of osteosarcoma or for diminishing the toxicity associated with inadvertent overdosage of folic acid antagonists. Injectable forms are also indicated for use in the treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible and for use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer. Folic acid is an essential B vitamin required by the body for the synthesis of purines, pyrimidines, and methionine before incorporation into DNA or protein. However, in order to function in this role, it must first be reduced by the enzyme dihydrofolate reductase (DHFR) into the cofactors dihydrofolate (DHF) and tetrahydrofolate (THF). This important pathway, which is required for de novo synthesis of nucleic acids and amino acids, is disrupted when high-dose methotrexate is used for cancer therapy. As methotrexate functions as a DHFR inhibitor to prevent DNA synthesis in rapidly dividing cells, it also prevents the formation of DHF and THF. This results in a deficiency of coenzymes and a resultant buildup of toxic substances that are responsible for numerous adverse side effects associated with methotrexate therapy. As levoleucovorin and leucovorin are analogs of tetrahydrofolate (THF), they are able to bypass DHFR reduction and act as a cellular replacement for the co-factor THF, thereby preventing these toxic side effects.

Mechanism of Action

As leucovorin is a derivative of folic acid, it can be used to increase levels of folic acid under conditions favoring folic acid inhibition (following treatment of folic acid antagonists such as methotrexate). Leucovorin enhances the activity of fluorouracil by stabilizing the bond of the active metabolite (5-FdUMP) to the enzyme thymidylate synthetase.

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.

Leucovorin is one of several active, chemically reduced derivatives of folic acid. It is useful as an antidote to drugs which act as folic acid antagonists. Leucovorin is a mixture of the diastereoisomers of the 5-formyl derivative of tetrahydrofolic acid (THF). The biologically active compound of the mixture is the (-)-l-isomer, known as Citrovorum factor or (-)-folinic acid. Leucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “one-carbon” moieties. Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. Leucovorin has also been used to enhance the activity of fluorouracil.

Indications

For the treatment of osteosarcoma (after high dose methotrexate therapy). Used to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists, and to treat megaloblastic anemias due to folic acid deficiency. Also used in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer.
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.
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.
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.
For use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer
Leucovorin rescue after high dose methotrexate therapy; diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages.
Advanced Colorectal Cancer
Advanced Esophageal Cancers
Advanced Gastric Cancer
Anemia of Pregnancy
Bladder Cancer, Cancer
Folate and iron deficiency
Folate deficiency
Folic acid antagonist overdose
Iron Deficiency (ID)
Macrocytic anemia
Megaloblastic anemia
Pancreatic Metastatic Cancer
Postpartum Anemia
Hypochromic anemia
Methotrexate toxicity
Normochromic anemia
Pyrimethamine hematologic toxicity

Use in Cancer

Leucovorin calcium is approved to be used alone or with other drugs to treat:

Colorectal cancer. It is used with fluorouracil as a palliative treatment in patients with advanced disease.
Anemia. It is used to treat megaloblastic anemia which occurs when the body does not get enough of a vitamin called folic acid. It is used by patients who cannot take the vitamin by mouth.

Leucovorin calcium is also used to prevent and treat the toxic effects of high-dose methotrexate when used to treat osteosarcoma and other types of cancer. It is also used to treat overdoses of methotrexate or other folic acid antagonists. The drug is also being studied in the treatment of other conditions and types of cancer.

Contraindications

If the clinician is using leucovorin alone to treat megaloblastic anemia, they must rule out B12 deficiency. Treating vitamin B12 deficient patients with leucovorin may reverse the megaloblastic anemia; however, it will worsen the neurological manifestations of B12 deficiency.
inadequate vitamin B12
anemia due to vitamin B12 deficiency-pernicious anemia

Dosage

Strengths: 15 mg; 5 mg; 10 mg; 25 mg; 10 mg/mL; 100 mg; 200 mg; 350 mg; 50 mg; 500 mg

Colorectal Cancer

200 mg/m2, by slow IV injection (minimum 3 minutes), followed by 5-fluorouracil (the manufacturer product information should be consulted), once a day for 5 days
OR
20 mg/m2, IV, followed by 5-fluorouracil (the manufacturer product information should be consulted), once a day for 5 days
Do not be mix in the same infusion as 5-fluorouracil; a precipitate may form.
May repeat 5 day treatment course at 4 week (28 day) intervals for 2 courses, then repeat at 4 to 5 week (28 to 35 day) intervals provided the patient is completely recovered from toxicities of the prior course.

Methotrexate Rescue

Leucovorin Rescue:

15 mg (approximately 10 mg/m2), orally, IV, or IM, every 6 hours for 10 doses; start 24 hours after beginning of methotrexate infusion (based on a methotrexate dose of 12 to 15 g/m2 IV over 4 hours)

Impaired Methotrexate Elimination or Inadvertent Overdosage:

10 mg/m2 orally, IV, or IM, every 6 hours until methotrexate level is less than 10(-8) mol
Determine serum creatinine and methotrexate levels at least once a day.
Continue leucovorin, hydration, and urinary alkalization until methotrexate levels are below 5 x 10(-8) mol.
Give parenterally if gastrointestinal toxicity, nausea, or vomiting are present.

Methotrexate Overdosage

Leucovorin Rescue:

15 mg (approximately 10 mg/m2), orally, IV, or IM, every 6 hours for 10 doses; start 24 hours after beginning of methotrexate infusion (based on a methotrexate dose of 12 to 15 g/m2 IV over 4 hours)

Impaired Methotrexate Elimination or Inadvertent Overdosage:

10 mg/m2 orally, IV, or IM, every 6 hours until methotrexate level is less than 10(-8) mol
Determine serum creatinine and methotrexate levels at least once a day.
Continue leucovorin, hydration, and urinary alkalization until methotrexate levels are below 5 x 10(-8) mol.
Give parenterally if gastrointestinal toxicity, nausea, or vomiting are present.

Megaloblastic Anemia

Up to 1 mg, IV or IM, once a day
There is no evidence that doses above 1 mg daily have greater efficacy; additionally, urinary folate loss becomes roughly logarithmic as the amount administered exceeds 1 mg.
Treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible

Folic Acid Antagonist Overdose

5 to 15 mg orally once a day
Diminish the toxicity and counteract the effects of inadvertent overdosages of folic acid antagonists.

Pneumocystis Pneumonia

Treatment of pneumocystis pneumonia is not is not a labeled indication.
20 mg/m2 or 0.5 mg/kg, IV or orally, every 6 hours, continued for 3 days after last trimetrexate dose
Use in combination with trimetrexate.
Treatment of pneumocystis pneumonia in HIV infected patients

Pneumocystis Pneumonia Prophylaxis

Prophylaxis of pneumocystis pneumonia is not a labeled indication.
25 mg, orally, once a week, in combination with dapsone and pyrimethamine
Prophylaxis in HIV infected patients usually begins when the CD4+ count is less than 200 cells/mm or for a history of oropharyngeal candidiasis.
Prophylaxis is usually discontinued when CD4+ count is 200 cells/mm or higher for 3 months.
Pneumocystis pneumonia prophylaxis in immunocompromised patients

Toxoplasmosis

Use in the treatment of toxoplasmosis is not a labeled indication.

Ocular toxoplasmosis:

5 to 25 mg orally, IV, or IM, with each dose of pyrimethamine

Acute/primary treatment of toxoplasma encephalitis in AIDS patients:

Standard dose: 10 to 20 mg, orally, IM, or IV, once a day, during and for 1 week after pyrimethamine treatment
Maximum dose: 50 mg once a day

Pediatric Dose for Colorectal Cancer

200 mg/m2, by slow IV injection (minimum 3 minutes), followed by 5-fluorouracil (the manufacturer product information should be consulted), once a day for 5 days
OR
20 mg/m2, IV, followed by 5-fluorouracil (the manufacturer product information should be consulted), once a day for 5 days
Do not be mix in the same infusion as 5-fluorouracil; a precipitate may form.
May repeat 5 day treatment course at 4 week (28 day) intervals for 2 courses, then repeat at 4 to 5 week (28 to 35 day) intervals provided the patient is completely recovered from toxicities of the prior course.

Pediatric Dose for Methotrexate Rescue

Leucovorin Rescue:

15 mg (approximately 10 mg/m2), orally, IV, or IM, every 6 hours for 10 doses; start 24 hours after beginning of methotrexate infusion (based on a methotrexate dose of 12 to 15 g/m2 IV over 4 hours)

Impaired Methotrexate Elimination or Inadvertent Overdosage:

10 mg/m2 orally, IV, or IM, every 6 hours until methotrexate level is less than 10(-8) mol
Determine serum creatinine and methotrexate levels at least once a day.
Continue leucovorin, hydration, and urinary alkalization until methotrexate levels are below 0.05 micromol.
Give parenterally if gastrointestinal toxicity, nausea, or vomiting are present.

Pediatric Dose for Megaloblastic Anemia

Up to 1 mg, IV or IM, once a day
There is no evidence that doses above 1 mg daily have greater efficacy; additionally, urinary folate loss becomes roughly logarithmic as the amount administered exceeds 1 mg.

Pediatric Dose for Folic Acid Antagonist Overdose

5 to 15 mg orally once a day
Diminish the toxicity and counteract the effects of inadvertent overdosages of folic acid antagonists.

Dose Adjustments

Leucovorin Rescue for Methotrexate (MTX):

Normal MTX elimination (MTX approximately 10 micromol 24 hours after administration, 1 micromol at 48 hours, and less than 0.2 micromol at 72 hours): Leucovorin 15 mg oral, IM, or IV every 6 hours for 60 hours (10 doses)
Delayed late MTX elimination (MTX above 0.2 micromol at 72 hours, and more than 0.05 micromol at 96 hours): Continue 15 mg orally, IM, or IV every 6 hours until MTX level is under 0.05 micromol
Delayed early MTX elimination and/or acute renal injury (MTX 50 micromol or higher at 24 hours, or 5 micromol at 48 hours, OR a 100% or greater increase in serum creatinine at 24 hours): 150 mg leucovorin IV every 3 hours, until MTX is less than 1 micromol; then 15 mg IV every 3 hours until MTX is less than 0.05 micromol.
Patients with delayed early methotrexate elimination are likely to develop reversible renal failure; continue hydration, and urinary alkalization, and close monitoring of fluid and electrolytes, in addition to leucovorin, until MTX level is below 0.05 micromol and renal failure has resolved.
Abnormalities in MTX elimination or renal function, which are significant but less severe than abnormalities described above, may or may not be associated with significant clinical toxicity.
If significant clinical toxicity is observed, extend leucovorin rescue for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy.
Consider the possibility that the patient is taking other medications which interact with MTX when laboratory abnormalities or clinical toxicities are observed.

Impaired Methotrexate Elimination or Inadvertent Overdosage:

If the 24 hour serum creatinine has increased 50% over baseline, or if the 24 hour MTX level is higher than 9 x 10(-7) mol, increase leucovorin dose to 100 mg/m2 IV every 3 hours until MTX level is less than 10(-8) mol.
Hydration and urinary alkalinization should be used concomitantly with leucovorin.

Colorectal Cancer:

After the initial treatment, adjust the dosage of 5-fluorouracil based on patient tolerance and prior treatment course.
Do not adjust leucovorin dose for toxicity.

Administration advice:

Do not administer intrathecally; may be harmful or fatal if given intrathecally.
Because of the calcium content of the solution, no more than 160 mg should be injected intravenously per minute (16 mL of a 10 mg/mL, or 8 mL of a 20 mg/mL solution per minute).

Reconstitution/preparation techniques:

Because of the benzyl alcohol in certain diluents, when administering doses greater than 10 mg/m2, reconstitute with Sterile Water for Injection, USP, and use immediately.

Side Effects

The Most Common

Stomatitis (75%, when used with fluorouracil), nausea (74%, when used with fluorouracil), diarrhea (66%, when used with fluorouracil), vomiting (46%, when used with fluorouracil), dehydration (when used with fluorouracil)
Constipation (when used with fluorouracil)
Gastrointestinal disorders (after high doses)
diarrhea
rash
hives
itching
difficulty breathing or swallowing

More Common

Mucositis (when used with fluorouracil), cheilitis (when used with fluorouracil)
Leucopenia (69%, when used with fluorouracil)
Thrombocytopenia (when used with fluorouracil)
Allergic reactions (sensitization, including anaphylactoid reactions, shock, and urticaria)
Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (in combination with other agents)
Alopecia (42%, when used with fluorouracil), dermatitis (21%, when used with fluorouracil)
Palmar-plantar erythrodysesthesia (when used with fluorouracil)
Lethargy/malaise/fatigue (13%, when used with fluorouracil)
Pyrexial reactions (following parenteral administration)^[rx]

Rare

Skin rash, hives, or itching
wheezing
Convulsions (seizures)
Anorexia (14%, when used with fluorouracil)
Hyperammonemia (when used with fluorouracil)
Infection (when used with fluorouracil)
Increase in the frequency of attacks in epileptics, seizures, syncope
Insomnia, agitation, depression

Drug Interactions

Acamprosate	The excretion of Acamprosate can be decreased when combined with Leucovorin.
Acetylsalicylic acid	The excretion of Leucovorin can be decreased when combined with Acetylsalicylic acid.
Acyclovir	The excretion of Acyclovir can be decreased when combined with Leucovorin.
Allopurinol	The excretion of Allopurinol can be decreased when combined with Leucovorin.
Alprostadil	The excretion of Alprostadil can be decreased when combined with Leucovorin.
Aminohippuric acid	The excretion of Leucovorin can be decreased when combined with Aminohippuric acid.
Apalutamide	The excretion of Leucovorin can be decreased when combined with Apalutamide.
Ataluren	The excretion of Leucovorin can be decreased when combined with Ataluren.
Avatrombopag	The excretion of Leucovorin can be decreased when combined with Avatrombopag.
Avibactam	The excretion of Avibactam can be decreased when combined with Leucovorin.
Baricitinib	The serum concentration of Baricitinib can be increased when it is combined with Leucovorin.
Benzoic acid	The excretion of Leucovorin can be decreased when combined with Benzoic acid.
Benzylpenicillin	The excretion of Benzylpenicillin can be decreased when combined with Leucovorin.
Bumetanide	The excretion of Bumetanide can be decreased when combined with Leucovorin.
Cabotegravir	The excretion of Leucovorin can be decreased when combined with Cabotegravir.
Capecitabine	The risk or severity of adverse effects can be increased when Leucovorin is combined with Capecitabine.
Captopril	The excretion of Captopril can be decreased when combined with Leucovorin.
Carbamazepine	The serum concentration of Leucovorin can be decreased when it is combined with Carbamazepine.
Cefaclor	The excretion of Cefaclor can be decreased when combined with Leucovorin.
Cefadroxil	The excretion of Leucovorin can be decreased when combined with Cefadroxil.
Cefalotin	The excretion of Leucovorin can be decreased when combined with Cefalotin.
Cefamandole	The excretion of Leucovorin can be decreased when combined with Cefamandole.
Cefazolin	The excretion of Cefazolin can be decreased when combined with Leucovorin.
Cefdinir	The excretion of Cefdinir can be decreased when combined with Leucovorin.
Cefoperazone	The excretion of Leucovorin can be decreased when combined with Cefoperazone.
Cefotaxime	The excretion of Leucovorin can be decreased when combined with Cefotaxime.
Cefotiam	The excretion of Leucovorin can be decreased when combined with Cefotiam.
Ceftibuten	The excretion of Ceftibuten can be decreased when combined with Leucovorin.
Ceftizoxime	The excretion of Ceftizoxime can be decreased when combined with Leucovorin.
Ceftriaxone	The excretion of Leucovorin can be decreased when combined with Ceftriaxone.
Cephalexin	The excretion of Leucovorin can be decreased when combined with Cephalexin.
Cholic Acid	The excretion of Cholic Acid can be decreased when combined with Leucovorin.
Cilastatin	The excretion of Leucovorin can be decreased when combined with Cilastatin.
Cimetidine	The excretion of Leucovorin can be decreased when combined with Cimetidine.
Clofarabine	The excretion of Clofarabine can be decreased when combined with Leucovorin.
Colestipol	The serum concentration of Leucovorin can be decreased when it is combined with Colestipol.
Conjugated estrogens	The excretion of Leucovorin can be decreased when combined with Conjugated estrogens.
Cycloguanil	The therapeutic efficacy of Cycloguanil can be decreased when used in combination with Leucovorin.
Dabrafenib	The excretion of Leucovorin can be decreased when combined with Dabrafenib.
Dapsone	The therapeutic efficacy of Dapsone can be decreased when used in combination with Leucovorin.
Dexamethasone	The excretion of Dexamethasone can be decreased when combined with Leucovorin.
Dexamethasone acetate	The excretion of Dexamethasone acetate can be decreased when combined with Leucovorin.
Diclofenac	The excretion of Leucovorin can be decreased when combined with Diclofenac.
Dinoprostone	The excretion of Dinoprostone can be decreased when combined with Leucovorin.
Dolutegravir	The excretion of Leucovorin can be decreased when combined with Dolutegravir.
Doripenem	The excretion of Doripenem can be decreased when combined with Leucovorin.
Dronedarone	The excretion of Leucovorin can be decreased when combined with Dronedarone.
Eluxadoline	The excretion of Eluxadoline can be decreased when combined with Leucovorin.
Enalapril	The excretion of Leucovorin can be decreased when combined with Enalapril.
Enasidenib	The excretion of Leucovorin can be decreased when combined with Enasidenib.
Esomeprazole	The excretion of Leucovorin can be decreased when combined with Esomeprazole.
Estradiol	The excretion of Estradiol can be decreased when combined with Leucovorin.
Famotidine	The excretion of Famotidine can be decreased when combined with Leucovorin.
Favipiravir	The excretion of Leucovorin can be decreased when combined with Favipiravir.
Fexinidazole	The excretion of Leucovorin can be decreased when combined with Fexinidazole.
Fexofenadine	The excretion of Fexofenadine can be decreased when combined with Leucovorin.
Flucytosine	The risk or severity of adverse effects can be increased when Leucovorin is combined with Flucytosine.
Fluorescein	The excretion of Fluorescein can be decreased when combined with Leucovorin.
Fluorouracil	The risk or severity of adverse effects can be increased when Leucovorin is combined with Fluorouracil.
Fosphenytoin	The serum concentration of Fosphenytoin can be decreased when it is combined with Leucovorin.
Furosemide	The excretion of Leucovorin can be decreased when combined with Furosemide.
Ganciclovir	The excretion of Leucovorin can be decreased when combined with Ganciclovir.
Gemfibrozil	The excretion of Leucovorin can be decreased when combined with Gemfibrozil.
Glucarpidase	The serum concentration of the active metabolites of Leucovorin can be reduced when Leucovorin is used in combination with Glucarpidase resulting in a loss in efficacy.
Guanidine	The excretion of Leucovorin can be decreased when combined with Guanidine.
Hydrochlorothiazide	The excretion of Hydrochlorothiazide can be decreased when combined with Leucovorin.
Hydrocortisone	The excretion of Hydrocortisone can be decreased when combined with Leucovorin.
Ibuprofen	The excretion of Leucovorin can be decreased when combined with Ibuprofen.
Indomethacin	The excretion of Leucovorin can be decreased when combined with Indomethacin.
Ketoprofen	The excretion of Leucovorin can be decreased when combined with Ketoprofen.
Lansoprazole	The excretion of Leucovorin can be decreased when combined with Lansoprazole.
Lenvatinib	The excretion of Leucovorin can be decreased when combined with Lenvatinib.
Letermovir	The excretion of Leucovorin can be decreased when combined with Letermovir.
Levocarnitine	The excretion of Levocarnitine can be decreased when combined with Leucovorin.
Linezolid	The excretion of Leucovorin can be decreased when combined with Linezolid.
Liothyronine	The excretion of Leucovorin can be decreased when combined with Liothyronine.
Liotrix	The excretion of Leucovorin can be decreased when combined with Liotrix.
Melatonin	The excretion of Leucovorin can be decreased when combined with Melatonin.
Mercaptopurine	The excretion of Mercaptopurine can be decreased when combined with Leucovorin.
Methotrexate	The excretion of Leucovorin can be decreased when combined with Methotrexate.
Methyltestosterone	The excretion of Leucovorin can be increased when combined with Methyltestosterone.
Minocycline	The excretion of Leucovorin can be decreased when combined with Minocycline.
Novobiocin	The excretion of Leucovorin can be decreased when combined with Novobiocin.
Oseltamivir	The excretion of Oseltamivir can be decreased when combined with Leucovorin.
Ouabain	The excretion of Leucovorin can be decreased when combined with Ouabain.
Oxytetracycline	The excretion of Leucovorin can be decreased when combined with Oxytetracycline.
Pafolacianine	Leucovorin may decrease effectiveness of Pafolacianine as a diagnostic agent.
Pantoprazole	The excretion of Leucovorin can be decreased when combined with Pantoprazole.
Pemetrexed	Leucovorin may decrease the excretion rate of Pemetrexed which could result in a higher serum level.
Phenobarbital	The serum concentration of Phenobarbital can be decreased when it is combined with Leucovorin.
Phenylbutazone	The excretion of Leucovorin can be decreased when combined with Phenylbutazone.
Phenytoin	The serum concentration of Phenytoin can be decreased when it is combined with Leucovorin.
Piperacillin	The excretion of Piperacillin can be decreased when combined with Leucovorin.
Piroxicam	The excretion of Leucovorin can be decreased when combined with Piroxicam.
Polythiazide	The excretion of Polythiazide can be decreased when combined with Leucovorin.
Pralatrexate	The therapeutic efficacy of Pralatrexate can be decreased when used in combination with Leucovorin.
Pravastatin	The excretion of Leucovorin can be decreased when combined with Pravastatin.
Prednisolone phosphate	The excretion of Prednisolone phosphate can be decreased when combined with Leucovorin.
Primidone	The serum concentration of Primidone can be decreased when it is combined with Leucovorin.
Probenecid	The excretion of Leucovorin can be decreased when combined with Probenecid.

Proguanil	The therapeutic efficacy of Proguanil can be decreased when used in combination with Leucovorin.
Pyrimethamine	The therapeutic efficacy of Pyrimethamine can be decreased when used in combination with Leucovorin.
Quinapril	The excretion of Quinapril can be decreased when combined with Leucovorin.
Quinidine	The excretion of Leucovorin can be decreased when combined with Quinidine.
Raltitrexed	The therapeutic efficacy of Raltitrexed can be decreased when used in combination with Leucovorin.
Ranitidine	The excretion of Ranitidine can be decreased when combined with Leucovorin.
Relebactam	The excretion of Relebactam can be decreased when combined with Leucovorin.
Rifampicin	The excretion of Leucovorin can be decreased when combined with Rifampicin.
Rosuvastatin	The excretion of Rosuvastatin can be decreased when combined with Leucovorin.
Salicylic acid	The excretion of Leucovorin can be decreased when combined with Salicylic acid.
Saxagliptin	The excretion of Saxagliptin can be decreased when combined with Leucovorin.
Sitagliptin	The excretion of Sitagliptin can be decreased when combined with Leucovorin.
Succinic acid	The excretion of Succinic acid can be decreased when combined with Leucovorin.
Sulfasalazine	The serum concentration of Leucovorin can be decreased when it is combined with Sulfasalazine.
Tafamidis	The excretion of Leucovorin can be decreased when combined with Tafamidis.
Taurocholic acid	The excretion of Taurocholic acid can be decreased when combined with Leucovorin.
Tazobactam	The excretion of Tazobactam can be decreased when combined with Leucovorin.
Tegafur	The risk or severity of adverse effects can be increased when Leucovorin is combined with Tegafur.
Tenofovir alafenamide	The excretion of Tenofovir alafenamide can be decreased when combined with Leucovorin.
Tenofovir disoproxil	The excretion of Tenofovir disoproxil can be decreased when combined with Leucovorin.
Tenoxicam	The excretion of Leucovorin can be decreased when combined with Tenoxicam.
Teriflunomide	The excretion of Leucovorin can be decreased when combined with Teriflunomide.
Testosterone	The excretion of Leucovorin can be increased when combined with Testosterone.
Testosterone cypionate	The excretion of Leucovorin can be increased when combined with Testosterone cypionate.
Testosterone enanthate	The excretion of Leucovorin can be increased when combined with Testosterone enanthate.
Tetracycline	The excretion of Tetracycline can be decreased when combined with Leucovorin.
Trifluridine	The excretion of Trifluridine can be decreased when combined with Leucovorin.
Trimetrexate	The therapeutic efficacy of Trimetrexate can be decreased when used in combination with Leucovorin.
Valaciclovir	The excretion of Valaciclovir can be decreased when combined with Leucovorin.
Valproic acid	The serum concentration of Leucovorin can be decreased when it is combined with Valproic acid.
Zidovudine	The excretion of Leucovorin can be decreased when combined with Zidovudine.

Pregnancy and Lactation

FDA Pregnancy Category C

Pregnancy

Animal reproduction studies have not been conducted with leucovorin. It is also not known whether leucovorin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Leucovorin should be given to a pregnant woman only if clearly needed.

Lactation

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when leucovorin is administered to a nursing mother.

How should this medicine be used?

Leucovorin comes as a tablet to take by mouth. It is usually taken every 6 hours until laboratory tests show it is no longer needed. Sometimes leucovorin is taken on a different schedule, depending on the reason it is needed. Take leucovorin at around the same time(s) every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take leucovorin exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

What special precautions should I follow?

Before taking leucovorin,

tell your doctor and pharmacist if you are allergic to leucovorin, levoleucovorin, folic acid (Folicet, in multivitamins), any other medications, or any of the ingredients in leucovorin tablets. Ask your pharmacist for a list of the ingredients.
tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: certain medications for seizures such as phenobarbital, phenytoin (Dilantin), and primidone (Mysoline); and trimethoprim-sulfamethoxazole (Bactrim, Septra). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
tell your doctor if you have anemia (low number of red blood cells) caused by lack of vitamin B12 or inability to absorb vitamin B12. Your doctor will not prescribe leucovorin to treat this type of anemia.
tell your doctor if you have or have ever had a buildup of fluid in the chest cavity or the stomach area or kidney disease. Also tell your doctor if you are nauseated.
tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking leucovorin, call your doctor.

References