leucovorin

loo-koe-VOR-in

Therapeutic Classification: antidotes (for methotrexate), vitamins

Pharmacologic Classification: folic acid analogues

REMS

Minimizes hematologic effects of high-dose methotrexate therapy (leucovorin rescue).
Advanced colorectal carcinoma (with 5-fluorouracil).
Management of overdoses/prevention of toxicity from folic acid antagonists (pyrimethamine, trimethoprim).
Folic acid deficiency (megaloblastic anemia) unresponsive to oral replacement.

The reduced form of folic acid that serves as a cofactor in the synthesis of DNA and RNA.

Therapeutic effects:

Reversal of toxic effects of folic acid antagonists.
Reversal of folic acid deficiency.

Absorption: 38% absorbed following oral administration. ↓ bioavailability with larger doses. Oral absorption is saturated at doses >25 mg. Well absorbed following IM administration. IV administration results in complete bioavailability.

Distribution: Widely distributed to tissues. Concentrates in the CNS and liver.

Metabolism/Excretion: Extensively converted to tetrahydrofolic derivatives, including 5-methyltetrahydrofolate, a major storage form.

Half-Life: 3.5 hr.

(serum folate concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	20–30 min	unknown	3–6 hr
IM	10–20 min	unknown	3–6 hr
IV	<5 min	unknown	3–6 hr

Contraindicated in:

Hypersensitivity;
Pedi: Preparations containing benzyl alcohol should not be used in neonates.

Use Cautiously in:

Undiagnosed anemia (may mask the progression of pernicious anemia);
Ascites;
Renal failure;
Dehydration;
Pleural effusions;
Urine pH <7;
OB: Safety not established in pregnancy;
Lactation: Safety not established in breastfeeding.

Hemat: thrombocytosis

Misc: allergic reactions (rash, urticaria, wheezing)

Drug-drug:

May ↓ anticonvulsant effect of barbiturates, phenytoin, or primidone.
May ↓ effectiveness of trimethoprim/sulfamethoxazole when used to treat Pneumocystis jirovecii pneumonia in patients with HIV.
May ↑ effects and toxicity of fluorouracil; therapy may be combined for this purpose.

High-Dose Methotrexate: Leucovorin Rescue

Must start within 24 hr of methotrexate.
PO IM IV (Adults and Children ): Normal methotrexate elimination: 10 mg/m² every 6 hr (1st dose IV/IM; then change to PO) until methotrexate concentration <5 × 10^–8 M (0.05 micromolar). Larger doses/longer duration may be required in patients with aciduria, ascites, dehydration, renal impairment, GI obstruction, or pleural/peritoneal effusions. Dose of leucovorin should be determined based on the plasma methotrexate concentrations.

Advanced Colorectal Cancer

IV (Adults ): 200 mg/m², followed by 5-fluorouracil 370 mg/m², or leucovorin 20 mg/m², followed by 5-fluorouracil 425 mg/m². Regimen is given daily for 5 days every 4–5 wk.

Prevention of Hematologic Toxicity from Pyrimethamine

PO IV (Adults and Children ): 5–15 mg/day.

Inadvertent Overdose of Folic Acid Antagonists

IM IV (Adults and Children ): Methotrexate, large doses: 75 mg IV followed by 12 mg IM every 6 hr for 4 doses; Methotrexate, average doses: 6–12 mg IM every 6 hr for 4 doses; Other folic acid antagonists: Amount equal in mg to folic acid antagonist.

Megaloblastic Anemia

PO IM IV (Adults and Children ): Up to 1 mg/day (up to 6 mg/day for dihydrofolate reductase deficiency).

(Generic available)

Tablets: 5 mg; 10 mg; 15 mg; 25 mg
Powder for injection: 50 mg/vial; 100 mg/vial; 200 mg/vial; 350 mg/vial; 500 mg/vial
Solution for injection (preservative-free): 10 mg/mL

Assess for nausea and vomiting secondary to methotrexate therapy or folic acid antagonist (pyrimethamine and trimethoprim) overdose. Parenteral route may be necessary to ensure that patient receives dose.
- Monitor for development of allergic reactions (rash, urticaria, wheezing). Notify health care provider if these occur and implement supportive measures as needed.
Megaloblastic Anemia: Assess degree of weakness and fatigue.

Lab Test Considerations:

Leucovorin rescue: Monitor serum methotrexate concentrations to determine dose and effectiveness of therapy. Leucovorin concentration should be equal to or greater than methotrexate concentrations. Rescue continues until serum methotrexate concentration <5 × 10 M.
- Monitor CCr and serum creatinine before and every 24 hr during therapy to detect methotrexate toxicity. An ↑ of >50% over the pretreatment concentration at 24 hr is associated with severe renal toxicity.
- Monitor urine pH every 6 hr during therapy; pH should be maintained at >7 to ↓ nephrotoxic effects of high-dose methotrexate. Sodium bicarbonate or acetazolamide may be ordered to alkalinize urine.
- Megaloblastic anemia: Monitor folic acid, hemoglobin, hematocrit, and reticulocyte count before and periodically during therapy.

Do not confuse leucovorin with levoleucovorin. Do not confuse leucovorin with Leukeran.
- Make sure leucovorin is available before administering high-dose methotrexate. Administration must be initiated within 24 hr of methotrexate therapy.
- Administer as soon as possible after toxic dose of folic acid antagonist (pyrimethamine and trimethoprim). Effectiveness of therapy begins to ↓ 1 hr after overdose.
PO: Parenteral therapy should be used in patients with GI toxicity, with nausea and vomiting, or with doses >25 mg.
IM: IM route is preferred for treatment of megaloblastic anemia. Ampules of leucovorin injection for IM use do not require reconstitution.

IV Administration:

IV Push: Reconstitution: Reconstitute with bacteriostatic water or sterile water. Do not use product containing benzyl alcohol. Use immediately if reconstituted with sterile water for injection. Stable for 7 days when reconstituted with bacteriostatic water. Concentration: Reconstitute 50-mg, 100-mg, and 200-mg vials to a concentration of 10 mg/mL; reconstitute 350-mg vial to a concentration of 20 mg/mL. Do not administer with methotrexate; start leucovorin 24 hr after start of methotrexate.
Rate: Administer by slow injection over ≥3 min (not to exceed 160 mg/min).
Intermittent Infusion: Diluent: May be diluted in 100–500 mL of D5W, D10W, 0.9% NaCl, Ringer’s, or LR. Stable for 24 hr.
Y-Site Compatibility:
- acyclovir
- alemtuzumab
- allopurinol
- amikacin
- aminocaproic acid
- aminophylline
- ampicillin
- ampicillin/sulbactam
- anidulafungin
- argatroban
- arsenic trioxide
- atracurium
- azithromycin
- aztreonam
- bivalirudin
- bleomycin
- bumetanide
- buprenorphine
- busulfan
- butorphanol
- calcium chloride
- calcium gluconate
- carmustine
- caspofungin
- cefazolin
- cefepime
- cefotaxime
- cefotetan
- cefoxitin
- ceftazidime
- cefuroxime
- chloramphenicol
- ciprofloxacin
- cisatracurium
- cisplatin
- cladribine
- clindamycin
- cyclophosphamide
- cyclosporine
- cytarabine
- dacarbazine
- dactinomycin
- daptomycin
- daunorubicin
- dexamethasone
- dexmedetomidine
- dexrazoxane
- digoxin
- diltiazem
- diphenhydramine
- dobutamine
- docetaxel
- dopamine
- doxorubicin hydrochloride
- doxorubicin liposomal
- doxycycline
- enalaprilat
- ephedrine
- epinephrine
- eptifibatide
- ertapenem
- erythromycin
- esmolol
- etoposide
- etoposide phosphate
- famotidine
- fentanyl
- filgrastim
- fluconazole
- fludarabine
- fluorouracil
- fosphenytoin
- furosemide
- ganciclovir
- gemcitabine
- gentamicin
- glycopyrrolate
- granisetron
- haloperidol
- heparin
- hydralazine
- hydrocortisone
- hydromorphone
- idarubicin
- ifosfamide
- imipenem/cilastatin
- insulin regular
- irinotecan
- isoproterenol
- ketorolac
- labetalol
- levofloxacin
- lidocaine
- linezolid
- lorazepam
- magnesium sulfate
- mannitol
- melphalan
- meperidine
- meropenem
- mesna
- methadone
- methotrexate
- metoclopramide
- metoprolol
- metronidazole
- midazolam
- milrinone
- minocycline
- mitomycin
- mitoxantrone
- morphine
- moxifloxacin
- mycophenolate
- nafcillin
- nalbuphine
- nicardipine
- nitroglycerin
- nitroprusside
- norepinephrine
- octreotide
- ondansetron
- oxaliplatin
- oxytocin
- paclitaxel
- palonosetron
- pemetrexed
- pentobarbital
- phenobarbital
- phentolamine
- phenylephrine
- piperacillin/tazobactam
- potassium acetate
- potassium chloride
- procainamide
- prochlorperazine
- promethazine
- propranolol
- remifentanil
- rituximab
- rocuronium
- sodium acetate
- sodium phosphates
- succinylcholine
- sufentanil
- tacrolimus
- theophylline
- thiotepa
- tigecycline
- tirofiban
- tobramycin
- topotecan
- trastuzumab
- trimethoprim/sulfamethoxazole
- vasopressin
- vecuronium
- verapamil
- vinblastine
- vincristine
- vinorelbine
- voriconazole
- zidovudine
Y-Site Incompatibility:
- amiodarone
- amphotericin B deoxycholate
- amphotericin B liposomal
- carboplatin
- ceftriaxone
- chlorpromazine
- dantrolene
- diazepam
- droperidol
- epirubicin
- foscarnet
- gemtuzumab ozogamicin
- methylprednisolone
- naloxone
- pamidronate
- pantoprazole
- pentamidine
- phenytoin
- potassium phosphates
- sodium bicarbonate
- vancomycin

Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy. Emphasize need to take exactly as ordered. Advise patient to contact health care provider if a dose is missed.
Advise patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care provider before taking other medications.
Leucovorin Rescue: Instruct patient to drink >3 liters of fluid each day during leucovorin rescue.
Folic Acid Deficiency: Encourage patient to eat a diet high in folic acid (meat proteins, bran, dried beans, green leafy vegetables).
Rep: Advise women of reproductive potential to notify health care provider if pregnancy is planned or suspected or if breastfeeding.

Reversal of toxic effects of folic acid antagonists.
Reversal of folic acid deficiency.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Time/Action Profile ⬆ ⬇

Contraind./Precautions ⬆ ⬇

Adv. Reactions/Side Effects ⬆ ⬇

Interactions ⬆ ⬇

Route/Dosage ⬆ ⬇

Availability ⬆ ⬇

Assessment ⬆ ⬇

Implementation ⬆ ⬇

Patient/Family Teaching ⬆ ⬇

Evaluation/Desired Outcomes ⬆