Levoleucovorin

What is Levoleucovorin?

• Levoleucovorin for injection is a folate analog used to decrease the toxic effects of methotrexate and for the treatment of adults with metastatic colorectal cancer in combination with fluorouracil.

Leucovorin2DACS

Leucovorin molecule ball

What are the uses of this medicine?

Levoleucovorin for injection is indicated for:

• rescue after high-dose methotrexate therapy in adult and pediatric patients with osteosarcoma.
• diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination in adult and pediatric patients.
• the treatment of adults with metastatic colorectal cancer in combination with fluorouracil.

Limitations of Use:

• Levoleucovorin for injection is not indicated for pernicious anemia and megaloblastic anemia secondary to the lack of vitamin B12.

How does this medicine work?

• Levoleucovorin is the pharmacologically active isomer of 5-formyl tetrahydrofolic acid.
• Administration of levoleucovorin counteracts the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase.

Combination with Fluorouracil in Colorectal Cancer:

• Levoleucovorin enhances the therapeutic and toxic effects of fluorouracil.
• Fluorouracil is metabolized to 5-fluoro-2'- deoxyuridine-5'-monophosphate (FdUMP), which binds to and inhibits thymidylate synthase (an enzyme important in DNA repair and replication).
• Levoleucovorin is converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of FdUMP to thymidylate synthase and thereby enhancing the inhibition of thymidylate synthase.

Who Should Not Use this medicine ?

This medicine cannot be used in patients:

• who have had severe hypersensitivity to leucovorin products, folic acid or folinic acid.

What drug interactions can this medicine cause?

• Monitor patients taking folinic acid in combination with antiepileptic drugs.
• Leucovorin products increase the toxicity of fluorouracil. Do not initiate or continue therapy with levoleucovorin and fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved.
• The concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jiroveci pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity.

Is this medicine FDA approved?

• Initial U.S. Approval: 1952 (d,l-leucovorin)

How should this medicine be used?

Recommended dosage: Rescue After High-Dose Methotrexate Therapy:

• Rescue recommendations are based on methotrexate dose of 12 grams/m2 administered by intravenous infusion over 4 hours.
• Initiate rescue at a dose of 7.5 mg (approximately 5 mg/m2) every 6 hours, 24 hours after the beginning of methotrexate infusion.
• Continue until the methotrexate level is below 5 x 10-8 M (0.05 micromolar).
• Adjust dose if necessary based on methotrexate elimination.

Overdosage of Folic Acid Antagonists or Impaired Methotrexate Elimination:

• Start as soon as possible after methotrexate overdosage or within 24 hours of delayed methotrexate elimination.
• Administer levoleucovorin for injection 7.5 mg (approximately 5 mg/m2) intravenously every 6 hours until methotrexate level is less than 5 x 10-8 M (0.05 micromolar).

Metastatic Colorectal Cancer in Combination with Fluorouracil:

• The following regimens have been used for the treatment of colorectal cancer:
• Levoleucovorin for injection 100 mg/m2 by intravenous injection over a minimum of 3 minutes, followed by fluorouracil 370 mg/m2 once daily for 5 consecutive days.
• Levoleucovorin for injection 10 mg/m2 by intravenous injection followed by fluorouracil 425 mg/m2 once daily for 5 consecutive days.
• Administer fluorouracil and levoleucovorin for injection separately to avoid the formation of precipitate.
• The above five-day courses may be repeated every 4 weeks for 2 courses, then every 4 to 5 weeks, if the patient has recovered from toxicity from the prior course.
• Do not adjust levoleucovorin for injection dosage for toxicity.

Administration:

• Prior to intravenous injection, reconstitute the 50 mg vial of levoleucovorin for Injection with 5.3 mL of 0.9% Sodium Chloride Injection, USP to yield a levoleucovorin concentration of 10 mg per mL.
• The reconstituted 10 mg per mL levoleucovorin contains no preservative. Observe strict aseptic technique during reconstitution of the drug product. Discard unused portion.
• Saline reconstituted levoleucovorin solutions may be further diluted, immediately, to concentrations of 0.5 mg/mL to 5 mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.
• Do not store the reconstituted product or reconstituted product diluted using 0.9% Sodium Chloride Injection, USP for more than 12 hours at room temperature.
• Do not store reconstituted product diluted using 5% Dextrose Injection, USP for more than 4 hours at room temperature.
• Visually inspect the reconstituted solution for particulate matter and discoloration prior to administration.
• Do not use if cloudiness or precipitate is observed.
• Do not intravenously inject more than 16 mL of reconstituted solutions (160 mg of levoleucovorin) per minute, because of the calcium content of the levoleucovorin solution.

What are the dosage forms and brand names of this medicine?

This medicine is available in fallowing doasage form:

• As Injection: 50 mg of levoleucovorin as a lyophilized powder in a single-dose vial for reconstitution.

This medicine is available in fallowing brand namesː

• FUSILEV ; KHAPZORY

What side effects can this medication cause?

The most common side effects of this medicine include: In patients receiving high-dose methotrexate therapy:

• stomatitis
• vomiting

In patients receiving levoleucovorin in combination with fluorouracil for metastatic colorectal cancer:

• stomatitis
• diarrhea
• nausea

What special precautions should I follow?

• Because of the calcium content of the levoleucovorin solution, inject no more than 16 mL (160 mg of levoleucovorin) intravenously per minute.
• Leucovorin products increase the toxicities of fluorouracil . Gastrointestinal toxicities, including stomatitis and diarrhea, occur more commonly and may be of greater severity and of prolonged duration. Do not initiate or continue therapy with levoleucovorin and fluorouracil in patients with symptoms of gastrointestinal toxicity until symptoms have resolved. Monitor patients with diarrhea until it has resolved as rapid deterioration leading to death can occur.
• Increased rates of treatment failure and morbidity with concomitant use of d,l-leucovorin with trimethoprim-sulfamethoxazole for Pneumocystis jiroveci pneumonia in patients with HIV.

What to do in case of emergency/overdose?

• In case of overdose, call the poison control helpline of your country. In the United States, call 1-800-222-1222.

• Overdose related information is also available online at poisonhelp.org/help.
• In the event that the victim has collapsed, had a seizure, has trouble breathing, or can't be awakened, immediately call emergency services. In the United States, call 911.

Can this medicine be used in pregnancy?

• There are limited data with levoleucovorin use in pregnant women.
• Levoleucovorin is administered in combination with methotrexate or fluorouracil, which can cause embryo-fetal harm.

Can this medicine be used in children?

• The safety and effectiveness of levoleucovorin have been established in pediatric patients for rescue after high-dose methotrexate therapy in osteosarcoma and diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination.
• The safety and effectiveness of levoleucovorin have not been established for the treatment of pediatric patients with advanced metastatic colorectal cancer.

What are the active and inactive ingredients in this medicine?

Active ingredient:

• LEVOLEUCOVORIN CALCIUM

Inactive ingredient:

• MANNITOL
• SODIUM HYDROXIDE
• HYDROCHLORIC ACID

Who manufactures and distributes this medicine?

Manufactured by:

• Amneal Pharmaceuticals Pvt. Ltd.,
• Parenteral Unit
• Ahmedabad , INDIA

Distributed by:

• Amneal Pharmaceuticals LLC
• Bridgewater, NJ

What should I know about storage and disposal of this medication?

• Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F).
• Store in carton until contents are used.
• Protect from light.

• Dailymed label info on Levoleucovorin
• FDA Levoleucovorin

Levoleucovorin Resources
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Vitamins A Vitamin A B Biotin Vitamin B1 (see Thiamin) Vitamin B12 Vitamin B6 C Calcium Choline Chromium Copper Vitamin C D Vitamin D

E Energy Drinks Exercise and Athletic Performance Vitamin E F Fluoride Folate I Iodine Iron K Vitamin K

M Magnesium Multivitamin/mineral Supplements N Niacin P Pantothenic Acid Phosphorus Potassium Primary Mitochondrial Disorders R Riboflavin

S Selenium T Thiamin V Vitamin A Vitamin B1 (see Thiamin) Vitamin B12 Vitamin B6 Vitamin C Vitamin D Vitamin E Vitamin K Z Zinc