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Levoleucovorin 50 mg/5mL Injection, Powder, Lyophilized, For Solution — NDC 00143-9558-01 package photo
Label image from the product's FDA listing (DailyMed) — may show a different pack size or an older label revision.

Levoleucovorin 50 mg/5mL Injection, Powder, Lyophilized, For Solution — NDC 0143-9558-01 (Billing 00143-9558-01)

by Hikma Pharmaceuticals USA Inc. · 1 VIAL in 1 BOX / 5 mL in 1 VIAL

This is a package of Levoleucovorin 50 mg/5mL Injection, Powder, Lyophilized, For Solution from Hikma Pharmaceuticals USA Inc., marketed since Jul 2016 and currently FDA-listed. It is this product's only package size.

NDC 00143-9558-01
🏷️ FDA NDC (as labeled) 0143-9558-01 billing pads the labeler segment with a zero
Rx only Generic On market Non-controlled ⇄ Compare with another NDC
🗂️ FDA directory synced Oct 1, 2026 · this listing last changed Jul 24, 2026 · sources: openFDA · FDA label (DailyMed) · FDA Orange & Purple Book · First Databank · CMS NADAC, ASP, Medicare & Medicaid · RxNorm
📋 All sources & update times →

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Compiled from public FDA, CMS, DailyMed, NADAC, and related drug data sources. Editorial policy

NDC database record

One package, one record: these facts belong to NDC 0143-9558-01 alone.

Record
FDA NDC Directory package listing · Human prescription drug
Code segments
0143 labeler · 9558 product · 01 package
Package marketed since
Jul 7, 2016
Sample package
No — commercial package
Listing certified through
Dec 31, 2026
Barcode (UPC-A, from the NDC)
3 0143955801 9
FDA record last changed
Jul 24, 2026

Identity & classification

Regulatory identifiers FDA, NLM and CMS codes for this package

FDA NDC (as labeled) 0143-9558-01
Product NDC 0143-9558
11-digit billing NDC 00143955801
NCPDP billing unit EA — each (per item)
RxCUI 1720760
UNII 778XL6VBS8
Application # ANDA206263
SPL Set ID 54f01988-aac2-4b0e-9d20-b7f621a0cd50
Established class (EPC) Folate Analog
Chemical class Folic Acid
DEA schedule Non-controlled
Marketing category ANDA
Marketing status On market
FDA listing status Listed (active directory)
Marketing start 2016-07-07
Route INTRAVENOUS
Dosage form INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION
Substance LEVOLEUCOVORIN CALCIUM

Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification

GPI-14 21755050102120
GPI class LEVOleucovorin Calcium
GCN Seq No 046762
GCN 89655
HICL code 011043
Ingredient (HICL) Levoleucovorin Calcium
HIC1 code V
Therapeutic class — broad (HIC1) Neoplasms
HIC2 code V1
Therapeutic class — intermediate (HIC2) Antineoplastic Drugs
HIC3 code V1I
Therapeutic class — specific (HIC3) Chemotherapy Rescue/Antidote Agents
AHFS code 91:04.12.00
AHFS class Chemotherapy Antidotes/Protectants
FDB label name LEVOLEUCOVORIN 50 MG VIAL
FDB brand name Levoleucovorin Calcium
Legend status F — Federal legend — prescription drug or device
Quick answers
  • GSN (GCN sequence number): 046762
  • GCN: 89655
  • GPI-14 (Medi-Span): 21755050102120
  • HICL (First Databank): 011043
  • AHFS class code: 91:04.12.00
  • RxCUI (RxNorm): 1720760
Why two NDCs? The FDA registers this code as 0143-9558-01 — a 4-4-2 layout, and that's what's printed on the package and shown on DailyMed. For insurance claims, every NDC is standardized to a uniform 11-digit 5-4-2 format by adding a zero to the labeler segment → 00143-9558-01. Same drug, same package — only the format differs.
Where does this data come from?
Identifiers from the FDA openFDA NDC Directory and Structured Product Labeling; RxCUI from RxNorm (NLM); GPI from Medi-Span; GCN / HIC / AHFS / legend from First Databank.

RxNorm drug class

This medicine belongs to the Folate Analog class.

Pharmacologic class Folate Analog
Where does this data come from?
Therapeutic classes from RxNorm RxClass (U.S. National Library of Medicine) — Established Pharmacologic Class (FDA), ATC drug family (WHO) and mechanism of action, matched by this product’s RxCUI.

Clinical

Label name LEVOLEUCOVORIN 50 MG VIAL Ingredient Levoleucovorin Calcium
📖 What it is MedlinePlus · NLM

Levoleucovorin injection is used in adults and children to prevent harmful effects of methotrexate (Trexall) when methotrexate is used to treat osteosarcoma (cancer that forms in bones). Levoleucovorin injection is also used to treat adults and children who have accidentally received an overdose of methotrexate or similar medications or who are not able to eliminate these medications properly from their bodies. Levoleucovorin injection is also used with fluorouracil (5-FU, a chemotherapy medication) to treat adults with colorectal cancer (cancer that begins in the large intestine) that has spr...

Read the full MedlinePlus article ↗
📗 Our plain-language guide HelloPharmacist
  • It is used to rescue your body after high-dose methotrexate for osteosarcoma and to reduce methotrexate toxicity if it clears too slowly or is overdosed. It is also used with 5-flu...
  • It is given through a vein by a healthcare professional. It must never be given into the spinal fluid. Your team decides the timing and checks your blood tests as you go.
  • Nausea, vomiting and mouth sores are common. With 5-fluorouracil, diarrhea is very common too. Tiredness, reduced appetite, skin irritation and hair loss can also occur.
  • Call right away for diarrhea, mouth sores, vomiting or dehydration, especially with 5-fluorouracil, since this can worsen quickly. Also report rash, itching, trouble breathing, chi...
📖 Read our full Levoleucovorin Injection guide →

Supplement & herbal interactions

🌿 Drug–supplement interaction checker →
Where does this data come from?
Plain-language summary from MedlinePlus (U.S. National Library of Medicine); supplement & herbal interactions and nutrient depletion data from the Natural Medicines database; our full guide is HelloPharmacist editorial content.

Pricing

A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.

Price systemPer mLPer package
Retail pharmacies payNADAC · weekly Not in the retail survey — common for institutional, discontinued, or low-volume packs.
Medicaid paysCMS SDUD · 12 mo No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data.
Medicare drug plans payPart D · quarterly No Part D plan price is available for this NDC in our data.
Medicare Part B allowsASP · J0641 $0.049 / J0641 unit —
Where does this data come from?
NADAC (National Average Drug Acquisition Cost) is the CMS weekly pharmacy-acquisition-cost survey — what pharmacies pay. ASP (Average Sales Price) is the CMS Medicare Part B drug-payment file, published quarterly. Medicaid pays is computed by us from CMS State Drug Utilization Data (total reimbursed ÷ units, trailing 12 months) — gross of rebates and inclusive of dispensing fees, so it reflects what Medicaid paid, not an acquisition cost. Medicare drug plans pay is the median negotiated point-of-sale unit cost across plans listing this NDC in the CMS quarterly Prescription Drug Plan pricing files, before rebates. The VA pays is the federal contract price (FSS, and the statutory Big 4 ceiling where listed) from the VA National Acquisition Center pharmaceutical price file. All are free public government data; each measures a different payer, so the figures are not directly comparable.

Billing & reimbursement

FDA NDC (as labeled)0143-9558-01
11-digit billing NDC00143-9558-01
Format4-4-2 as registered → padded to 5-4-2 for billing (zero added to the labeler segment)
HCPCS J-codeJ0641
DescriptorINJECTION, LEVOLEUCOVORIN, NOT OTHERWISE SPECIFIED, 0.5MG
Billing units / pkg100 units
How the units are derivedThis package is 1 EA; the HCPCS unit is 0.5 MG, so one package = 100 billing units.
Medicare Part B spend (2026 (Q1))$6,222 · 264 claims · $23.57 per claim (all NDCs under J0641)
Crosswalk sourcePDAC NDC-HCPCS crosswalk (DME MAC / DMEPOS)
Where does this data come from?
The HCPCS J-code crosswalk comes from the CMS ASP NDC-HCPCS crosswalk and the DMEPDAC (DME MAC) NDC-HCPCS crosswalk — free public CMS data. Billing units are derived from the code’s descriptor and the package amount.

Packaging — all sizes for this product

Package NDCDescription Marketing startMarketing endStatus
00143-9558-01 You're viewing this Main listing 1 VIAL in 1 BOX / 5 mL in 1 VIAL 2016-07-07 — Active

Therapeutic equivalents

ProductLabelerPackNADAC/unitTEStatusPrice vs. this
Levoleucovorin 50 mg/5mLthis 00143-9558-01 Hikma 1 vial — — FDA listed —
About this product: this is a generic version of the medicine. FDA equivalence ratings are shown when available, and other versions are listed above, least expensive first.
Where does this data come from?
Equivalents are other NDCs of the same ingredient, form and route from the openFDA NDC Directory, ranked least-expensive-first by NADAC. Therapeutic-equivalence (AB) ratings come from the FDA Orange Book; biologics use the FDA Purple Book for biosimilar & interchangeable status.

Availability & generic status

🏛️
2016
On the market since
Jul 2016
📍
2026
Currently FDA-listed
10 years listed
🔓
·
Generic on the market
this product is a generic
✅This is a generic drug

This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.

Where does this data come from?
Patents and exclusivity from the FDA Orange Book (small-molecule drugs), refreshed from public FDA data. Generic launch timing is an estimate, not a guarantee.

Inactive Ingredients / Excipients

Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.

💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.

  • UNII QTT17582CB
    A strong acid used to adjust and maintain the proper pH level in liquid medicines, ensuring stability and preventing breakdown of active ingredients.
  • 50 mg / 5 mL UNII 3OWL53L36A
    A natural sugar alcohol derived from seaweed or synthesized in the lab. It's used as a filler to add bulk, a sweetener in sugar-free formulas, and a disintegrant to help tablets break apart in the stomach.
  • UNII 55X04QC32I
    A strong alkaline chemical used to adjust and maintain the pH balance of liquid medicines. It helps keep the medicine stable and ensures it stays effective during storage.

3 inactive ingredients listed in the exact product block matched to this NDC.

Where does this data come from?
Data sourced from official FDA Structured Product Labeling (SPL) via DailyMed — ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.

Inactive ingredient FAQ

Are inactive ingredients the same for every manufacturer?
No. Inactive ingredients can differ by manufacturer, dosage form, strength, and package / product version.
Why might an inactive ingredient be missing?
Some SPLs do not provide a complete structured inactive-ingredient list, and older or unusual labels may only include the information in narrative text.
Can inactive ingredients matter?
Yes. They can matter for allergies, intolerances, dyes, gluten / lactose concerns, preservatives, and formulation differences — but confirm with a pharmacist or the manufacturer when it’s clinically important.

Manufacturer & labeler

LabelerHikma Pharmaceuticals USA Inc.
Application holderHIKMA PHARMACEUTICALS USA INC
FDA applicationANDA206263 (ANDA)
Labeler code00143
First marketedJul 2016
Product typeHuman Prescription Drug
Portfolio726 products on file

More NDCs from Hikma Pharmaceuticals USA Inc. labeler code 00143

The labeler markets the product; the application holder owns the FDA approval. They’re often the same company but can differ (e.g. a repackager or an authorized generic). A mailing address / phone appears here when the manufacturer includes it in the product’s FDA label (not all do).
Where does this data come from?
Labeler, application holder and registered establishment from the FDA openFDA NDC Directory and Drugs@FDA; address/contact from the product’s FDA label.

Full prescribing information FDA SPL

The complete FDA label for this product — the official prescribing information, verbatim, section by section. Very long sections are excerpted here and marked; the full text is on DailyMed (linked in the sources below). Jump with a chip, search within the label, or expand everything.
🎯 Indications and Usage ⏱️ Dosage and Administration 💊 Dosage Forms and Strengths ⛔ Contraindications ⚠️ Warnings and Cautions 🤒 Adverse Reactions 🔄 Drug Interactions 👥 Use in Specific Populations 🤰 Pregnancy 🧒 Pediatric Use 🧓 Geriatric Use 🧬 Clinical Pharmacology 🧬 Mechanism of Action 📦 How Supplied / Storage and Handling 📋 Description 🍼 Nursing Mothers 🧬 Pharmacokinetics 🔬 Clinical Studies 🧪 Nonclinical Toxicology 📄 Carcinogenesis, Mutagenesis, Impairment of Fertility 📄 Recent Major Changes 📄 Package Label / Principal Display Panel
🎯 Indications and Usage 186 words ▾

1 INDICATIONS AND USAGE 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, because of the risk of progression of neurologic manifestations despite hematologic remission.

Levoleucovorin for Injection is a folate analog indicated for: Rescue after high-dose methotrexate therapy in adult and pediatric patients with osteosarcoma. ( 1 ) Diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination in adult and pediatric patients. ( 1 ) Treatment of adults with metastatic colorectal cancer in combination with fluorouracil.

( 1 ) Limitations of Use: Levoleucovorin for Injection is not indicated for the treatment of pernicious anemia and megaloblastic anemia secondary to lack of vitamin B12, because of the risk of progression of neurologic manifestations despite hematologic remission. ( 1 )

⏱️ Dosage and Administration ~3 min read ▾

2 DOSAGE AND ADMINISTRATION For intravenous administration only. Do not administer intrathecally. ( 2.1 ) Rescue After High-Dose Methotrexate Therapy Rescue recommendations are based on methotrexate dose of 12 grams/m 2 administered by intravenous infusion over 4 hours.

Initiate rescue at a dose of 7.5 mg (approximately 5 mg/m 2 ) every 6 hours, 24 hours after the beginning of methotrexate infusion. ( 2.2 ) Continue until the methotrexate level is below 5 x 10 -8 M (0.05 micromolar). Adjust dose if necessary based on methotrexate elimination; refer to Full Prescribing Information.

( 2.2 ) 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. ( 2.3 ) Administer Levoleucovorin for Injection 7.5 mg (approximately 5 mg/m 2 ) intravenously every 6 hours until methotrexate level is less than 5 x 10 -8 M (0.05 micromolar). ( 2.3 ) Metastatic Colorectal Cancer in Combination with The following regimens have been used for the treatment of colorectal cancer: Levoleucovorin for Injection 100 mg/m 2 by intravenous injection over a minimum of 3 minutes, followed by fluorouracil 370 mg/m 2 once daily for 5 consecutive days.

( 2.4 ) Levoleucovorin for Injection 10 mg/m 2 by intravenous injection followed by fluorouracil 425 mg/m 2 once daily for 5 consecutive days. ( 2.4 ) 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. ( 2.5 )

2.1Important Use Information Levoleucovorin for Injection is indicated for intravenous administration only. Do not administer intrathecally .

2.2Co-administration of Levoleucovorin for Injection with other agents Due to the risk of precipitation, do not co-administer Levoleucovorin for Injection with other agents in the same admixture.

2.3Recommended Dosage for Rescue After High-Dose Methotrexate Therapy The recommended dosage for Levoleucovorin for Injection is based on a methotrexate dose of 12 grams/m 2 administered by intravenous infusion over 4 hours. Twenty-four hours after starting the methotrexate infusion, initiate Levoleucovorin for Injection at a dose of 7.5 mg (approximately 5 mg/m 2 ) as an intravenous infusion every 6 hours. Monitor serum creatinine and methotrexate levels at least once daily.

Continue Levoleucovorin for Injection administration, hydration, and urinary alkalinization (pH of 7 or greater) until the methotrexate level is below 5 x 10 -8 M (0.05 micromolar). Adjust the Levoleucovorin for Injection dose or extend the duration as recommended in Table 1. Table 1 Recommended Dosage for Levoleucovorin for Injection based on Serum Methotrexate and Creatinine Levels Clinical Situation Laboratory Findings Recommendation Normal Methotrexate Elimination Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours Administer 7.5 mg by intravenous infusion every 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion).

Delayed Late Methotrexate Elimination Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration. Continue 7.5 mg by intravenous infusion every 6 hours until methotrexate level is less than 0.05 micromolar. Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration OR 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more).

Administer 75 mg… [Excerpted — this section continues on DailyMed.]

💊 Dosage Forms and Strengths 45 words ▾

3 DOSAGE FORMS AND STRENGTHS 50 mg of levoleucovorin as a sterile white to pale yellow lyophilized powder in a single dose vial for reconstitution. For Injection: 50 mg of levoleucovorin as a lyophilized powder in a single dose vial for reconstitution ( 3 )

⛔ Contraindications 47 words ▾

4 CONTRAINDICATIONS Levoleucovorin for Injection is contraindicated in patients who have had severe hypersensitivity to leucovorin products, folic acid or folinic acid [see Adverse Reactions ( 6.2 )] . Patients who have had severe hypersensitivity reactions to leucovorin products, folic acid or folinic acid. ( 4 )

⚠️ Warnings and Cautions ~1 min read ▾

5 WARNINGS AND PRECAUTIONS Hypercalcemia: Due to calcium content, inject no more than 16 mL (160 mg) of levoleucovorin solution intravenously per minute. ( 5.1 ) Increased Gastrointestinal Toxicities with Fluorouracil : Do not initiate or continue therapy with Levoleucovorin for Injection 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.

( 5.2 , 7 ) Drug Interaction with Trimethoprim-Sulfamethoxazole : 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. ( 5.3 )

5.1Hypercalcemia Because of the calcium content of the levoleucovorin solution, inject no more than 16 mL (160 mg of levoleucovorin) intravenously per minute.

5.2Increased Gastrointestinal Toxicities with Fluorouracil Leucovorin products increase the toxicities of fluorouracil [see Drug Interactions ( 7 )] . Gastrointestinal toxicities, including stomatitis and diarrhea, occur more commonly and may be of greater severity and of prolonged duration. Deaths from severe enterocolitis, diarrhea, and dehydration have occurred in elderly patients receiving weekly d,l- leucovorin and fluorouracil.

Monitor patients for gastrointestinal toxicities. Do not initiate or continue therapy with Levoleucovorin for Injection and fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved. Monitor patients with diarrhea until resolved, as rapid deterioration leading to death can occur.

5.3Drug Interaction with Trimethoprim-Sulfamethoxazole 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 [see Drug Interactions ( 7 )] .

🤒 Adverse Reactions ~3 min read ▾

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypercalcemia [see Warnings and Precautions ( 5.1 )] Increased gastrointestinal toxicities with fluorouracil [see Warnings and Precautions ( 5.2 )] The most common adverse reactions (≥20%) in patients receiving high-dose methotrexate therapy with Levoleucovorin for Injection rescue are stomatitis and vomiting. ( 6.1 ) The most common adverse reactions (>50%) in patients receiving Levoleucovorin for Injection in combination with fluorouracil for metastatic colorectal cancer are stomatitis, diarrhea, and nausea ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. High-Dose Methotrexate Therapy Table 2 presents the frequency of adverse reactions which occurred during the administration of 58 courses of high-dose methotrexate 12 grams/m 2 followed by Levoleucovorin for Injection rescue for osteosarcoma in 16 patients aged 6 to 21 years.

Most patients received Levoleucovorin for Injection 7.5 mg every 6 hours for 60 hours or longer, beginning 24 hours after completion of methotrexate administration. Table 2 Adverse Reactions with High-Dose Methotrexate Therapy Adverse Reactions Levoleucovorin for Injection n = 16 All Grades (%) Grades 3-4 (%) Gastrointestinal Stomatitis 38 6 Vomiting 38 0 Nausea 19 0 Diarrhea 6 0 Dyspepsia 6 0 Typhlitis 6 6 Respiratory Dyspnea 6 0 Skin and Appendages Dermatitis 6 0 Other Confusion 6 0 Neuropathy 6 0 Renal function abnormal 6 0 Taste perversion 6 0 Combination with Fluorouracil in Colorectal Cancer Table 3 presents the frequency of adverse reaction which occurred in 2 arms of a randomized controlled trial conducted by the North Central Cancer Treatment Group (NCCTG) in patients with metastatic colorectal cancer.

The trial failed to show superior overall survival with fluorouracil + levoleucovorin compared to fluorouracil + d,l -leucovorin. Patients were randomized to fluorouracil 370 mg/m 2 intravenously and levoleucovorin 100 mg/m 2 intravenously, both daily for 5 days, or to fluorouracil 370 mg/m 2 intravenously and d,l -leucovorin 200 mg/m 2 intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, and then every 5 weeks until disease progression or unacceptable toxicity.

Table 3 Adverse Reactions Occurring in ≥ 10% of Patients in Either Arm Adverse Reaction Levoleucovorin/fluorouracil n=318 d,l -Leucovorin/fluorouracil n=307 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Gastrointestinal Disorders Stomatitis 72 12 72 14 Diarrhea 70 19 65 17 Nausea 62 8 61 8 Vomiting 40 5 37 6 Abdominal Pain1 14 3 19 3 General Disorders Asthenia/Fatigue/Malaise 29 5 32 11 Skin Disorders Dermatitis 29 1 28 1 Alopecia 26 0.3 28 1 Metabolism and Nutrition Anorexia/Decreased Appetite 24 4 25 2 1 Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness

6.2Postmarketing Experience The following adverse reaction have been identified during postapproval use of levoleucovorin products. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dermatologic: pruritus, rash Respiratory: dyspnea Other: temperature change, rigors, allergic reactions

🔄 Drug Interactions 169 words ▾

7 DRUG INTERACTIONS

7.1Effects of Leucovorin Products on Other Drugs Antiepileptic Drugs Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone and increase the frequency of seizures in susceptible children. It is not known whether folinic acid has the same effects; however, both folic and folinic acids share some common metabolic pathways. Monitor patients taking folinic acid in combination with antiepileptic drugs.

Fluorouracil Leucovorin products increase the toxicity of fluorouracil. Do not initiate or continue therapy with Levoleucovorin for Injection and fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved. Monitor patients with diarrhea until the diarrhea has resolved, as rapid deterioration leading to death can occur [see Warnings and Precautions ( 5.2 )].

Trimethoprim-Sulfamethoxazole 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 in a placebo-controlled study [see Warnings and Precautions ( 5.3 )] .

👥 Use in Specific Populations ~1 min read ▾

8 USE IN SPECIFIC POPULATIONS

8.1Pregnancy Risk Summary There are limited data with Levoleucovorin for Injection use in pregnant women. Animal reproduction studies have not been conducted with levoleucovorin. Levoleucovorin is administered in combination with methotrexate or fluorouracil, which can cause embryo-fetal harm.

Refer to methotrexate and fluorouracil prescribing information for additional information. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.2Lactation Risk Summary There are no data on the presence of levoleucovorin in human milk or its effects on the breastfed infant or on milk production. Levoleucovorin is administered in combination with methotrexate or fluorouracil. Refer to methotrexate and fluorouracil prescribing information for additional information.

8.4Pediatric Use The safety and effectiveness of Levoleucovorin for Injection 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. Use of levoleucovorin in pediatric patients is supported by open-label clinical trial data in 16 pediatric patients 6 years of age and older, with additional supporting evidence from literature [see Clinical Studies ( 14.1 )].

The safety and effectiveness of Levoleucovorin for Injection have not been established for the treatment of pediatric patients with advanced metastatic colorectal cancer.

8.5Geriatric Use Clinical studies of Levoleucovorin for Injection in the treatment of osteosarcoma did not include patients aged 65 and over to determine whether they respond differently from younger patients. In the NCCTG clinical trial of Levoleucovorin for Injection in combination with fluorouracil for the treatment of metastatic colorectal cancer, no overall differences in safety or effectiveness were observed between patients age 65 years and older and younger patients.

🤰 Pregnancy 77 words ▾

8.1Pregnancy Risk Summary There are limited data with Levoleucovorin for Injection use in pregnant women. Animal reproduction studies have not been conducted with levoleucovorin. Levoleucovorin is administered in combination with methotrexate or fluorouracil, which can cause embryo-fetal harm.

Refer to methotrexate and fluorouracil prescribing information for additional information. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

🧒 Pediatric Use 98 words ▾

8.4Pediatric Use The safety and effectiveness of Levoleucovorin for Injection 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. Use of levoleucovorin in pediatric patients is supported by open-label clinical trial data in 16 pediatric patients 6 years of age and older, with additional supporting evidence from literature [see Clinical Studies ( 14.1 )].

The safety and effectiveness of Levoleucovorin for Injection have not been established for the treatment of pediatric patients with advanced metastatic colorectal cancer.

🧓 Geriatric Use 70 words ▾

8.5Geriatric Use Clinical studies of Levoleucovorin for Injection in the treatment of osteosarcoma did not include patients aged 65 and over to determine whether they respond differently from younger patients. In the NCCTG clinical trial of Levoleucovorin for Injection in combination with fluorouracil for the treatment of metastatic colorectal cancer, no overall differences in safety or effectiveness were observed between patients age 65 years and older and younger patients.

🧬 Clinical Pharmacology ~1 min read ▾

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action High-Dose Methotrexate Therapy Levoleucovorin is the pharmacologically active isomer of 5-formyl tetrahydrofolic acid. Levoleucovorin 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 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.

12.3Pharmacokinetics The pharmacokinetics of levoleucovorin after intravenous administration of a 15 mg dose was studied in healthy subjects. The mean maximum serum total tetrahydrofolate (total-THF) concentrations was 1722 ng/mL (CV 39%) and the mean maximum serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentrations was 275 ng/mL (CV 18%) observed around 0.9 hours post injection. Distribution Exploratory studies show that small quantities of systemically administered leucovorin enter the cerebrospinal fluid (CSF), primarily as its major metabolite 5-methyltetrahydrofolate (5-MTHFA).

In humans, the CSF levels of 5-MTHFA remain 1-3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. Elimination The mean terminal half-life was 5.1 hours for total-THF and 6.8 hours for (6S)-5-methyl-5,6,7,8-tetrahydrofolate. Drug Interaction Studies The mean dose-normalized steady-state plasma concentrations for both levoleucovorin and 5-methyl-THF were comparable whether fluorouracil (370 mg/m 2 /day as an intravenous bolus) was given in combination with levoleucovorin (250 mg/m 2 and 1000 mg/m 2 as a continuous intravenous infusion for 5.5 days) or with d,l -leucovorin (500 mg/m 2 as a continuous intravenous infusion for 5.5 days).

🧬 Mechanism of Action 128 words ▾

12.1Mechanism of Action High-Dose Methotrexate Therapy Levoleucovorin is the pharmacologically active isomer of 5-formyl tetrahydrofolic acid. Levoleucovorin 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 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.

📦 How Supplied / Storage and Handling 87 words ▾

16 HOW SUPPLIED/STORAGE AND HANDLING Levoleucovorin for Injection is a sterile white to pale yellow lyophilized powder in a single dose vial available as: 50 mg vial – NDC 0143-9558-01 Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature]. Retain in carton until contents are used. Protect from light.

Manufactured by: HIKMA FARMACÊUTICA (PORTUGAL), S.A. Estrada do Rio da Mó, 8, 8A e 8B – Fervença – 2705-906 Terrugem SNT, PORTUGAL Distributed by: West-Ward Pharmaceuticals Eatontown, NJ 07724 USA Revised April 2021 PIN396-WES/4

📋 Description 104 words ▾

11 DESCRIPTION Levoleucovorin is a folate analog and the pharmacologically active levo-isomer of d,l -leucovorin. The chemical name of levoleucovorin calcium is Calcium N-[p-[[[(6S)-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6- pteridinyl]methyl]amino]benzoyl]-L-glutamate (1:1) mixed hydrate. The molecular formula is C20H21CaN7O7 .nH2O (n = 3 to 6) and the molecular weight is 565.6 to 619.6.

The molecular structure is: Levoleucovorin for Injection, for intravenous use is supplied as a sterile white to pale yellow lyophilized powder consisting of 50 mg levoleucovorin (equivalent to 64 mg levoleucovorin calcium mixed hydrate) and 50 mg mannitol per 50 mg single dose vial. Sodium hydroxide and/or hydrochloric acid are used to adjust the pH. resized structure

🍼 Nursing Mothers 46 words ▾

8.2Lactation Risk Summary There are no data on the presence of levoleucovorin in human milk or its effects on the breastfed infant or on milk production. Levoleucovorin is administered in combination with methotrexate or fluorouracil. Refer to methotrexate and fluorouracil prescribing information for additional information.

🧬 Pharmacokinetics 171 words ▾

12.3Pharmacokinetics The pharmacokinetics of levoleucovorin after intravenous administration of a 15 mg dose was studied in healthy subjects. The mean maximum serum total tetrahydrofolate (total-THF) concentrations was 1722 ng/mL (CV 39%) and the mean maximum serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentrations was 275 ng/mL (CV 18%) observed around 0.9 hours post injection. Distribution Exploratory studies show that small quantities of systemically administered leucovorin enter the cerebrospinal fluid (CSF), primarily as its major metabolite 5-methyltetrahydrofolate (5-MTHFA).

In humans, the CSF levels of 5-MTHFA remain 1-3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. Elimination The mean terminal half-life was 5.1 hours for total-THF and 6.8 hours for (6S)-5-methyl-5,6,7,8-tetrahydrofolate. Drug Interaction Studies The mean dose-normalized steady-state plasma concentrations for both levoleucovorin and 5-methyl-THF were comparable whether fluorouracil (370 mg/m 2 /day as an intravenous bolus) was given in combination with levoleucovorin (250 mg/m 2 and 1000 mg/m 2 as a continuous intravenous infusion for 5.5 days) or with d,l -leucovorin (500 mg/m 2 as a continuous intravenous infusion for 5.5 days).

🔬 Clinical Studies ~2 min read ▾

14 CLINICAL STUDIES

14.1Rescue after High-Dose Methotrexate Therapy in Patients with Osteosarcoma The efficacy of levoleucovorin rescue following high-dose methotrexate was evaluated in 16 patients aged 6 to 21 years who received 58 courses of therapy for osteogenic sarcoma. High-dose methotrexate was one component of several different combination chemotherapy regimens evaluated across several trials. Methotrexate 12 grams/m 2 as an intravenous infusion over 4 hours was administered to 13 patients, who received Levoleucovorin for Injection 7.5 mg by intravenous infusion every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate.

Three patients received methotrexate 12.5 grams/m 2 intravenously over 6 hours, followed by Levoleucovorin for Injection 7.5 mg by intravenous infusion every 3 hours for 18 doses beginning 12 hours after completion of methotrexate. The mean number of Levoleucovorin for Injection doses per course was 18.2 and the mean total dose per course was 350 mg. The efficacy of Levoleucovorin for Injection rescue following high-dose methotrexate was based on the adverse reaction profile [See Adverse Reactions ( 6.1 )].

14.2Metastatic Colorectal Cancer In a randomized clinical study conducted by Mayo Clinic and North Central Cancer Treatment Group (NCCTG) in patients with metastatic colorectal cancer comparing d,l -leucovorin 200 mg/m 2 and fluorouracil 370 mg/m 2 versus d,l -leucovorin 20 mg/m 2 and fluorouracil 425 mg/m 2 versus fluorouracil 500 mg/m 2 , with all drugs administered by intravenous infusion daily for 5 days every 28 to 35 days, response rates were 26% (p=0.04 versus fluorouracil alone), 43% (p=0.001 versus fluorouracil alone) and 10%, respectively.

Respective median survival times were 12.2 months (p=0.037), 12 months (p=0.050), and 7.7 months. The low dose d,l -leucovorin regimen was associated with a statistically significant improvement in weight gain of more than 5%, relief of symptoms, and improvement in performance status. The high dose d,l -leucovorin regimen was associated with a statistically significant improvement in performance status and trended toward improvement in weight gain and in relief of symptoms but these were not statistically significant.

In a second randomized clinical study conducted by Mayo Clinic and NCCTG, the fluorouracil alone arm was replaced by a regimen of sequentially administered methotrexate, fluorouracil, and d,l -leucovorin. Response rates with d,l -leucovorin 200 mg/m 2 and fluorouracil 370 mg/m 2 versus d,l -leucovorin 20 mg/m 2 and fluorouracil 425 mg/m 2 versus sequential methotrexate and fluorouracil and d,l -leucovorin were respectively 31% (p≤0.01), 42% (p≤0.01), and 14%. Respective median survival times were 12.7 months (p≤0.04), 12.7 months (p≤0.01), and 8.4 months.

There was no statistically significant difference in weight gain of more than 5% or in improvement in performance status was seen between the treatment arms. A randomized controlled trial conducted by NCCTG in patients with metastatic colorectal cancer failed to show superiority of a regimen of fluorouracil + levoleucovorin to fluorouracil + d,l -leucovorin in overall survival. Patients were randomized to fluorouracil 370 mg/m 2 intravenously and levoleucovorin 100 mg/m 2 intravenously, both daily for 5 days, or to fluorouracil 370 mg/m 2 intravenously and d,l -leucovorin 200 mg/m 2 intravenously, both daily for 5 days.

Treatment was repeated week 4 and week 8, and then every 5 weeks until disease progression or unacceptable toxicity.

🧪 Nonclinical Toxicology 27 words ▾

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been conducted to evaluate the potential of levoleucovorin for carcinogenesis, mutagenesis and impairment of fertility.

📄 Carcinogenesis, Mutagenesis, Impairment of Fertility 24 words ▾

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been conducted to evaluate the potential of levoleucovorin for carcinogenesis, mutagenesis and impairment of fertility.

📄 Recent Major Changes 44 words ▾

Indication and Usage (1) 01/2020 Dosage and Administration (2) 11/2020 Contraindications (4) 01/2020 Warning and Precautions (5) 01/2020 Indication and Usage ( 1 ) 01/2020 Dosage and Administration ( 2 ) 11/2020 Contraindications ( 4 ) 01/2020 Warning and Precautions ( 5 ) 01/2020

📄 Package Label / Principal Display Panel 60 words ▾

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0143-9558-01 Levoleucovorin For Injection 50 mg/vial present as levoleucovorin calcium For Intravenous Use Lyophilized Sterile Single-dose Vial Rx only PLB906-WES.3

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0143-9558-01 Sterile, Single-dose Vial Levoleucovorin For Injection 50 mg/vial present as levoleucovorin calcium For Intravenous Use Lyophilized Rx only PBX396-WES.3

SERIALIZATION IMAGE Representative Serialization Carton Image Representative Serialization Carton Image

Source: FDA Structured Product Labeling, mirrored from DailyMed / openFDA. Prefer the government’s original formatting? View this label on DailyMed ↗

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Why is there no price listed?
The pricing shown on our NDC pages comes from CMS NADAC, a voluntary survey of retail community pharmacy invoices. CMS does not publish a NADAC for every NDC — packages outside the retail survey (institutional and hospital products, bulk packages, discontinued items, and many OTC items) may never receive one. A missing price reflects the survey's scope, not this product's actual cost, and does not mean the product is free or unavailable.
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