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VYKOURA leucovorin calcium 350 mg/35mL Injection — NDC 83831-0148-35 package photo

VYKOURA leucovorin calcium 350 mg/35mL Injection

by Avyxa Pharma, LLC · 1 VIAL, SINGLE-USE in 1 CARTON (83831-148-35) / 35 mL in 1 VIAL, SINGLE-USE
NDC 83831-0148-35
🏷️ FDA NDC (as labeled) 83831-148-35 billing pads the product segment with a zero
Rx only Brand On market Non-controlled
🗂️ Data synced Jul 24, 2026 · sources: openFDA · FDA label (DailyMed) · FDA Orange & Purple Book · First Databank · CMS NADAC, ASP, Medicare & Medicaid · RxNorm
📋 All sources & update times →

This page is curated, coded, and maintained by

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

🆔 Identity & classification

FDA NDC (as labeled) 83831-148-35
Product NDC 83831-148
11-digit billing NDC 83831014835
NCPDP billing unit ML — per mL (volume)
RxCUI 2104714, 2735355, 2735359, 2735364, 2735365, 2735366
UNII RPR1R4C0P4
UPC 0383831147053, 0383831148357, 0383831149507
Application # NDA220406
SPL Set ID d122b875-435e-4e00-b945-7a0546df95c2
Established class (EPC) Folate Analog
Chemical class Folic Acid
DEA schedule Non-controlled
Marketing category NDA
Marketing status On market
FDA listing status Listed (active directory)
Marketing start 2026-03-16
Route INTRAMUSCULAR, INTRAVENOUS
Dosage form INJECTION
Substance LEUCOVORIN CALCIUM
GPI-14 21755040102051
GCN Seq No 044540
GCN 87559
HICL code 001063
Ingredient (HICL) Leucovorin 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 VYKOURA 350 MG/35 ML VIAL
FDB brand name Vykoura
Legend status F — Federal legend — prescription drug or device
Why two NDCs? The FDA registers this code as 83831-148-35 — a 5-3-2 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 product segment → 83831-0148-35. 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
Drug family (ATC) Detoxifying agents for antineoplastic treatment
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.

🏭 Manufacturer & labeler

LabelerAvyxa Pharma, LLC
Application holderAVYXA HOLDINGS LLC
FDA applicationNDA220406 (NDA)
Labeler code83831
First marketedMar 2026
Product typeHuman Prescription Drug
Portfolio29 products on file
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.

🩺 Clinical

Label name VYKOURA 350 MG/35 ML VIAL Ingredient Leucovorin Calcium
📖 What it is MedlinePlus · NLM

Leucovorin is used to prevent harmful effects of methotrexate (a cancer chemotherapy medication) or to treat an overdose of methotrexate or similar medications. It is also used to treat people who have an inherited condition that prevents folate from reaching the brain. Leucovorin is in a class of medications called folic acid analogs. It works by protecting healthy cells from the effects of methotrexate or similar medications while allowing methotrexate to enter and kill cancer cells.

Read the full MedlinePlus article ↗
📗 Our plain-language guide HelloPharmacist
  • Not exactly — it depends on your situation. If you're receiving high-dose methotrexate, leucovorin's job is to protect your healthy cells from the drug's toxic effects; think of it...
  • Why am I getting leucovorin injections — is it a treatment for my cancer itself?
  • The most common issues — especially when leucovorin is combined with fluorouracil for colorectal cancer — are nausea, vomiting, diarrhea, mouth sores, and fatigue. These can be mor...
  • What side effects should I watch out for?
📖 Read our full Leucovorin Injection guide →
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.

🧪 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 2PP9364507
    A modified form of beta-cyclodextrin, a natural sugar-like molecule. It helps dissolve and stabilize drugs in liquid medicines and improves how well the body absorbs certain medications.
  • 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.
  • UNII 451W47IQ8X
    Sodium chloride is common table salt. It's used in medicines as a buffer to maintain proper pH, as a filler to add bulk, or to adjust the osmotic balance in liquid formulations.
  • 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.
  • UNII 023C2WHX2V
    Tromethamine is a chemical buffer that helps maintain the proper acidity level in liquid medicines. It neutralizes acids and stabilizes the solution so the medication remains effective and safe throughout its shelf life.

5 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.

💲 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 eachPer 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.
ℹ️
No price is published for this exact package yet. CMS surveys NADAC per package size, so a different pack of the same drug often has one.
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.

🔁 Therapeutic equivalents

ProductLabelerPackNADAC/unitTEStatusPrice vs. this
Vykoura 350 mg/35mLthis 83831-0148-35 Avyxa 1 vial — — FDA listed —
About this product: this is the brand-name version. Some generic versions are approved by the FDA, but we could not confirm current pharmacy availability from our pricing/market data.
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

🏛️
2026
First FDA approval
Feb 2026
📍
2026
Currently FDA-listed
listed with the FDA
🛡️
2044
Latest patent/protection listed
not a guaranteed launch date
🔒Generic approved by FDA, but pharmacy availability is not confirmed

The FDA lists approved generic versions of this medicine, but that does not always mean a pharmacy can get one today. Patent rules, launch agreements, supply and pricing can affect when generics actually arrive.

🛡️ Latest patent/protection date listed: FDA patent/protection data lists protections through Dec 2044. This may affect when a full generic version becomes widely available, but it is not a guaranteed launch date.
📅 FDA approved Feb 3, 2026 RLD RS ⏳ ~18.3 yr to latest listed protection

Why the date isn’t exact: Generic timing can change because patents may be challenged, settled, licensed, added, removed, or worked around with a narrower label — and FDA approval does not always mean a pharmacy can get the generic today.

Patents & exclusivity — FDA Orange Book
US 12564592 — drug product
US 12564592 — drug product
US 12564592 — drug product
2026 2028 2030 2032 2034 2036 2038 2040 2042 2044
Today
LOE
Substance patent Formulation patent Method-of-use patent Exclusivity Pediatric +6mo
🏛️FDA exclusivity
FDA-granted marketing protection. It’s separate from patents and may be shorter than patent protection.
🧪Product / substance patents
Patents covering the active ingredient, product, formulation, or related drug features.
🎯Method-of-use patents
Patents covering specific approved uses. These can sometimes be carved out with a “skinny label,” but not always.
🛈 What do these terms mean?
Patent
Legal protection listed in the Orange Book that may delay generic approval or launch. Issued by the U.S. Patent & Trademark Office.
Substance patent
Covers the active drug molecule itself — the hardest to design around. A generic generally can’t launch until it expires.
Formulation (product) patent
Covers a specific formulation or dosage form. A generic can sometimes work around it with a different formulation.
Method-of-use patent
A patent covering one specific approved use of the drug — not necessarily the whole molecule. A generic can sometimes launch with a “skinny label” that carves out the protected use and keeps the others.
Skinny label
A generic label that omits a still-patented use when the FDA allows it — letting a generic reach the market for the unprotected uses.
Exclusivity
FDA-granted marketing protection, separate from patents — e.g. 5-yr new chemical entity, 7-yr orphan drug, or a +6-month pediatric extension.
Paragraph IV
A generic applicant’s formal challenge to a listed patent. It can potentially lead to earlier generic entry, but often involves litigation or a settlement.
RLD / RS
Reference Listed Drug — the brand product the FDA uses as the reference for generic applications. Reference Standard — the product the FDA expects generics to compare against in bioequivalence testing.
TE / AB rating
FDA therapeutic-equivalence rating. An AB rating generally means the FDA considers a generic therapeutically equivalent to — and substitutable for — the brand.
LOE (loss of exclusivity)
The latest patent or exclusivity currently listed — the loss-of-exclusivity / latest-listed-protection date shown on this page. Paragraph-IV challenges and settlements can move the real date earlier; FDA approval and a manufacturer’s decision to market can move it later.

Built from the FDA Orange Book. The bars above are scaled to each protection’s expiry; the red LOE marker is the last one to lapse.

Listed patents (3)
PatentTypeUse codeExpires
US 12564592 ↗ Drug product — Dec 23, 2044
US 12564592 ↗ Drug product — Dec 23, 2044
US 12564592 ↗ Drug product — Dec 23, 2044
Common questions
Is there a generic version of VYKOURA 350 MG/35 ML VIAL?
Yes — an FDA-approved generic equivalent is listed in the FDA Orange Book for VYKOURA 350 MG/35 ML VIAL. See the alternatives section for substitutable, lower-cost products.
The FDA approved a generic — why can’t I get it at my pharmacy yet?
FDA approval and pharmacy availability are two different things. The FDA can approve a generic years before it actually reaches pharmacies, because the brand company may still hold patents or have a settlement that delays the launch. A manufacturer also has to choose to make and sell it, and have supply ready. So a drug can be “FDA-approved generic exists” and still be brand-only at the counter today.
Why do different websites show different generic release dates?
Generic availability is not based on one single date. Some sources use the first exclusivity expiration, some use the last product patent, and others use the latest method-of-use patent. Patent challenges, settlements, licenses, and label carve-outs can also change the real-world launch date. This page shows the underlying Orange Book dates so you can see why estimates may differ.
What does “FDA listed” mean?
It means the product appears in the FDA’s official NDC directory. That’s a good sign a product exists and is intended for the U.S. market, but on its own it does not confirm a pharmacy can fill it today. Where we have recent retail pricing data (NADAC) for a product, we label it “Availability likely” instead.
What does a patent or protection date mean here?
It’s the latest date currently listed in the FDA Orange Book for a patent or exclusivity on the brand product. It can affect when a full generic version becomes widely available — but it is not a guaranteed generic launch date. Generics sometimes arrive earlier (through a settlement or patent challenge) or later (a manufacturer still has to make and sell one).
What does “current Orange Book estimate” mean?
It means we are using the latest patent and exclusivity dates currently listed in the FDA Orange Book. It is not a guaranteed launch date.
Can a generic come out before the last patent expires?
Sometimes. A generic company may challenge a patent, settle with the brand manufacturer, receive a license, or obtain approval with a narrower label that avoids a patented use. In other cases, the last listed protection may delay full-label generic competition.
Can a generic come out after the listed dates?
Yes. Even after patents or exclusivity expire, a generic still needs FDA approval and a manufacturer must choose to market it. Supply, litigation, business decisions, or regulatory issues can delay actual availability.
What is the difference between patents and exclusivity?
Patents are legal protections usually issued by the U.S. Patent and Trademark Office. FDA exclusivity is marketing protection granted by the FDA. They are separate, and either one can affect generic timing.
Why are there multiple patent dates?
One drug can have several patents covering different things: the active ingredient, a formulation, a manufacturing process, or a specific approved use. That is why a page may show several expiration dates instead of one simple generic date.
Built from FDA Orange Book patent and exclusivity data. Dates are refreshed from public FDA data when available; the marker is max(latest patent expiry, latest exclusivity expiry). Paragraph-IV settlements and first-filer 180-day exclusivity can shift the real date; a method-of-use patent may allow an earlier skinny-label generic for non-protected indications. Generic launch timing is an estimate, not a guarantee.
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.

📊 Medicare Part D spend CMS · PART D · 2026 (Q1)

Medicare Part D (outpatient prescription) spending for Leucovorin Calcium (matched by generic name) — the program that covers self-administered drugs. 10 manufacturers.
⚠️ Drug-level data: CMS publishes Part D spending by drug, not by NDC — these figures combine every manufacturer, strength and package size sold under the name Leucovorin Calcium. That’s a different level of aggregation than the Medicaid card above, which is specific to this exact 11-digit NDC (pack size included), so the two aren’t directly comparable.
Period
Total Part D spend
$1.78M
Claims incl. refills
30.9K
Beneficiaries
21.1K
Spend / beneficiary
$84.30
Spend / claim
$57.57
Trend by period
💵 About the dollar figures: spending is what Part D plans paid before confidential manufacturer rebates, so the program’s real net cost is lower. A blank patient count means fewer than 11 people — CMS hides counts that small to protect privacy. Source: CMS Medicare Quarterly Part D Spending by Drug (data.cms.gov), updated quarterly.

🔬 Reported adverse events (FAERS)

Read carefully: FAERS reports are voluntary and unverified. Counts are not incidence, do not establish causation, are subject to reporting bias, and cannot be used to compare one drug to another. Shown for signal context only. Reports for VYKOURA (this brand).

Top reported reactions

Diarrhoea1,799
Nausea1,388
Vomiting1,135
Neutropenia1,094
Pyrexia1,011
Fatigue873
Disease Progression772

Age at onset

Neonate36
Infant17
Child99
Adolescent41
Adult1,593
Elderly1,093

Reporter sex

19,003 reports
Male · 54%
Female · 45%
Unknown · 1%

Serious outcomes

Hospitalization9,240
Death2,532
Life-threatening1,479
Disabling414
Reports over time (by year) — tap or hover for the count & year
2019 2021 2023 2026 1,950 0
Most recent year is provisional (FAERS lags ~3 months).
Where does this data come from?
Adverse-event reports from the FDA Adverse Event Reporting System (FAERS) via openFDA. FAERS reports are voluntary and unverified — counts are not incidence and don’t establish causation.

📦 Packaging — all sizes for this product

Package NDCDescription Marketing startStatus
83831-0148-35 You're viewing this 1 VIAL, SINGLE-USE in 1 CARTON (83831-148-35) / 35 mL in 1 VIAL, SINGLE-USE 2026-03-16 Active

🧭 About this NDC listing & data coverage

Finished prescription product
What data is (and isn’t) available for this NDC — tap to expand
NDC identity (package / product / labeler codes) ✓ Available
Labeler ✓ Available
Product & package description ✓ Available
Marketing category & status ✓ Available
Active ingredient / dosage form / route ✓ Available
FDA label (SPL via DailyMed) ✓ Available
Package photos ✓ Available
Inactive ingredients (structured) ✓ Available
NADAC pharmacy acquisition price (CMS) — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey.
Orange Book / therapeutic-equivalence data ✓ Available
HCPCS J-code billing crosswalk — Not published for this NDC Most self-administered / retail products have no J-code — that is normal.
Medicaid utilization (CMS SDUD) — Not published for this NDC CMS reports utilization only for NDCs with Medicaid claims above its privacy threshold.
“Not published” reflects what the public FDA / CMS / NLM sources provide for this exact package code — it is a property of the data feeds, not a judgment about the product.

Questions about this listing

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.
Is the NDC printed on the package the same as the 11-digit billing NDC?
Yes, they identify this exact package in different formats. The FDA registers it as 83831-148-35, which is what is printed on the packaging and shown on DailyMed. Insurance claims use a fixed 11-digit 5-4-2 format, so the short segment is padded with a leading zero: 83831-0148-35, written without dashes as 83831014835. The Identity section at the top of this page lists every form of this code.
What do the three segments of this NDC mean?
In 83831-0148-35, the first segment (83831) is the labeler code FDA assigned to Avyxa Pharma, LLC; the middle segment (0148) identifies this specific product — its ingredient, strength, and dosage form; and the last segment (35) identifies this exact package size and type. Together they name one specific package of one specific product.
Is this package still being marketed?
Yes, per the latest FDA NDC Directory data on this page: this package is listed as actively marketed, with no marketing end date reported by Avyxa Pharma, LLC. Listing status can change — the directory data on this page refreshes weekly.
Who lists this product with the FDA?
Avyxa Pharma, LLC is the labeler of record for this NDC — the company under whose FDA-assigned code the package is listed. The labeler may be the manufacturer itself or a distributor marketing the product under its own code.
Do I need a prescription for this product?
This NDC is listed with FDA as a prescription product, so it is dispensed under a prescriber's order. Your pharmacist can tell you whether any over-the-counter forms of the same medication exist.
This page identifies an FDA-listed package (the NDC) and reports public regulatory and pricing data about the listing. It is reference information, not a medical recommendation — talk to your pharmacist or prescriber about your own medication.
Where does this data come from?
Listing facts (marketing category, packager status, marketing dates) from the FDA openFDA NDC Directory; label availability from DailyMed; pricing coverage from CMS NADAC; equivalence scope from the FDA Orange Book.

📄 Full prescribing information FDA SPL

The complete FDA label for this product — the official prescribing information, verbatim, section by section. 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 💬 Information for Patients
🎯 Indications and Usage ~1 min read ▾

1 INDICATIONS AND USAGE VYKOURA is indicated for:

1.1Rescue after high-dose methotrexate (MTX) therapy in adult and pediatric patients.

1.2Reducing the toxicity of: Methotrexate in adult and pediatric patients with impaired methotrexate elimination or Folic acid antagonists or dihydrofolate reductase (DHFR) inhibitors following an overdose in adult and pediatric patients.

1.3Treatment of megaloblastic anemias due to folic acid deficiency in adult and pediatric patients when oral therapy is not feasible.

1.4Treatment of patients with metastatic colorectal cancer in combination with fluorouracil. Limitations of Use VYKOURA is not indicated for pernicious anemia and megaloblastic anemia secondary to the lack of vitamin B 12 , because of the risk of progression of neurologic manifestations despite hematologic remission. VYKOURA is a folate analog indicated for: Rescue after high-dose methotrexate therapy in adult and pediatric patients.

( 1.1 ) Reducing the toxicity of methotrexate in adult and pediatric patients with impaired methotrexate elimination or folic acid antagonists or dihydrofolate reductase (DHFR) inhibitors following an overdose in adult and pediatric patients. ( 1.2 ) Treatment of megaloblastic anemias due to folic acid deficiency in adult and pediatric patients when oral therapy is not feasible. ( 1.3 ) Treatment of patients with metastatic colorectal cancer in combination with 5-fluorouracil.

( 1.4 ) Limitations of Use : VYKOURA is not indicated for the treatment of pernicious anemia and megaloblastic anemia secondary to lack of vitamin B 12 , because of the risk of progression of neurologic manifestations despite hematologic remission. ( 1.3 )

⏱️ Dosage and Administration ~3 min read ▾

2 DOSAGE AND ADMINISTRATION VYKOURA is indicated for intravenous or intramuscular administration. Do not administer intrathecally. ( 2.1 ) Rescue After High-Dose Methotrexate Therapy : Rescue recommendations are based on methotrexate dose of 12 to 15 grams/m 2 administered by intravenous infusion over 4 hours.

Initiate rescue at a dose of 15 mg (approximately 10 mg/m 2 ) every 6 hours beginning 24 hours after the beginning of methotrexate infusion. ( 2.2 ) Continue until the methotrexate level is below 0.05 micromolar (5 x 10 -8 M). Adjust dose, if necessary, based on methotrexate elimination.

( 2.2 ) Reducing the Toxicity of Methotrexate in Patients with Impaired Methotrexate Elimination or Following an Overdosage of Folic Acid Antagonists or DHFR Inhibitors : Start as soon as possible after methotrexate overdosage or within 24 hours of delayed methotrexate elimination. ( 2.3 ) Administer VYKOURA 10 mg/m 2 intravenously or intramuscularly every 6 hours until methotrexate level is less than 0.01 micromolar (1 x 10 -8 M). ( 2.3 ) Metastatic Colorectal Cancer in Combination with Fluorouracil : 20 mg/m 2 to 500 mg/m 2 based on specific combination regimen.

Administer VYKOURA before fluorouracil. ( 2.4 ) Do not mix VYKOURA with other drugs or administer other drugs through the same intravenous line. ( 2.4 ).

Megaloblastic Anemia Due to Folic Acid Deficiency: Up to 1 mg/day administered intravenously until adequate hematologic response is achieved.

2.1Important Administration Information VYKOURA is indicated for intravenous (IV) and intramuscular (IM) administration. Do not administer intrathecally. VYKOURA may be harmful or fatal if given intrathecally.

Do NOT mix VYKOURA with other drugs or administer other drugs through the same intravenous line. A precipitate may form if VYKOURA is mixed with fluorouracil. Due to the calcium content of VYKOURA, do NOT exceed the maximum infusion rate of 160 mg/minute to avoid hypercalcemia . [See Warnings and Precautions (5.2) ]

2.2Recommended Dosage for Rescue After High-Dose Methotrexate Therapy The recommended dosage for VYKOURA is based on serum methotrexate levels obtained 24 hours following the methotrexate infusion (refer to the methotrexate prescribing information). Table 1 describes the VYKOURA regimen in patients who receive a dose of 12-15 grams/m 2 of methotrexate. Consult institutional guidelines for additional dosing information as appropriate.

Begin VYKOURA twenty-four hours after starting the methotrexate infusion. As the time interval between methotrexate administration and VYKOURA increases, the effectiveness of VYKOURA to diminish methotrexate toxicity may decrease. VYKOURA may be administered intravenously or intramuscularly [see Dosage and Administration (2.6) ] .

Monitor serum creatinine and methotrexate levels at least once daily. Administer intravenous fluids (3 Liters per day) and alkalinize the urine to a pH of 7 or greater until the methotrexate level is below 0.05 micromolar (5 x 10 -8 M). Table 1 Recommended Dosage for VYKOURA After High-Dose Methotrexate Based on Serum Methotrexate and Serum Creatinine Levels * These patients are likely to develop reversible renal failure.

In addition to appropriate VYKOURA therapy, continue hydration and urinary alkalinization and monitor fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. Clinical Situation Laboratory Findings Recommended Dosage 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. 15 mg intravenously or intramuscularly every 6 hours for 60 hours for a total of 10 doses.

Begin VYKOURA 24 hours after the 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 administra…

💊 Dosage Forms and Strengths 56 words ▾

3 DOSAGE FORMS AND STRENGTHS Injection: 50 mg/5 mL (10 mg/mL), 350 mg/35 mL (10 mg/mL), and 500 mg/50 mL (10 mg/mL) of leucovorin as a clear, colorless to yellow color solution in a single-dose vial. Injection: 50 mg/5 mL, 350 mg/35 mL, and 500 mg/50 mL (10 mg/mL) in a single-dose vial. ( 3 )

⛔ Contraindications 56 words ▾

4 CONTRAINDICATIONS VYKOURA is contraindicated in patients who have had a severe hypersensitivity reaction to leucovorin (folinic acid), levoleucovorin, or folic acid [see Warnings and Precautions (5.1) ]. Reactions have included anaphylactic reactions. VYKOURA is contraindicated in patients who have had a severe hypersensitivity reaction to leucovorin (folinic acid), levoleucovorin, or folic acid. ( 4 )

⚠️ Warnings and Cautions 174 words ▾

5 WARNINGS AND PRECAUTIONS Hypersensitivity : Hypersensitivity reactions, including anaphylactic reactions and urticaria can occur. Withhold or permanently discontinue VYKOURA based on the severity of hypersensitivity. ( 5.1 ) Hypercalcemia : Due to calcium content, inject no more than 16 mL (160 mg) of VYKOURA intravenously per minute. ( 5.2 ) Risk of Administration Errors : Do not administer VYKOURA intrathecally. ( 5.3 )

5.1Hypersensitivity Hypersensitivity reactions, including anaphylactic reactions and urticaria, have been reported following the administration of leucovorin. VYKOURA is contraindicated in patients who have had a severe hypersensitivity reaction to leucovorin, levoleucovorin, or folic acid [see Contraindications (4) ]. Withhold or permanently discontinue VYKOURA based on the severity of hypersensitivity.

5.2Hypercalcemia Because of the calcium content of the VYKOURA, do not administer more than 160 mg of VYKOURA intravenously per minute [see Dosing and Administration (2.6) ] .

5.3Risk of Administration Errors In the treatment of accidental overdosages of intrathecally administered folic acid antagonists, do not administer VYKOURA intrathecally. VYKOURA MAY BE HARMFUL OR FATAL IF GIVEN INTRATHECALLY.

🤒 Adverse Reactions ~2 min read ▾

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity [see Warnings and Precautions (5.1) ] Hypercalcemia [see Warnings and Precautions (5.2) ] The most common adverse reactions (≥20%) in patients receiving high-dose methotrexate therapy with leucovorin rescue are stomatitis and vomiting. ( 6.1 ) The most common adverse reactions (>50%) in patients receiving leucovorin in combination with fluorouracil for metastatic colorectal cancer are stomatitis, diarrhea, and nausea.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Avyxa Pharma, LLC at 1-888-520-0954 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 clinical practice. Table 2 summarizes significant adverse events occurring in 316 patients treated with the leucovorin/5-fluorouracil combinations compared against 70 patients treated with 5-fluorouracil alone for advanced colorectal carcinoma.

These data are taken from the Mayo/NCCTG large multicenter prospective trial evaluating the efficacy and safety of the combination regimen. Table 2: Percentage of Patients Treated with Leucovorin and Fluorouracil for Advanced Colorectal Carcinoma Reporting Adverse Experiences or Hospitalized for Toxicity High LV = Leucovorin 200 mg/m 2 , Low LV = Leucovorin 20 mg/m 2 Any = percentage of patients reporting toxicity of any severity Grade 3+ = percentage of patients reporting toxicity of Grade 3 or higher (High LV)/5-FU (N = 155) (Low LV)/5-FU (N = 161) 5-FU Alone (N = 70) Any (%) Grade 3+ (%) Any (%) Grade 3+ (%) Any (%) Grade 3+ (%) Leukopenia 69 14 83 23 93 48 Thrombocytopenia 8 2 8 1 18 3 Infection 8 1 3 1 7 2 Nausea 74 10 80 9 60 6 Vomiting 46 8 44 9 40 7 Diarrhea 66 18 67 14 43 11 Stomatitis 75 27 84 29 59 16 Constipation 3 0 4 0 1 - Lethargy/Malaise/Fatigue 13 3 12 2 6 3 Alopecia 42 5 43 6 37 7 Dermatitis 21 2 25 1 13 - Anorexia 14 1 22 4 14 - Hospitalization for Toxicity 5% 15% 7%

🔄 Drug Interactions 162 words ▾

7 DRUG INTERACTIONS

7.1Effects of Other Drugs on VYKOURA Glucarpidase Administer VYKOURA at least 2 hours before or 2 hours after the glucarpidase dose when administering concomitantly. Glucarpidase can decrease leucovorin concentrations, which may decrease the effect of leucovorin rescue.

7.2Effects of VYKOURA on Other Drugs Certain Antiepileptic Drugs Increase monitoring for seizure activity in patients taking certain concomitant antiepileptic drugs. Folic acid in high doses may reduce the effectiveness of certain antiepileptic drugs (e.g., phenobarbital, phenytoin, and primidone) and thereby increase the frequency of seizures. It is not known whether folinic acid, including VYKOURA, has the same effects; however, both folic and folinic acids, including VYKOURA share some common metabolic pathways.

Trimethoprim-Sulfamethoxazole Avoid concomitant use of VYKOURA with trimethoprim-sulfamethoxazole . The effectiveness of trimethoprim-sulfamethoxazole can be decreased if used concomitantly with VYKOURA which was associated with increased rates of treatment failure and mortality in patients with HIV infection who receive trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jirovecii pneumonia.

👥 Use in Specific Populations ~1 min read ▾

8 USE IN SPECIFIC POPULATIONS

8.1Pregnancy Risk Summary Available data on the use of leucovorin during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Adequate animal reproduction studies have not been conducted with leucovorin. Agents administered in combination with VYKOURA may cause fetal harm.

Refer to the Prescribing Information for agents administered in combination with VYKOURA for additional information, as appropriate. 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 available data on the presence of leucovorin in either human or animal milk, the effect on the breastfed infant, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for VYKOURA and any potential adverse effects on the breastfed infant from VYKOURA or from the underlying maternal condition. Refer to the Prescribing Information for agents administered in combination with VYKOURA for breastfeeding recommendations, as appropriate.

8.4Pediatric Use VYKOURA is indicated to reduce the toxicity of MTX in pediatric patients with impaired MTX elimination, and folic acid antagonists or dihydrofolate reductase (DHFR) inhibitors following an overdose .

8.5Geriatric Use Clinical studies of leucovorin calcium did not show differences in safety or effectiveness between subjects over 65 and younger subjects. Other clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older patients cannot be ruled out. This drug is known to be excreted by the kidney and the risk of toxic reactions to the drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in this patient population.

🤰 Pregnancy 95 words ▾

8.1Pregnancy Risk Summary Available data on the use of leucovorin during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Adequate animal reproduction studies have not been conducted with leucovorin. Agents administered in combination with VYKOURA may cause fetal harm.

Refer to the Prescribing Information for agents administered in combination with VYKOURA for additional information, as appropriate. 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 32 words ▾

8.4Pediatric Use VYKOURA is indicated to reduce the toxicity of MTX in pediatric patients with impaired MTX elimination, and folic acid antagonists or dihydrofolate reductase (DHFR) inhibitors following an overdose .

🧓 Geriatric Use 99 words ▾

8.5Geriatric Use Clinical studies of leucovorin calcium did not show differences in safety or effectiveness between subjects over 65 and younger subjects. Other clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older patients cannot be ruled out. This drug is known to be excreted by the kidney and the risk of toxic reactions to the drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in this patient population.

🧬 Clinical Pharmacology ~2 min read ▾

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action High-Dose Methotrexate Therapy 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. l -Leucovorin (l-5 formyltetrahydrofolate) is rapidly metabolized (via 5, 10-methenyltetrahydrofolate then 5, 10-methylenetetrahydrofolate) to l -5-methyltetrahydrofolate.

L -5-methyltetrahydrofolate can in turn be metabolized via other pathways back to 5,10 methylenetetrahydrofolate, which is converted to 5-methyltetrahydrofolate by an irreversible, enzyme catalyzed reduction using the cofactors FADH 2 and NADPH. Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. Combination with Fluorouracil in Colorectal Cancer Leucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy, such as 5-fluorouracil.

Concurrent administration of leucovorin does not appear to alter the plasma pharmacokinetics of 5-fluorouracil. 5-Fluorouracil is metabolized to fluorodeoxyuridylic acid, which binds to and inhibits the enzyme thymidylate synthase (an enzyme important in DNA repair and replication). Leucovorin is readily converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of fluorodeoxyuridylic acid to thymidylate synthase and thereby enhances the inhibition of this enzyme.

12.2Pharmacodynamics Leucovorin exposure-response relationships and time course of pharmacodynamic response is not fully characterized.

12.3Pharmacokinetics Leucovorin pharmacokinetics were observed after a single intramuscular dose of 10 mg/m 2 in healthy subjects and are presented as mean (CV%) unless otherwise specified. Leucovorin baseline-corrected maximum plasma concentration (Cmax) is 1,832 ng/mL (14%) and the total systemic exposure (AUC) is 23,043 ng*hr/mL (15%). Absorption Leucovorin median (min, max) time to maximum plasma concentration (Tmax) is 1.7 hours (0.7, 4.5).

Elimination Leucovorin estimated terminal half-life is approximately 9.5 hours (CV 17%). Metabolism Leucovorin is rapidly metabolized (via 5, 10-methenyltetrahydrofolate then 5, 10-methylenetetrahydrofolate) to l,5-methyltetrahydrofolate. l,5-Methyltetrahydrofolate can be metabolized via other pathways back to 5,10-methylenetetrahydrofolate, which is converted to 5-methyltetrahydrofolate by an irreversible, enzyme catalyzed reduction using the cofactors FADH 2 and NADPH.

🧬 Mechanism of Action ~1 min read ▾

12.1Mechanism of Action High-Dose Methotrexate Therapy 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. l -Leucovorin (l-5 formyltetrahydrofolate) is rapidly metabolized (via 5, 10-methenyltetrahydrofolate then 5, 10-methylenetetrahydrofolate) to l -5-methyltetrahydrofolate.

L -5-methyltetrahydrofolate can in turn be metabolized via other pathways back to 5,10 methylenetetrahydrofolate, which is converted to 5-methyltetrahydrofolate by an irreversible, enzyme catalyzed reduction using the cofactors FADH 2 and NADPH. Administration of leucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. Combination with Fluorouracil in Colorectal Cancer Leucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy, such as 5-fluorouracil.

Concurrent administration of leucovorin does not appear to alter the plasma pharmacokinetics of 5-fluorouracil. 5-Fluorouracil is metabolized to fluorodeoxyuridylic acid, which binds to and inhibits the enzyme thymidylate synthase (an enzyme important in DNA repair and replication). Leucovorin is readily converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of fluorodeoxyuridylic acid to thymidylate synthase and thereby enhances the inhibition of this enzyme.

📦 How Supplied / Storage and Handling 86 words ▾

16 HOW SUPPLIED/STORAGE AND HANDLING VYKOURA (leucovorin calcium) injection is a clear, colorless to yellow color solution supplied in single-dose vial. Each carton contains one single-dose vial delivering 10 mg/mL leucovorin in the following strengths: Strength NDC Number 50 mg/5 mL (10 mg/mL) 83831-147-05 350 mg/35 mL (10 mg/mL) 83831-148-35 500 mg/50 mL (10 mg/mL) 83831-149-50 This container closure is not made with natural rubber latex. Storage and Handling Store in refrigerator at 2°C to 8°C (36°F to 46°F) in original carton to protect from light.

📋 Description 158 words ▾

11 DESCRIPTION Leucovorin is a folate analog, also known as folinic acid, Citrovorum factor, or 5-formyl-5,6,7,8-tetrahydrofolic acid calcium salt. This compound has the chemical designation of Calcium N-(p-((((6RS)-2-amino-5-formyl 5,6,7,8-tetrahydro-4-hydroxy-6-pteridinyl)methyl)amino)benzoyl)-L-glutamate (1:1). The structural formula of leucovorin calcium is: Leucovorin calcium is a white to light yellow crystalline powder with the molecular formula C 20 H 21 N 7 O 7 Ca and a molecular weight of 511.50 (calculated on the anhydrous basis).

VYKOURA (leucovorin calcium), for intravenous and intramuscular use, is supplied as a sterile, preservative-free, clear, colorless to yellow solution available in 50 mg/5 mL, 350 mg/35 mL and 500 mg/50 mL single-dose vials containing 10 mg/mL of leucovorin. Each mL contains 10.803 mg leucovorin calcium (equivalent to 10 mg leucovorin), 50 mg betadex sulfobutyl ether sodium, 4 mg sodium chloride, 7 mg tromethamine, and sodium hydroxide and/or hydrochloric acid for pH adjustment (pH 6.5 to 8.5). There is 0.004 mEq of calcium per mg of leucovorin.

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💬 Information for Patients 137 words ▾

17 PATIENT COUNSELING INFORMATION Advise patients of the following risks of VYKOURA: Hypersensitivity Reactions Inform patients that hypersensitivity reactions can occur with VYKOURA including anaphylactic reactions and urticaria. Inform patients about the signs and symptoms of hypersensitivity reactions and to contact their healthcare provider immediately if these occur during or after the administration of VYKOURA [see Warnings and Precautions (5.1) ] . Hypercalcemia Advise patients that hypercalcemia may occur with the use of VYKOURA and to report nausea, vomiting, headache and decreased alertness during or after the administration of VYKOURA. [see Warnings and Precautions (5.2) ].

Drug Interactions Advise patients to inform their health care providers of all concomitant drugs, including prescription drugs, nonprescription drugs, vitamins, and herbal products [see Drug Interactions (7) ]. Manufactured for: Avyxa Pharma, LLC New Jersey 07054, USA Made in Switzerland Image

Source: FDA Structured Product Labeling, mirrored from DailyMed / openFDA. Prefer the government’s original formatting? View this label on DailyMed ↗
← 83831-0147-05 · Avyxa 83831-0149-50 · Avyxa →
For educational and professional reference only — not medical advice. Pricing reflects published NADAC and CMS ASP (free public data) and may differ from your acquisition cost; always verify before billing or dispensing.