Home › NDC Lookup › Ingredients › Methotrexate › 16729-0277-30

Methotrexate 25 mg/mL Injection

by Accord Healthcare, Inc. · 1 VIAL in 1 CARTON (16729-277-30) / 2 mL in 1 VIAL

NDC 16729-0277-30

🏷️ FDA NDC (as labeled) 16729-277-30 billing pads the product segment with a zero

This package

Contains2 mL in 1 vial Cost per mL$1.76 NADAC Per package$3.51 / 2 ml Pack sizes3 compare ↓

Also priced by: Medicaid pays $2.51/unit · Part D plans $1.41/unit — full pricing hub ↓

Also comes in: 10 mL 16729-0277-03 40 mL 16729-0277-35

Rx only Generic On market Non-controlled ⚠ On shortage

🗂️ Data synced Sep 17, 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 Dr. Brian Staiger, PharmD

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

⚠️

Active FDA shortage. Methotrexate Sodium Injection is currently reported in shortage by the FDA (Other). Unavailable Shortage details →

🆔 Identity & classification

FDA NDC (as labeled) 16729-277-30

Product NDC 16729-277

11-digit billing NDC 16729027730

NCPDP billing unit ML — per mL (volume)

RxCUI 1655956, 1655959, 1655960

UNII YL5FZ2Y5U1

UPC 0316729277037, 0316729277358, 0316729277303

Application # ANDA040716

SPL Set ID dd035a9f-cd40-4314-b9d8-2294b8a924e2

Established class (EPC) Folate Analog Metabolic Inhibitor

Mechanism of action Folic Acid Metabolism Inhibitors

DEA schedule Non-controlled

Marketing category ANDA

Marketing status On market

FDA listing status Listed (active directory)

Marketing start 2014-03-07

Route INTRA-ARTERIAL, INTRAMUSCULAR, INTRATHECAL, INTRAVENOUS

Dosage form INJECTION

Substance METHOTREXATE

GCN Seq No 051610

GCN 18936

HICL code 024819

Ingredient (HICL) Methotrexate Sodium/Pf

HIC1 code V

Therapeutic class — broad (HIC1) Neoplasms

HIC2 code V1

Therapeutic class — intermediate (HIC2) Antineoplastic Drugs

HIC3 code V1B

Therapeutic class — specific (HIC3) Antineoplastic - Antimetabolites

AHFS code 10:00.00.00

AHFS class Antineoplastic Agents

FDB label name METHOTREXATE 50 MG/2 ML VIAL

FDB brand name Methotrexate Sodium

Legend status F — Federal legend — prescription drug or device

TE code (Orange Book) AP · RLD · RS

Why two NDCs? The FDA registers this code as 16729-277-30 — 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 → 16729-0277-30. 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 Metabolic Inhibitor class.

Pharmacologic class Folate Analog Metabolic Inhibitor

Drug family (ATC) Folic acid analogues, Other immunosuppressants

How it works Folic Acid Metabolism Inhibitors

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

LabelerAccord Healthcare, Inc.

Application holderACCORD HEALTHCARE INC

FDA applicationANDA040716 (ANDA)

Labeler code16729

First marketedMar 2014

Product typeHuman Prescription Drug

Portfolio67 products on file

🔎 All NDCs from Accord Healthcare, Inc.

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 METHOTREXATE 50 MG/2 ML VIAL Ingredient Methotrexate Sodium/Pf

📖 What it is MedlinePlus · NLM

Methotrexate injection is used alone or in combination with other medications: to treat certain types of acute lymphocytic leukemia (ALL) in adults and children; to treat or prevent meningeal leukemia (cancer in the covering of the spinal cord and brain) in adults and children; to treat certain types of non-Hodgkin's lymphoma (types of cancer that begin in a type of white blood cells that normally fights infection) in adults and children; to treat osteosarcoma (cancer that forms in bones) after surgery to remove the tumor in adults and children; to treat cutaneous T-cell lymphoma (CTCL,...

Read the full MedlinePlus article ↗

📗 Our plain-language guide HelloPharmacist

That's a great question, and it's really important you keep that in mind. For arthritis and psoriasis, methotrexate is always dosed once weekly — not daily. The drug works in a way...
Why am I only taking this once a week? That seems unusual.
Mild nausea, some fatigue, or the occasional mouth sore are common and manageable — let your doctor know, but they usually don't require an urgent call. However, if you develop a f...
What side effects should I just watch and wait on, versus call the doctor about right away?

📖 Read our full Methotrexate guide →

Patient education

📘 MedlinePlus patient leaflet ↗

Supplement & herbal interactions

Some supplements/herbs that may interact with Methotrexate — tap one for details:

Activated CharcoalMajor Coffee CharcoalModerate European MandrakeModerate GlucomannanModerate Guar GumModerate Gum ArabicModerate Slippery ElmModerate TragacanthModerate

🌿 Every supplement checked against Methotrexate (82 interactions) — ranked by severity →

Nutrient depletion considerations

Methotrexate may be associated with lower levels of 1 nutrient — worth a chat with your pharmacist, not a cause for alarm.

FOLIC ACID Major Depletion

🧪 Full Methotrexate nutrient depletion report →

An association is not a deficiency. Educational only — don't start or stop anything without professional guidance.

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 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.

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.

💲 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 system	Per mL	Per package
Retail pharmacies payNADAC · weekly	$1.756	$3.51 / 2 ml
Medicaid paysCMS SDUD · 12 mo	$2.51	$5.03 / 2 ml
Medicare drug plans payPart D · Q2 2026	$1.41	$2.82 / 2 ml
Medicare Part B allowsASP · J9260	$2.941 / J9260 unit	—

NADAC price history (per mL) — tap or hover for the price & month

▲ Up 15% over the last 22 months.

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)16729-277-30

11-digit billing NDC16729-0277-30

Format5-3-2 as registered → padded to 5-4-2 for billing (zero added to the product segment)

HCPCS J-codeJ9260

DescriptorMethotrexate sodium, 50 mg

Billing units / pkg1 units

Crosswalk sourceCMS ASP NDC-HCPCS Crosswalk

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.

🔁 Therapeutic equivalents

Product	Labeler	Pack	NADAC/unit	TE	Status	Price vs. this
Methotrexate 25 mg/mL 00143-9519-10	Hikma	10 vials	$1.238	AP	Availability likely	save 30%
Methotrexate 25 mg/mLthis 16729-0277-30	Accord	1 vial	$1.756	AP	Availability likely	—
Methotrexate 25 mg/mL 00143-9516-01	Hikma	1 vial	—	AP	FDA listed	—
Methotrexate 25 mg/mL 00143-9517-01	Hikma	1 vial	—	AP	FDA listed	—
Methotrexate 25 mg/mL 00143-9518-01	Hikma	1 vial	—	AP	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

🏛️

2014

On the market since

Mar 2014

📍

2026

Currently FDA-listed

12 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.

🗺️ Medicaid utilization & spend

📍 This exact package only: Medicaid data is reported per full 11-digit NDC — labeler, product and pack size — so every number here is for 16729-0277-30, not the drug overall. Other pack sizes report separately.

💊 Pharmacy benefit only: These are Medicaid outpatient pharmacy claims, billed by NDC. They exclude the medical benefit — clinic- or hospital-administered drugs billed under HCPCS J-codes — so drugs used mostly that way (e.g. Avastin, Lucentis, Keytruda) can look low or missing here. That’s expected, not an error.

📅 Q1 2025 – Q4 2025 · 4 quarters of data

ⓘ The newest quarter is usually incomplete when first published; states restate recent quarters in later CMS releases, so the latest figures typically revise upward. State coverage-policy changes can also shift quarter-to-quarter totals.

Prescriptions last 4 qtrs

4.6K

Units reimbursed last 4 qtrs

27.3K

Gross reimbursed last 4 qtrs

$68.7K

Avg / prescription

$14.85

Avg / unit

$2.5137

Latest quarter Q4 2025

798Rx

Medicaid pays / mL

$2.5137

gross reimbursed

NADAC / mL

$1.7563

acquisition cost

Spread

+$0.7574

+43% vs cost

What Medicaid paid per mL (before rebates; includes the pharmacy’s dispensing fee) compared with NADAC — the average price pharmacies pay to buy the drug. A positive spread means Medicaid reimbursed more than the purchase price, before manufacturer rebates.

Fee-for-service vs managed care ⓘ

30% FFS 70% MCO

Fee-for-service · 1,373 Rx Managed care · 3,251 Rx

State Medicaid map

Units reimbursed · per 100k residents

0.928.3

gray = no data reported ⓘ

Colors are per 100,000 residents, so big states don’t automatically dominate. Tap or hover a state for its actual totals.

Tap or hover a state

…for its Medicaid breakdown

🏆 Top states by units · per 100k residents

1 Kentucky 28.3 /100k

2 Oklahoma 20.0 /100k

3 New York 17.2 /100k

4 Indiana 16.3 /100k

5 Nevada 13.8 /100k

6 Iowa 13.0 /100k

7 West Virginia 12.7 /100k

8 New Mexico 12.1 /100k

National units — by quarter

💵 About the dollar figures: “reimbursed” is what Medicaid paid pharmacies before confidential manufacturer rebates, so the program’s real net cost is lower than these numbers. Fee-for-service and managed-care claims are combined unless split above. Source: CMS State Drug Utilization Data; per-100k rates use 2023 Census population estimates.

💊 Medicaid utilization by pack size

Medicaid (SDUD) totals over the four most recent reported quarters for every package size of this drug — handy when a specific package (e.g. a starter/titration pack) carries little or no Medicaid volume on its own.

1 vial this page16729-0277-30 4,624 Rx · $68,657

1 vial16729-0277-03 No Medicaid data

1 vial16729-0277-35 No Medicaid data

Drug total (last 4 qtrs): 4,624 Rx · 27,313 units · $68,657 gross reimbursed

Tap a pack size to open its page. Source: CMS State Drug Utilization Data, last 4 quarters.

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

Medicare Part D (outpatient prescription) spending for Methotrexate — the program that covers self-administered drugs. 15 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 Methotrexate. 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

$13.05M

Claims incl. refills

612.4K

Beneficiaries

415.6K

Spend / beneficiary

$31.40

Spend / claim

$21.31

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 Methotrexate — the ingredient across all brands.

Top reported reactions

Rheumatoid Arthritis42,798

Arthralgia40,830

Pain39,716

Fatigue33,049

Nausea28,999

Joint Swelling25,026

Drug Intolerance24,402

Reporter sex

Male · 29%

Female · 71%

Unknown · 0%

Reports over time (by year) — tap or hover for the count & year

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 NDC	Description	Per unit	Per pack	Marketing start	Status
16729-0277-03	1 VIAL in 1 CARTON (16729-277-03) / 10 mL in 1 VIAL	$0.7020 / mL	$7.02	2014-03-07	Active
16729-0277-30 You're viewing this	1 VIAL in 1 CARTON (16729-277-30) / 2 mL in 1 VIAL	$1.76 / mL	$3.51	2014-03-07	Active
16729-0277-35	1 VIAL in 1 CARTON (16729-277-35) / 40 mL in 1 VIAL	—	—	2014-03-07	Active

Per mL, this pack runs about 150% above the cheapest pack (NDC 16729-0277-03, $0.7020 vs $1.76 NADAC).

In Medicaid, this is the most-dispensed pack of this product — about 100% of fills over the last four reported quarters. See all packs ↓

Pack size FAQ

What quantity is in NDC 16729-0277-30?

NDC 16729-0277-30 is listed by the FDA — 1 vial in 1 carton / 2 ml in 1 vial.

What NDC number is used to bill for this package of Methotrexate 25 mg/mL Injection?

Bill NDC 16729-0277-30 — the 11-digit billing format is 16729027730. Pharmacy and medical claims use the 11-digit form; the FDA label may print a shorter form of the same code.

Prices are the latest CMS NADAC pharmacy acquisition cost per NDC; per-pack figures are per-unit × pack quantity, shown only when the pack is denominated in the same measure NADAC prices.

📄 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.

🚨 Boxed Warning 🎯 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 🆘 Overdosage 🧬 Clinical Pharmacology 🧬 Mechanism of Action 📦 How Supplied / Storage and Handling 📋 Description 💬 Information for Patients

🚨 Boxed Warning ~3 min read ▾

WARNING: EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS, BENZYL ALCOHOL TOXICITY, and OTHER SERIOUS ADVERSE REACTIONS Methotrexate Injection can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, Methotrexate Injection is contraindicated in pregnancy. Advise females and males of reproductive potential to use effective contraception [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and Use in Specific Populations ( 8.1 , 8.3 )].

Methotrexate Injection can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, Methotrexate Injection is contraindicated in pregnancy. Advise females and males of reproductive potential to use effective contraception [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and Use in Specific Populations ( 8.1 , 8.3 )].

Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis [see Contraindications ( 4 ) and Warnings and Precautions ( 5.2 )]. Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis [see Contraindications ( 4 ) and Warnings and Precautions ( 5.2 )]. Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis.

Use only preservative-free Methotrexate Injection for treatment of neonates or low-birth weight infants and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available [see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.3 )]. Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis.

Use only preservative-free Methotrexate Injection for treatment of neonates or low-birth weight infants and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available [see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.3 )]. Other serious adverse reactions, including death, have been reported with methotrexate.

Closely monitor for infections and adverse reactions of the bone marrow, kidneys, liver, nervous system, gastrointestinal tract, lungs, and skin. Withhold or discontinue Methotrexate Injection as appropriate [see Warnings and Precautions ( 5.4 , 5.5 , 5.6 , 5.7 , 5.8 , 5.9 , 5.10 , 5.11 )]. Other serious adverse reactions, including death, have been reported with methotrexate.

Closely monitor for infections and adverse reactions of the bone marrow, kidneys, liver, nervous system, gastrointestinal tract, lungs, and skin. Withhold or discontinue Methotrexate Injection as appropriate [see Warnings and Precautions ( 5.4 , 5.5 , 5.6 , 5.7 , 5.8 , 5.9 , 5.10 , 5.11 )]. WARNING: EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS, BENZYL ALCOHOL TOXICITY, and OTHER SERIOUS ADVERSE REACTIONS See full prescribing information for complete boxed warning.

Methotrexate Injection can cause embryo-fetal toxicity, including fetal death. Use in non-neoplastic diseases is contraindicated during pregnancy. Advise females and males of reproductive potential to use effective contraception during and after treatment with Methotrexate Injection.

( 4 , 5.1 , 8.1 , 8.3 ) Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis. ( 4 , 5.2 ). Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis.

Use only preservative-free Methotrexate Injection for treatment of neonates or low-birth weight infants, and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not avai…

🎯 Indications and Usage ~2 min read ▾

1 INDICATIONS AND USAGE Methotrexate Injection is a folate analog metabolic inhibitor indicated for The following neoplastic diseases for the: Treatment of adult and pediatric patients with acute lymphoblastic leukemia as part of a combination chemotherapy regimen ( 1.1 ) Prophylaxis and treatment of adult and pediatric patients with meningeal leukemia ( 1.2 ) Treatment of adult and pediatric patients with non-Hodgkin lymphoma ( 1.3 ) Treatment of adult and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen ( 1.4 ) Treatment of adults with breast cancer as part of a combination chemotherapy regimen ( 1.5 ) Treatment of adults with squamous cell carcinoma of the head and neck as single-agent ( 1.6 ) Treatment of adults with gestational trophoblastic neoplasia as part of a combination chemotherapy regimen ( 1.7 ) Treatment of adults with rheumatoid arthritis (RA).

( 1.8 ) Treatment of pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA). ( 1.9 ) Treatment of adults with severe psoriasis. ( 1.10 )

1.1Acute Lymphoblastic Leukemia Methotrexate Injection is indicated for the treatment of adult and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy regimen.

1.2Meningeal Leukemia: Prophylaxis and Treatment Methotrexate Injection is indicated for the prophylaxis and treatment of meningeal leukemia in adult and pediatric patients.

1.3Non-Hodgkin Lymphoma Methotrexate Injection is indicated for the treatment of adults and pediatric patients with non-Hodgkin lymphoma.

1.4Osteosarcoma Methotrexate Injection is indicated for the treatment of adults and pediatric patients with osteosarcoma as part of a combination chemotherapy regimen.

1.5Breast Cancer Methotrexate Injection is indicated for the treatment of adults with breast cancer as part of a combination chemotherapy regimen.

1.6Squamous Cell Carcinoma of the Head and Neck Methotrexate Injection is indicated for the treatment of adults with squamous cell carcinoma of the head and neck as a single-agent.

1.7Gestational Trophoblastic Neoplasia Methotrexate Injection is indicated for the treatment of adults with gestational trophoblastic neoplasia (GTN) as part of a combination chemotherapy regimen.

1.8Rheumatoid Arthritis Methotrexate Injection is indicated for the treatment of adults with rheumatoid arthritis (RA).

1.9Polyarticular Juvenile Idiopathic Arthritis Methotrexate Injection is indicated for the treatment of pediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA).

1.10Psoriasis Methotrexate Injection is indicated for the treatment of adults with severe psoriasis.

⏱️ Dosage and Administration ~3 min read ▾

2 DOSAGE AND ADMINISTRATION Verify pregnancy status in females of reproductive potential before starting Methotrexate Injection. ( 2.1 , 4 , 5.1 ) Neoplastic diseases: Refer to the prescribing information for disease specific dosing recommendations. Follow guidelines for high-dose regimens.

( 2.2 , 2.3 , 2.4 , 2.5 , 2.6 , 2.7 , 2.8 , 2.9 ) RA: Recommended starting dosage of 7.5 mg once weekly intramuscularly; adjust dose to achieve an optimal response. ( 2.10 ) pJIA: Recommended starting dosage of 10 mg/m2 once weekly subcutaneously or intramuscularly; adjust dose to achieve an optimal response. ( 2.11 ) Psoriasis: Recommended dosage of 10 mg to 25 mg once weekly intramuscularly or intravenously; adjust dose to achieve optimal response.

Once achieved, reduce to lowest possible dosage. ( 2.12 )

2.1Important Dosage and Safety Information Use only preservative-free Methotrexate Injection for treatment of neonates or low-birth weight infants and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required and preservative-free formulations are not available [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.4 )]. Verify pregnancy status in females of reproductive potential before starting Methotrexate Injection [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )].

For patients switching between a methotrexate product administered orally and Methotrexate Injection, consider potential differences in bioavailability.

2.2Recommended Monitoring and Concomitant Therapies for Intermediate- and High-Dose Regimens To decrease the risk of severe adverse reactions [see Warnings and Precautions (5) ]: Administer leucovorin rescue in patients receiving Methotrexate Injection doses of 500 mg/m 2 or greater (e.g., high-dose). Consider leucovorin rescue for patients receiving Methotrexate Injection doses between 100 mg/m 2 to less than 500 mg/m 2 (e.g., intermediate-dose). Refer to the leucovorin prescribing information for additional information.

For high-dose Methotrexate Injection regimens, follow the supportive care and monitoring instructions below. Also consider for patients receiving intermediate-dose Methotrexate Injection regimens. - Monitor serum creatinine, electrolytes, at baseline and at least daily during therapy - Administer intravenous fluids starting before the first dose and continuing throughout treatment to maintain adequate hydration and urine output - Alkalinize urine starting before the first dose and continuing throughout treatment to maintain a urinary pH of 7 or higher - Monitor methotrexate concentrations at least daily and adjust hydration and leucovorin dosing as needed Administer glucarpidase in patients who have toxic plasma methotrexate concentrations (>1 micromole per liter) and delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase prescribing information for additional information)

2.3Recommended Dosage for Acute Lymphoblastic Leukemia Methotrexate Injection is used as part of a multi-drug regimen. The recommended dosage varies from 10 to 5000 mg/m 2 intravenously. For high dose Methotrexate Injection regimens, use leucovorin rescue in accordance with high-dose methotrexate regimen guidelines [see Dosage and Administration ( 2.2 )] .

Lower doses (e.g., 20 to 30 mg/m 2 /week) may be used intramuscularly. Individualize the dose and schedule of Methotrexate Injection based on disease state, patient risk category, concurrent drugs used, phase of treatment, and response to treatment.

2.4Recommended Dosage for Meningeal Leukemia: Prophylaxis and Treatment Use only preservative-free Methotrexate Injection for intrathecal use. Prior to administration, dilute preservative-free Methotrexate Injection to a concentration of 1 mg/mL in preservative-free 0.9% Sodium Chloride Injection, USP. The recommended intrathecal dose of Methotrexate Injection (preservative-free) is based on a…

💊 Dosage Forms and Strengths 71 words ▾

3 DOSAGE FORMS AND STRENGTHS Injection: Methotrexate Injection, USP is a clear, yellow solution and is supplied in single-dose vials (preservative - free) in the following strengths: Preservative-Free (Single-Dose Vial) 50 mg/ 2 mL (25 mg/mL) 250 mg/ 10 mL (25 mg/mL) 1 g/40 mL (25 mg/mL) Injection: ( 3 ) Preservative-free (single-dose vials): 50 mg/ 2 mL (25 mg/mL), 250 mg/ 10 mL (25 mg/mL) and 1g/40 mL (25 mg/mL)

⛔ Contraindications 63 words ▾

4 CONTRAINDICATIONS Methotrexate Injection is contraindicated in: Patients with history of severe hypersensitivity to methotrexate [see Warnings and Precautions ( 5.2 )] . Pregnancy in patients with non-neoplastic diseases [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )] . History of severe hypersensitivity to methotrexate. ( 4 ) Pregnancy: in patients with non-neoplastic diseases. ( 4 )

⚠️ Warnings and Cautions ~3 min read ▾

5 WARNINGS AND PRECAUTIONS Secondary malignancies can occur. ( 5.13 ) Tumor lysis syndrome can occur in patients with rapidly growing tumors. ( 5.14 ) Immunizations and Risks associated with Live Vaccines: Immunizations may be ineffective. Live vaccines are not recommended due to risk of disseminated infection. ( 5.15 ) Infertility: Can cause impairment of fertility, oligospermia, and menstrual dysfunction. ( 5.16 , 8.3 )

5.1Embryo-Fetal Toxicity Based on published reports and its mechanism of action, methotrexate can cause embryo-fetal toxicity, including fetal death when administered to a pregnant woman. Methotrexate Injection is contraindicated for use in pregnant women with non-neoplastic diseases. Advise pregnant women with neoplastic diseases of the potential risk to a fetus.

The preservative benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when Methotrexate Injection is needed during pregnancy to treat a neoplastic disease [see Warnings and Precautions ( 5.3 )]. Advise females of reproductive potential to use effective contraception during Methotrexate Injection treatment and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during Methotrexate Injection treatment and for 3 months after the last dose [see Contraindications ( 4 ) and Use in Specific Populations ( 8.1 , 8.3 , 8.4 )].

5.2Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, can occur with methotrexate [see Adverse Reactions ( 6.1 )] . If signs or symptoms of anaphylaxis or any other serious hypersensitivity reaction occurs, immediately discontinue Methotrexate Injection and institute appropriate therapy [see Contraindications ( 4 )] .

5.3Risks of Serious Adverse Reactions due to Benzyl Alcohol-Preservative Formulations with benzyl alcohol can cause severe central nervous toxicity or metabolic acidosis, if used in neonates or low birth weight infants, intrathecally, or in high-dose regimens. Use only preservative-free Methotrexate Injection for treatment of neonates or low birth weight infants and for intrathecal use. Do not use benzyl alcohol-containing formulations for high-dose regimens unless immediate treatment is required, and preservative-free formulations are not available.

The preservative benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when Methotrexate Injection is needed during pregnancy to treat a neoplastic disease [see Use in Specific Populations ( 8.1 )] . Serious and Fatal Adverse Reactions Including Gasping Syndrome in Neonates and Low-Birth Weight Infants Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with drugs containing benzyl alcohol, including Methotrexate Injection with preservative.

The “gasping syndrome” is characterized by central nervous system (CNS) depression, metabolic acidosis, and gasping respirations. When prescribing in infants (non-neonate, non-low birth weight), if a preservative-free formulation of Methotrexate Injection is not available and use of a benzyl alcohol-containing formulation is necessary, consider the combined daily metabolic load of benzyl alcohol from all sources including Methotrexate Injection (Methotrexate Injection contains 9.4 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol.

The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations ( 8.4 )] . Neurotoxicity Due to Intrathecal Administration Serious neurotoxicity can occur following the intrathecal administration of Methotrexate Injection containing the preservative benzyl alcohol. Metabolic Acidosis with High-Dose Therapy Severe metabolic acidosis can occur with Methotrexate Injection that contains the preservative benzyl alcohol.

5.4 Myelosuppression Methotrexate suppresses hematopoiesis and can c…

🤒 Adverse Reactions ~3 min read ▾

6 ADVERSE REACTIONS The following adverse reactions are described, or described in greater detail, in other sections: Hypersensitivity Reactions [see Warnings and Precautions ( 5.2 )] Myelosuppression [see Warnings and Precautions ( 5.4 )] Serious Infections [see Warnings and Precautions ( 5.5 )] Renal Toxicity [see Warnings and Precautions ( 5.6 )] Hepatotoxicity [see Warnings and Precautions ( 5.7 )] Neurotoxicity [see Warnings and Precautions ( 5.8 )] Gastrointestinal Toxicity [see Warnings and Precautions ( 5.9 )] Pulmonary Toxicity [see Warnings and Precautions ( 5.10 )] Dermatologic Reactions [see Warnings and Precautions ( 5.11 )] Secondary Malignancies [see Warnings and Precautions ( 5.13 )] Tumor Lysis Syndrome [see Warnings and Precautions ( 5.14 )] Increased Risk of Adverse Reactions due to Third Space Accumulation [see Warnings and Precautions ( 5.17 )] Common adverse reactions include ulcerative stomatitis, leukopenia, nausea and abdominal distress.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience Because clinical trials and other studies 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. Commonly reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are infection, malaise, fatigue, chills, fever, and dizziness.

Rheumatoid Arthritis The approximate incidences of methotrexate-attributed (i.e., placebo rate subtracted) adverse reactions in 12- to 18-week double-blind studies in patients (n=128) with RA treated with low-dose oral (7.5 mg per week to 15 mg per week) pulse methotrexate are listed below. Most patients were on concomitant NSAIDs and some received corticosteroids. Hepatic histology was not examined in these short-term studies.

Incidence ≥10%: Elevated liver function tests 15%, nausea/vomiting 10%. Incidence 3% to <10%: Stomatitis, thrombocytopenia (platelet count less than 100,000/mm 3 ). Incidence 1% to <3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (white blood cell count less than 3000/mm 3 ), pancytopenia, dizziness.

Two other controlled trials of patients (n=680) with RA on 7.5 mg per week to 15 mg per week oral doses showed the following adverse reactions: Incidence 1%: Interstitial pneumonitis. Other less common adverse reactions: Decreased hematocrit, headache, upper respiratory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort, epistaxis, fever, infection, sweating, tinnitus, vaginal discharge. Polyarticular Juvenile Idiopathic Arthritis (pJIA) The approximate incidences of adverse reactions reported in patients 2 to 18 years of age with pJIA treated with oral, weekly doses of methotrexate (5 mg/m 2 per week to 20 mg/m 2 per week or 0.1 mg/kg per week to 0.65 mg/kg per week) were as follows (most patients were receiving concomitant NSAIDs, and some received corticosteroids): elevated liver function tests, 14%; gastrointestinal reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; rash, 0.2%.

Psoriasis In two published series of adult psoriasis patients (n=204, 248) treated with methotrexate doses up to 25 mg per week for up to 4 years, adverse reaction rates were similar to those in patients with RA, except for alopecia, photosensitivity, and “burning of skin lesions” (each 3% to 10%). Painful plaque erosions have been reported.

6.2Postmarketing Experience The following adverse reactions have been identified during post-approval use of methotrexate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably es…

🔄 Drug Interactions ~2 min read ▾

7 DRUG INTERACTIONS Refer to full prescribing information for drug interactions with Methotrexate Injection. ( 7 )

7.1Effects of Other Drugs on Methotrexate Drugs that Increase Methotrexate Exposure Coadministration of methotrexate with the following products may increase methotrexate plasma concentrations, which may increase the risk of methotrexate severe adverse reactions. Increased organ specific adverse reactions may also occur when methotrexate is coadministered with hepatotoxic or nephrotoxic products. If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions when coadministered with: Penicillin or sulfonamide antibiotics Highly protein-bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines) Proton pump inhibitors Probenecid Antifolate drugs (e.g., dapsone, pemetrexed, pyrimethamine and sulfonamides) Aspirin and other nonsteroidal anti-inflammatory drugs Unexpectedly severe and fatal gastrointestinal toxicity can occur with concomitant administration of methotrexate (primarily at high dose) and nonsteroidal anti-inflammatory drugs (NSAIDs) Mercaptopurine Hepatotoxic products Weak acids (e.g., salicylates) Nephrotoxic products Hematotoxic agents Nitrous Oxide Coadministration of methotrexate with nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, which may increase the risk of severe methotrexate adverse reactions.

Avoid nitrous oxide anesthesia in patients receiving methotrexate. Consider alternative therapies in patients who have received prior nitrous oxide anesthesia. Folic Acid Coadministration of methotrexate with folic acid or its derivatives decreases the clinical effectiveness of methotrexate in patients with neoplastic diseases.

Methotrexate competes with reduced folates for active transport across cell membranes. Instruct patients to take folic or folinic acid only as directed by their healthcare provider [see Warnings and Precautions ( 5.12 )] .

7.2Effects of Methotrexate on Other Drugs Theophylline Coadministration of methotrexate with theophylline increases theophylline plasma concentrations which may increase the risk of theophylline adverse reactions. Monitor theophylline levels and adjust the theophylline dosage in accordance with approved product labeling.

👥 Use in Specific Populations ~3 min read ▾

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed ( 8.2 ) Pediatric use: Intermediate-dose methotrexate can cause serious neurotoxicity in patients with acute lymphoblastic leukemia. ( 8.4 )

8.1Pregnancy Risk Summary Methotrexate Injection is contraindicated in pregnant women with non-neoplastic diseases. Based on published reports and its mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology ( 12.1 )] . There are no animal data that meet current standards for nonclinical developmental toxicity studies.

Advise pregnant women with neoplastic diseases of the potential risk to a fetus. The preservative benzyl alcohol can cross the placenta; when possible, use the preservative-free formulation when Methotrexate Injection is needed during pregnancy to treat a neoplastic disease [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.4 )] . 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.

Data Human Data Published data from case reports, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, CNS abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment.

Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure. A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg per week after conception.

The rate of spontaneous abortion/miscarriage in pregnant women exposed to methotrexate was 42.5% (95% confidence interval [95% CI] 29.2 to 58.7), which was higher than in unexposed patients with autoimmune disease (22.5%, 95% CI 16.8 to 29.7) and unexposed patients with non-autoimmune disease (17.3%, 95% CI 13 to 22.8). Of the live births, the rate of major birth defects in pregnant women exposed to methotrexate after conception was higher than in unexposed patients with autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI 0.6 to 5.7]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI 1.03 to 9.5]) (2.9%).

Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.

8.2Lactation Risk Summary Limited published literature reports the presence of methotrexate in human milk in low amounts, with the highest breast milk to plasma concentration ration reported to be 0.08:1. No information is available on the effects of methotrexate on a breastfed infant or on milk production. Because of the potential for serious adverse reactions from methotrexate in breastfed infants, advise women not to breastfeed during treatment with Methotrexate Injection and for 1 week after the last dose.

8.3Females and Males of Reproductive Potential Methotrexate can cause malformations and fetal death at doses less than or equal to the recommended clinical doses [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating Methotrexate Injection [see Contraindications ( 4 ) and Use in Specific Populations ( 8.1 )] . Contraception Females Advise females of reproductive potential to use…

🤰 Pregnancy ~2 min read ▾

Major birth defects associated with pregnancies exposed to methotrexate after conception were not always consistent with methotrexate-associated adverse developmental outcomes.

🧒 Pediatric Use ~2 min read ▾

8.4Pediatric Use The safety and effectiveness of Methotrexate Injection in pediatric patients have been established for ALL, meningeal leukemia prophylaxis and treatment, non-Hodgkin lymphoma, osteosarcoma and in pJIA. Clinical studies evaluating the use of methotrexate in pediatric patients with pJIA demonstrated safety comparable to that observed in adults with RA [see Adverse Reactions ( 6.1 )] . The safety and effectiveness of Methotrexate Injection have not been established in pediatric patients for the treatment of breast cancer, squamous cell carcinoma of the head and neck, gestational trophoblastic neoplasia, rheumatoid arthritis, and psoriasis.

Additional risk information is described below. Risks of Serious Adverse Reactions due to Benzyl Alcohol-Preservative Due to the risk of serious adverse reactions and fatal gasping syndrome following administration of intravenous solutions containing the preservative benzyl alcohol in neonates, use only preservative-free Methotrexate Injection in neonates and low-birth weight infants. The “gasping syndrome” is characterized by CNS depression, metabolic acidosis, and gasping respirations.

Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions include gradual neurological deterioration, seizures, intracranial hemorrhage, hematological abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.

Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. When prescribing in infants (non-neonate, non-low-birth weight), if a preservative-free formulation of Methotrexate Injection is not available and use of a benzyl alcohol-containing formulation is necessary, consider the combined daily metabolic load of benzyl alcohol from all sources including Methotrexate Injection (Methotrexate Injection contains 9.4 mg of benzyl alcohol/per mL) and other drugs containing benzyl alcohol.

The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. Do not administer methotrexate formulations containing benzyl alcohol intrathecally due to the risk of severe neurotoxicity [see Warnings and Precautions ( 5.3 )] . Leukemia/Lymphoma .

Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose intravenous methotrexate (1 g/m 2 ) [see Warnings and Precautions ( 5.8 )] .

🧓 Geriatric Use 27 words ▾

8.5Geriatric Use Clinical studies of methotrexate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

🆘 Overdosage ~1 min read ▾

10 OVERDOSAGE Manifestations . Overdosage, including fatal overdosage, has occurred with methotrexate [see Warnings and Precautions ( 5.19 )] . Manifestations of overdosage include adverse reactions reported at pharmacologic doses, particularly hematologic and gastrointestinal reactions (e.g., leukopenia, thrombocytopenia, anemia, pancytopenia, myelosuppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, or gastrointestinal bleeding).

In some cases, no symptoms were reported; however, sepsis or septic shock, renal failure, and aplastic anemia were also reported. Manifestations of intrathecal overdosage include CNS symptoms (e.g., headache, nausea and vomiting, seizure or convulsion, and acute toxic encephalopathy). In some cases, no symptoms were reported; however, cerebellar herniation associated with increased intracranial pressure and acute toxic encephalopathy have also been reported.

Management . Leucovorin and levoleucovorin are indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Administer leucovorin or levoleucovorin as soon as possible after overdosage (refer to the leucovorin or levoleucovorin prescribing information).

Monitor serum methotrexate concentrations closely to guide leucovorin or levoleucovorin therapy. Monitor serum creatinine concentrations closely because high serum methotrexate concentrations may cause renal damage leading to acute renal failure. Glucarpidase is indicated for the treatment of toxic methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function (refer to the glucarpidase prescribing information).

If glucarpidase is used, do not administer leucovorin within 2 hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase. Hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination.

However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer.

🧬 Clinical Pharmacology ~2 min read ▾

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication.

Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. The mechanism of action in rheumatoid arthritis, pJIA, and in psoriasis is unknown.

12.3Pharmacokinetics Distribution After intravenous administration, the initial volume of distribution is approximately

0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately

0.4 L/to

0.8L/kg (40% to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved.

Methotrexate in serum is approximately 50% protein bound. Methotrexate may be displaced from plasma albumin by various compounds, including sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given intravenously, intramuscularly, or subcutaneously.

Elimination The terminal half-life reported for methotrexate is approximately 3 to 10 hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low-dose antineoplastic therapy (less than 30 mg/m 2 ). Following intravenous administration of high-dose methotrexate, the terminal half-life is 8 hours to 15 hours. Metabolism Methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms that can be converted back to methotrexate by hydrolase enzymes.

These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues, and tumors.

Methotrexate undergoes minor metabolism to 7-hydroxymethotrexate, and accumulation may become significant following high dosages. The aqueous solubility of 7-hydroxymethotrexate is 3- to 5-fold lower than the solubility of methotrexate. Excretion Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration.

With intravenous administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed.

Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 mg and 30 mg. Specific Populations Pediatric Patients In pediatric patients receiving methotrexate for acute lymphoblastic leukemia (6.3 mg/m 2 30 mg/m 2 ), or for JIA (3.75 mg/m 2 26.2 mg/m 2 ), the terminal half-life has been reported to range from 0.7 to 5.8 hours or from 0.9 to 2.3 hours, respectively [see Use in Specific Populations ( 8.4 )].

Patients with Renal impairment The elimination half-life of methotrexate increases with the severity of renal impairment, with high inter-individual variability [see Use in Specific Populations ( 8.6 )].

🧬 Mechanism of Action 90 words ▾

📦 How Supplied / Storage and Handling 101 words ▾

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Methotrexate Injection, USP is a clear, yellow, sterile solution available as preservative-free (single-dose vials) as follows. Strength/Fill volume NDC number Pack style 50 mg/ 2 mL (25 mg/mL) 16729-277-30 Carton containing one (1) single-dose vial 250 mg/ 10 mL (25 mg/mL) 16729-277-03 Carton containing one (1) single-dose vial 1 g/40 mL (25 mg/mL) 16729-277-35 Carton containing one (1) single-dose vial Storage and Handling Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].

Protect from light. Methotrexate Injection, USP is a hazardous drug. Follow applicable special handling and disposal procedures.

📋 Description 108 words ▾

11 DESCRIPTION Methotrexate is a folate analog metabolic inhibitor with the chemical name of N-[4-[[(2,4-diamino-6-pteridinyl) methyl]methylamino]benzoyl]-L-glutamic acid and a molecular weight of 454.44. The molecular formula is C 20 H 22 N 8 O 5 , and the structural formula is shown below: Preservative-free Methotrexate Injection, USP is supplied in sterile single-dose vials for intravenous, intramuscular, subcutaneous, or intrathecal use. Each 25 mg/mL, 2 mL, 10 mL and 40 mL vial contains methotrexate sodium equivalent to 50 mg, 250 mg and 1000 mg methotrexate , and the following inactive ingredients: Sodium chloride 0.490 %w/v.

May contain sodium hydroxide and/or hydrochloric acid to adjust pH to 8.5. Structural Formula

💬 Information for Patients ~3 min read ▾

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Embryo-Fetal Toxicity Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and Use in Specific Populations ( 8.1 )]. Advise females of reproductive potential to use effective contraception during Methotrexate Injection therapy and for 6 months after the last dose [see Use in Specific Populations ( 8.3 )].

Advise males of reproductive potential to use effective contraception during Methotrexate Injection therapy and for 3 months after the last dose [see Use in Specific Populations ( 8.3 )]. Hypersensitivity Reactions Advise patients of the potential risk of hypersensitivity and that Methotrexate Injection is contraindicated in patients with a history of severe hypersensitivity to methotrexate. Advise patients to seek immediate medical attention if signs or symptoms of a hypersensitivity reaction occur [see Warnings and Precautions ( 5.2 )].

Myelosuppression and Serious Infections Advise patient to contact their healthcare provider immediately for new onset fever, symptoms of infection, easy bruising or persistent bleeding [see Warnings and Precautions ( 5.4 , 5.5 )]. Renal Toxicity Advise patients that methotrexate can cause renal toxicity. Advise patients to immediately contact their healthcare provider for signs or symptoms of renal toxicity, such as marked increases or decreases in urinary output [see Warnings and Precautions ( 5.6 )].

Hepatotoxicity Advise patients to report signs or symptoms of hepatic toxicity and avoidance of alcohol during methotrexate treatment [see Warnings and Precautions ( 5.7 )]. Neurotoxicity Advise patient to contact their healthcare provider immediately if they develop new neurological symptoms [see Warnings and Precautions ( 5.8 )]. Gastrointestinal Toxicity Advise patients to contact their healthcare provider if they develop diarrhea, vomiting, or stomatitis.

Advise patients to immediately contact their healthcare provider for high fever, rigors, persistent or severe abdominal pain, severe constipation, hematemesis, or melena [see Warnings and Precautions ( 5.9 )]. Pulmonary Toxicity Advise patients to contact their healthcare provider for symptoms of cough, fever, and dyspnea [see Warnings and Precautions ( 5.10 )]. Dermatologic Toxicity Advise patients that Methotrexate Injection can cause serious skin rash and to immediately contact their healthcare provider for new or worsening skin rash.

Advise patients to avoid excessive sun exposure and to use sun protection measures [see Warnings and Precautions ( 5.11 )]. Secondary Malignancies Advise patients on the risk of second primary malignancies during treatment with Methotrexate Injection [see Warnings and Precautions ( 5.13 )]. Lactation Advise women not to breastfeed during treatment with Methotrexate Injection and for 1 week after the last dose [see Use in Specific Populations ( 8.2 )].

Infertility Advise females and males of reproductive potential that Methotrexate Injection may cause impairment of fertility [see Use in Specific Populations ( 8.3 )]. Drug Interactions Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions ( 7 )]. Instruct patients being treated for neoplastic indication to not take products containing folic acid or folinic acid unless directed to do so by their healthcare provider [see Warnings and Precautions ( 5.12 )].

Manufactured for: Accord Healthcare, Inc., 8041 Arco Corporate Drive, Suite 200, Raleigh, NC 27617, USA. Manufactured by: Intas Pharmaceuticals Limited, Ahmedabad – 380 054, INDIA 10 3471 5 6037504 Issued December 2025

Glossary — plain-language definitions of medical terms used in this label:

contraindicated: Should not be used in that situation, because the risk is considered too high.

abdominal pain: Pain, cramping, or discomfort felt anywhere in the belly area.

accumulation: A buildup of a medicine in the body when new doses are taken before earlier ones are fully removed.

adverse reaction: An unwanted or harmful effect that a medicine causes in the body.

Adverse Reactions: Unwanted or harmful effects that people experienced while taking a medicine, listed on its official label.

alopecia: Loss of hair from the scalp or body.

anaphylaxis: A sudden, severe, whole-body allergic reaction that can cause trouble breathing, swelling, and a drop in blood pressure, needing emergency care.

anemia: A low level of red blood cells or the oxygen-carrying protein inside them, which can cause tiredness, weakness, and paleness.

anorexia: Loss of appetite, or not feeling hungry (on a drug label this means reduced appetite, not the eating disorder).

aplastic anemia: A serious condition where the bone marrow stops making enough new blood cells.

autoimmune: Describes a condition in which the body's defense system mistakenly attacks its own healthy cells or tissues.

baseline: A person's starting condition, measured before treatment begins, used to see how much they change later on.

Bioavailability: The share of a dose that actually reaches the bloodstream and is able to have an effect.

Boxed Warning: The strongest safety warning the FDA can require, set inside a bold black border because the risk it describes can be very serious.

bradycardia: A slower-than-normal heart rate, usually under 60 beats per minute.

clearance: How quickly the body removes a medicine from the blood, usually through the liver and kidneys.

Clinical Pharmacology: The label section explaining how a medicine works in the body and how the body processes it.

Clinical Studies: The label section summarizing the research trials used to show that a medicine works and is acceptably safe.

CNS depression: A slowing of brain and nervous-system activity that can cause drowsiness, slowed breathing, or reduced alertness.

confidence interval: A range of numbers that likely contains the true result, showing how sure researchers can be about a study's finding.

constipation: Having bowel movements less often than usual, or passing stools that are hard, dry, and difficult to move.

contraception: Methods used to prevent pregnancy, such as birth control pills, condoms, or an intrauterine device.

Contraindications: A list of situations or health conditions in which a medicine should not be used because the chance of harm is too high.

convulsion: Uncontrolled, rapid shaking of the body caused by muscles rapidly tightening and relaxing, often during a seizure.

depression: A lasting low mood with loss of interest that affects everyday life.

dermatitis: Inflammation of the skin, causing redness, itching, and sometimes swelling or blisters.

diarrhea: Loose, watery bowel movements that happen more often than normal.

Distribution: How a medicine spreads from the blood into the body's tissues and organs after it is absorbed.

Dosage and Administration: The label section explaining how much of a medicine to use and how to take or give it.

double-blind: A study in which neither the patients nor their doctors know who is getting the real medicine and who is getting the dummy.

Drug Interactions: The label section listing other medicines, foods, or substances that can change how a medicine works or raise the chance of side effects.

dyspnea: The medical word for shortness of breath, or the feeling that you cannot get enough air.

dysuria: Pain, burning, or discomfort when passing urine.

Elimination: The overall removal of a medicine from the body by breaking it down and passing it out.

embryo-fetal toxicity: Harm to a developing baby in the womb, such as birth defects, slowed growth, or loss of the pregnancy.

encephalopathy: Any condition that affects how the brain works, causing confusion, memory problems, or changes in alertness.

enterohepatic recirculation: A cycle where a medicine passes into the gut with bile, then is reabsorbed back into the blood.

epistaxis: A nosebleed.

estimated background risk: The normal chance that any pregnancy will have a birth defect or problem, even without taking any medicine.

Excretion: How the body removes a medicine or its leftover pieces, mainly through the urine or stool.

fertility: The natural ability to become pregnant or to father a child.

Full Prescribing Information: The complete, detailed label for a prescription medicine that follows the summary highlights.

gastrointestinal bleeding: Bleeding anywhere along the digestive tract, from the food pipe down to the bowel.

Half-life: The time it takes for the amount of medicine in the blood to drop by half.

hematemesis: Vomiting blood, which may look bright red or like dark coffee grounds.

hematocrit: A blood test showing what share of your blood is made up of red blood cells.

hemodialysis: A treatment that uses a machine to filter waste and extra fluid from the blood when the kidneys cannot.

hemorrhage: Bleeding, especially heavy or uncontrolled bleeding, either inside the body or from an outside wound.

hepatotoxicity: Damage to the liver caused by a medicine or other substance.

How Supplied/Storage and Handling: The label section describing the forms and strengths a medicine comes in and how to store it properly.

hypersensitivity: An overreaction of the body's defense system to a substance, causing symptoms such as rash, swelling, or trouble breathing.

hypotension: Blood pressure that is lower than normal, which can cause dizziness or fainting.

incidence: How often a new event, such as a side effect, happens in a group of people over a set period of time.

Indications and Usage: The label section stating which medical conditions the FDA has officially approved the medicine to treat, prevent, or manage.

inhibitor: A substance that blocks an enzyme or transporter, which can raise the levels of drugs it normally handles.

intramuscular: An injection given deep into a muscle; often written as IM.

intrathecal: Injected into the fluid that surrounds the spinal cord.

intrauterine growth restriction: When a baby grows more slowly than expected in the womb and is smaller than normal at birth.

intravenous: Given directly into a vein through a needle or thin tube; often written as IV.

lactation: The making and release of milk from a mother's breasts after giving birth.

leukopenia: A low level of white blood cells, the cells that help the body fight off infections.

liver function tests: Blood tests that check how well the liver is working and whether it is irritated or damaged.

malaise: A general feeling of being unwell, uneasy, or low on energy, without one clear symptom.

Mechanism of Action: How a medicine produces its effect in the body, described at the level of cells or body chemistry.

melena: Black, sticky, tar-like stools caused by blood that has been digested higher up in the gut.

metabolic acidosis: A condition where too much acid builds up in the body's blood and fluids.

Metabolism: How the body chemically changes a medicine, usually in the liver, into other substances.

mucositis: Painful swelling and sores in the moist lining of the mouth, throat, or digestive tract.

myelosuppression: A slowing of the bone marrow's job of making blood cells, which can lower red cells, white cells, or platelets.

NDC: A unique number that identifies a specific medicine, its maker, strength, and package size.

neonatal: Relating to a newborn baby during its first four weeks of life.

Overdosage: The label section describing what can happen if too much of a medicine is taken and how it may be treated.

pancytopenia: A low level of all three main blood cell types at once: red cells, white cells, and platelets.

Patient Counseling Information: The label section telling health professionals what to explain to patients about using a medicine safely.

Pharmacokinetics: The study of how the body takes in a medicine, spreads it around, breaks it down, and removes it over time.

photosensitivity: An unusually strong skin reaction, such as burning or rash, after being in sunlight or other ultraviolet light.

placebo: An inactive treatment with no real medicine in it, such as a sugar pill, used for comparison in a study.

plasma concentration: The amount of medicine measured in the liquid part of the blood at a given time.

pneumonitis: Inflammation of the lung tissue that is not caused by an infection and can lead to cough and breathlessness.

Prescribing Information: The official, detailed document approved by the FDA that tells health professionals how to use a prescription medicine.

prophylaxis: Treatment given to prevent an infection or illness before it starts, rather than to treat one that is already present.

pruritus: Itching of the skin.

renal excretion: Removal of a medicine from the body through the kidneys into the urine.

renal impairment: Reduced kidney function, meaning the kidneys do not filter waste and fluid from the blood as well as normal.

reproductive potential: The ability to have children, meaning a person who could become pregnant or could father a child.

seizure: A sudden burst of abnormal electrical activity in the brain that can cause shaking, staring, confusion, or loss of awareness.

sepsis: A serious, body-wide reaction to an infection in which the body's own response can start to injure its tissues and organs.

serum creatinine: A waste product measured in a blood test; higher levels can mean the kidneys are not filtering as well as normal.

single-dose vial: A small container holding one dose of medicine, meant to be used once and then thrown away.

spontaneous abortion: The natural loss of a pregnancy in its early stages, also called a miscarriage.

stomatitis: Soreness, swelling, or sores on the lining inside the mouth.

subcutaneous: An injection placed into the fatty layer just under the skin; often written as subcut or SC.

substrate: A drug or other substance that a particular enzyme or transporter acts on.

terminal half-life: The time it takes blood levels to fall by half during the final, slowest stage of removal.

thrombocytopenia: A low level of platelets, the blood cells that help form clots, which can lead to easier bruising or bleeding.

tinnitus: Ringing, buzzing, or other noise in the ears that is not coming from an outside sound.

trimester: One of the three roughly three-month stages that a pregnancy is divided into.

tumor lysis syndrome: A serious condition where many cancer cells break apart quickly, releasing their contents and upsetting the body's balance of salts and waste products.

ulceration: The forming of an open sore on the skin or on a lining inside the body, such as the stomach.

Use in Specific Populations: The label section describing how a medicine affects particular groups, such as pregnant people, children, or older adults.

volume of distribution: A calculated value showing how widely a medicine spreads into body tissues versus staying in the blood.

Warnings and Precautions: The label section describing serious risks to know about and safety steps to follow while using a medicine.

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

← 16729-0276-11 · Accord 16729-0278-01 · Accord →

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.

Methotrexate 25 mg/mL Injection

🆔 Identity & classification

🏷️ RxNorm drug class

🏭 Manufacturer & labeler

🩺 Clinical

Patient education

Supplement & herbal interactions

🧪 Inactive Ingredients / Excipients

Inactive ingredient FAQ

💲 Pricing

🧾 Billing & reimbursement

🔁 Therapeutic equivalents

⏳ Availability & generic status

🗺️ Medicaid utilization & spend

💊 Medicaid utilization by pack size

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

🔬 Reported adverse events (FAERS)

Top reported reactions

Reporter sex

📦 Packaging — all sizes for this product

Pack size FAQ

📄 Full prescribing information FDA SPL

5.4 Myelosuppression Methotrexate suppresses hematopoiesis and can c…

12 CLINICAL PHARMACOLOGY

0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately

0.4 L/to

🔗 Related NDC lookups

💊 Related drugs in this class