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Methotrexate 2.5 mg Tablet, 100-count — NDC 00378-0014-01 package photo

Methotrexate 2.5 mg Tablet, 100-count

by Mylan Pharmaceuticals Inc. · 100 TABLET in 1 BOTTLE, PLASTIC (0378-0014-01)
NDC 00378-0014-01
🏷️ FDA NDC (as labeled) 0378-0014-01 billing pads the labeler segment with a zero
Rx only Generic 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) 0378-0014-01
Product NDC 0378-0014
11-digit billing NDC 00378001401
NCPDP billing unit EA — each (per item)
RxCUI 105585
UNII 3IG1E710ZN
Application # ANDA081235
SPL Set ID 70c09984-2b36-424f-8b27-3fd0cd4e833d
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 1992-05-18
Route ORAL
Dosage form TABLET
Substance METHOTREXATE SODIUM
GPI-14 21300050100310
GPI class Methotrexate
GCN Seq No 036872
GCN 38489
HICL code 003905
Ingredient (HICL) Methotrexate Sodium
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 2.5 MG TABLET
FDB brand name Methotrexate
Legend status F — Federal legend — prescription drug or device
TE code (Orange Book) AB · RLD · RS
Why two NDCs? The FDA registers this code as 0378-0014-01 — a 4-4-2 layout, and that's what's printed on the package and shown on DailyMed. For insurance claims, every NDC is standardized to a uniform 11-digit 5-4-2 format by adding a zero to the labeler segment → 00378-0014-01. Same drug, same package — only the format differs.
Where does this data come from?
Identifiers from the FDA openFDA NDC Directory and Structured Product Labeling; RxCUI from RxNorm (NLM); GPI from Medi-Span; GCN / HIC / AHFS / legend from First Databank.

🏷️ RxNorm drug class

This medicine belongs to the Folate Analog 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

LabelerMylan Pharmaceuticals Inc.
Application holderMYLAN PHARMACEUTICALS INC
FDA applicationANDA081235 (ANDA)
Labeler code00378
First marketedMay 1992
Product typeHuman Prescription Drug
Portfolio473 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 METHOTREXATE 2.5 MG TABLET Ingredient Methotrexate Sodium
📗 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 →
1
Nutrient depletion considerations

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

🧪 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.

💊 What it looks like

Color Orange
ShapeRound
ImprintM;14
Size6 mm
ScoringScored — splits in 2
One label can cover several strengths, so colors may be combined — always confirm a loose pill against the dispensed prescription label or a pharmacist.
Where does this data come from?
Physical description (imprint, shape, color, scoring, coating) from this product’s FDA Structured Product Labeling (SPL), mirrored from DailyMed / openFDA.

🧪 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 WZB9127XOA
    A synthetic red dye used to color medications and make them easier to identify. It serves as a colorant in tablets, capsules, and liquid formulations.
  • UNII EWQ57Q8I5X
    Lactose monohydrate is a natural sugar derived from milk. It serves as a filler and binder in tablets and capsules, helping create the proper size, texture, and consistency of the medicine.
  • UNII 70097M6I30
    Magnesium stearate is a salt made from magnesium and stearic acid, a fatty substance. It's used in tablets and capsules as a lubricant and glidant to help ingredients flow smoothly during manufacturing and prevent sticking.
  • UNII 7T9FYH5QMK
    A plant-derived powder that serves as a binder and filler in tablets and capsules. It helps hold ingredients together, adds bulk, and aids in smooth tablet disintegration when swallowed.
  • UNII ETJ7Z6XBU4
    Silicon dioxide is a naturally occurring mineral used as a glidant and anti-caking agent. It helps powder ingredients flow smoothly and prevents clumping during manufacturing and storage.
  • UNII 2A1Q1Q3557
    Sodium carbonate monohydrate is an inorganic salt containing sodium, carbon, and water. It acts as a pH buffer and alkalizing agent in medicines, helping maintain the proper acid-base balance needed for product stability and function.
  • UNII 368GB5141J
    A detergent and foaming agent derived from coconut or palm oil. In medications, it helps break down and mix oil and water-based ingredients, aids in tablet disintegration, and improves how the drug dissolves and spreads in the mouth or digestive system.
  • UNII 5856J3G2A2
    A starch-based powder made from potatoes and processed with sodium. It acts as a disintegrant, helping the tablet or capsule break apart quickly in the stomach so the medicine can be absorbed.
  • UNII O8232NY3SJ
    A plant-based carbohydrate derived from corn kernels. It acts as a filler to add bulk, a binder to hold ingredients together, and a disintegrant to help the tablet break apart in your stomach for absorption.

9 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 eaPer package
Retail pharmacies payNADAC · weekly $0.157 $15.66 / 100 tablets
Medicaid paysCMS SDUD · 12 mo $0.4324 $43.24 / 100 tablets
Medicare drug plans payPart D · Q2 2026 $0.4031 $40.31 / 100 tablets
Medicare Part B allowsASP · NONE No ASP payment limit on file for NONE this quarter.
NADAC price history (per ea) — tap or hover for the price & month
Dec 2021 Jul 2022 Dec 2025 Aug 2026 $0.302 $0.157
▼ Down 45% over the last 24 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)0378-0014-01
11-digit billing NDC00378-0014-01
Format4-4-2 as registered → padded to 5-4-2 for billing (zero added to the labeler segment)
HCPCS J-codeNONE
DescriptorMETHOTREXATE, 2.5 MG, ORAL
Billing units / pkg1 units
Crosswalk sourcePDAC NDC-HCPCS crosswalk (DME MAC / DMEPOS)
Where does this data come from?
The HCPCS J-code crosswalk comes from the CMS ASP NDC-HCPCS crosswalk and the DMEPDAC (DME MAC) NDC-HCPCS crosswalk — free public CMS data. Billing units are derived from the code’s descriptor and the package amount.

🔁 Therapeutic equivalents

ProductLabelerPackNADAC/unitTEStatusPrice vs. this
Methotrexate 2.5 mgthis 00378-0014-01 Mylan 100 tablets $0.157 AB Availability likely —
Methotrexate 2.5 mg 00555-0572-02 Teva 100 tablets $0.157 AB Availability likely —
Methotrexate 2.5 mg 00904-7141-10 Major 20 tablets $0.157 AB Availability likely —
Methotrexate 2.5 mg 16729-0486-01 Accord 100 tablets $0.157 AB Availability likely —
Methotrexate 2.5 mg 47335-0235-83 Sun 100 tablets $0.157 AB Availability likely —
Methotrexate 2.5 mg 51079-0670-05 Mylan 20 tablets $0.157 AB Availability likely —
Methotrexate 2.5 mg 59651-0182-01 Aurobindo 100 tablets $0.157 AB Availability likely —
Methotrexate 2.5 mg 62135-0772-35 Chartwell 36 tablets $0.157 AB Availability likely —
Methotrexate 2.5 mg 62332-0730-31 Alembic 100 tablets $0.157 AB Availability likely —
Methotrexate Sodium 2.5 mg 64850-0330-01 Elite 100 tablets $0.157 AB Availability likely —
Methotrexate 2.5 mg 68382-0775-01 Zydus 100 tablets $0.157 AB Availability likely —
Methotrexate Sodium 2.5 mg 00054-4550-15 Hikma 36 tablets $0.192 AB Discontinued +23%
Methotrexate 2.5 mg 46708-0730-31 Alembic 100 tablets — AB FDA listed —
Methotrexate 2.5 mg 48433-0065-05 Safecor 20 tablets — AB FDA listed —
Methotrexate 2.5 mg 50090-5457-02 A-S 100 tablets — AB Discontinued —
Methotrexate 2.5 mg 50268-0554-15 AvPAK 50 tablets — AB FDA listed —
Methotrexate 2.5 mg 51407-0121-01 Golden 100 tablets — AB FDA listed —
Methotrexate 2.5 mg 67046-1524-03 Coupler 30 tablets — AB FDA listed —
Methotrexate 2.5 mg 68071-3765-06 NuCare 60 tablets — AB FDA listed —
Methotrexate 2.5 mg 68071-3991-09 NuCare 90 tablets — AB FDA listed —
Methotrexate 2.5 mg 70771-1058-00 Zydus 1000 tablets — AB FDA listed —
Methotrexate 2.5 mg 71335-0782-01 Bryant 30 tablets — AB FDA listed —
Methotrexate 2.5 mg 71335-1118-01 Bryant 30 tablets — AB FDA listed —
Methotrexate 2.5 mg 71335-1772-01 Bryant 30 tablets — AB FDA listed —
Methotrexate 2.5 mg 71335-2221-01 Bryant 30 tablets — AB FDA listed —
Methotrexate 2.5 mg 72162-2174-01 Bryant 100 tablets — AB FDA listed —
Methotrexate 2.5 mg 72162-2647-01 Bryant 100 tablets — AB FDA listed —
Methotrexate 2.5 mg 82804-0136-30 Proficient 30 tablets — AB FDA listed —
Methotrexate 2.5 mg 42291-0594-01 AvKARE 100 tablets — AB 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

🏛️
1992
On the market since
May 1992
📍
2026
Currently FDA-listed
34 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 00378-0014-01, 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
4.5K
Units reimbursed last 4 qtrs
155.4K
Gross reimbursed last 4 qtrs
$67.2K
Avg / prescription
$14.90
Avg / unit
$0.4324
Latest quarter Q4 2025
1.1KRx
Medicaid pays / ea
$0.4324
gross reimbursed
vs
NADAC / ea
$0.1566
acquisition cost
=
Spread
+$0.2758
+176% vs cost
What Medicaid paid per ea (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 ⓘ
54% FFS 46% MCO
Fee-for-service · 2,436 Rx Managed care · 2,075 Rx
State Medicaid map
Alaska: no data reported AK Maine: no data reported ME Washington: 10,403 units · 133 per 100k residents WA Idaho: no data reported ID Montana: no data reported MT North Dakota: no data reported ND Minnesota: no data reported MN Wisconsin: no data reported WI Michigan: no data reported MI New York: 65,421 units · 334 per 100k residents NY Vermont: 13,755 units · 2,126 per 100k residents VT New Hampshire: no data reported NH Oregon: 1,133 units · 26.8 per 100k residents OR Nevada: no data reported NV Wyoming: no data reported WY South Dakota: no data reported SD Iowa: no data reported IA Illinois: no data reported IL Indiana: no data reported IN Ohio: no data reported OH Pennsylvania: 2,268 units · 17.5 per 100k residents PA New Jersey: 2,178 units · 23.4 per 100k residents NJ Massachusetts: 9,258 units · 132 per 100k residents MA California: 11,469 units · 29.4 per 100k residents CA Utah: no data reported UT Colorado: no data reported CO Nebraska: no data reported NE Missouri: no data reported MO Kentucky: 1,803 units · 39.8 per 100k residents KY West Virginia: no data reported WV Virginia: 7,526 units · 86.3 per 100k residents VA Maryland: 3,126 units · 50.6 per 100k residents MD Connecticut: 2,560 units · 70.8 per 100k residents CT Rhode Island: 608 units · 55.5 per 100k residents RI Arizona: no data reported AZ New Mexico: no data reported NM Kansas: no data reported KS Arkansas: no data reported AR Tennessee: 857 units · 12.0 per 100k residents TN North Carolina: 5,100 units · 47.1 per 100k residents NC South Carolina: 1,340 units · 24.9 per 100k residents SC Delaware: no data reported DE Oklahoma: no data reported OK Louisiana: 340 units · 7.4 per 100k residents LA Mississippi: no data reported MS Alabama: 420 units · 8.2 per 100k residents AL Georgia: 4,416 units · 40.0 per 100k residents GA D.C.: 1,399 units · 206 per 100k residents DC Hawaii: no data reported HI Texas: 1,019 units · 3.3 per 100k residents TX Florida: no data reported FL
Units reimbursed · per 100k residents
3.32,126
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 Vermont 2,126 /100k
2 New York 334 /100k
3 D.C. 206 /100k
4 Washington 133 /100k
5 Massachusetts 132 /100k
6 Virginia 86.3 /100k
7 Connecticut 70.8 /100k
8 Rhode Island 55.5 /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.

📊 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

489,806 reports
Male · 29%
Female · 71%
Unknown · 0%
Reports over time (by year) — tap or hover for the count & year
2019 2021 2023 2026 46,596 9,029
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
00378-0014-01 You're viewing this 100 TABLET in 1 BOTTLE, PLASTIC (0378-0014-01) 1992-05-18 Active

📄 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 ~1 min read ▾

WARNING: EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS, SEVERE ADVERSE REACTIONS, and RISK OF MEDICATION ERRORS • Methotrexate tablets can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, methotrexate tablets are contraindicated in pregnancy. For neoplastic diseases, advise females and males of reproductive potential to use effective contraception [see Contraindications (4) , Warnings and Precautions (5.1) , Use in Specific Populations (8.1 , 8.3) ] . • Methotrexate tablets are contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis [see Contraindications (4) , Warnings and Precautions (5.2) ] . • Methotrexate tablets when inadvertently administered once daily have resulted in death [see Warnings and Precautions (5.9) ] . • Serious adverse reactions, including death, have been reported with methotrexate.

Closely monitor for adverse reactions of the bone marrow, gastrointestinal tract, liver, lungs, skin, and kidneys. Withhold or discontinue methotrexate tablets as appropriate [see Warnings and Precautions (5.3 , 5.4 , 5.5 , 5.6 , 5.7 , 5.8) ] . WARNING: EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS, SEVERE ADVERSE REACTIONS, and RISK OF MEDICATION ERRORS See full prescribing information for complete boxed warning. • Methotrexate tablets can cause embryo-fetal toxicity, including fetal death.

For non-neoplastic diseases, methotrexate tablets are contraindicated in pregnancy. For neoplastic diseases, advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception ( 4 , 5.1 , 8.1 , 8.3 ). • Methotrexate tablets are contraindicated in patients with a history of severe hypersensitivity reactions to methotrexate, including anaphylaxis ( 4 , 5.2 ). • Methotrexate tablets when inadvertently administered once daily have resulted in death ( 5.9 ). • Serious adverse reactions, including death, have been reported with methotrexate.

Closely monitor for adverse reactions of the bone marrow, gastrointestinal tract, liver, lungs, skin, and kidneys. Withhold or discontinue methotrexate tablets as appropriate ( 5.3 , 5.4 , 5.5 , 5.6 , 5.7 , 5.8 ).

🎯 Indications and Usage 220 words ▾

1 INDICATIONS AND USAGE Methotrexate tablets are a dihydrofolate reductase inhibitor indicated for the: • Treatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen ( 1.1 ) • Treatment of adults with mycosis fungoides ( 1.1 ) • Treatment of adults with relapsed or refractory non-Hodgkin lymphoma as part of a metronomic combination regimen ( 1.1 ) • Treatment of adults with rheumatoid arthritis ( 1.2 ) • Treatment of pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA) ( 1.3 ) • Treatment of adults with severe psoriasis ( 1.4 )

1.1Neoplastic Diseases Methotrexate tablets are indicated for the: • treatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen. • treatment of adults with mycosis fungoides (cutaneous T-cell lymphoma) as a single agent or as part of a combination chemotherapy regimen. • treatment of adults with relapsed or refractory non-Hodgkin lymphomas as part of a metronomic combination chemotherapy regimen.

1.2Rheumatoid Arthritis Methotrexate tablets are indicated for the treatment of adults with rheumatoid arthritis.

1.3Polyarticular Juvenile Idiopathic Arthritis Methotrexate tablets are indicated for the treatment of pediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA).

1.4Psoriasis Methotrexate tablets are indicated for the treatment of adults with severe psoriasis.

⏱️ Dosage and Administration ~3 min read ▾

2 DOSAGE AND ADMINISTRATION • Instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to deaths. ( 2.1 , 5.9 ) • Verify pregnancy status in females of reproductive potential before starting methotrexate tablets ( 4 , 5.1 ). • ALL : The recommended dosage is 20 mg/m 2 orally once weekly as a part of a combination chemotherapy maintenance regimen. ( 2.2 ) • Mycosis fungoides : The recommended dosage is 25 to 75 mg orally once weekly as monotherapy; 10 mg/m 2 orally twice weekly as part of combination chemotherapy.

( 2.2 ) • Relapsed or refractory non-Hodgkin lymphoma : The recommended dosage is 2.5 mg orally two to four times per week as part of metronomic combination chemotherapy. ( 2.2 ) • Rheumatoid Arthritis : The recommended starting dosage is 7.5 mg orally once weekly; adjust dose to achieve an optimal response ( 2.3 ) • pJIA : The recommended starting dosage is 10 mg/m 2 orally once weekly; adjust dose to achieve an optimal response ( 2.4 ) • Psoriasis : The recommended dosage is 10 to 25 mg orally once weekly until adequate response is achieved.

( 2.5 )

2.1Important Dosage and Safety Information Verify pregnancy status in females of reproductive potential before starting methotrexate tablets [see Contraindications (4) , Warnings and Precautions (5.1) ] . Instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to deaths [see Warnings and Precautions (5.9) ] . When switching the dosing regimen from oral administration to intravenous, intramuscular, or subcutaneous administration, an alternative dosing regimen may be necessary.

Do not administer to patients who are unable to swallow a tablet. Methotrexate tablets are a cytotoxic drug. Follow applicable special handling and disposal procedures.

1

2.2Recommended Dosage for Neoplastic Diseases Acute Lymphoblastic Leukemia The recommended starting dosage of methotrexate tablets is 20 mg/m 2 orally once weekly, as part of a combination chemotherapy maintenance regimen. After initiating methotrexate tablets, periodically monitor absolute neutrophil count (ANC) and platelet count and adjust the dose to maintain ANC at a desirable level and for excessive myelosuppression. Mycosis Fungoides The recommended dosage of methotrexate tablets is 25 to 75 mg orally once weekly when administered as a single agent or 10 mg/m 2 orally twice weekly as part of a combination chemotherapy regimen.

Relapsed or Refractory Non-Hodgkin Lymphomas The recommended dosage of methotrexate tablets is 2.5 mg orally 2 to 4 times per week (maximum 10 mg per week) as part of a metronomic combination chemotherapy regimen.

2.3Recommended Dosage for Rheumatoid Arthritis The recommended starting dosage of methotrexate tablets is 7.5 mg orally once weekly with escalation to achieve optimal response. Dosages of more than 20 mg once weekly result in an increased risk of serious adverse reactions, including myelosuppression. When responses are observed, the majority occurred between 3 and 6 weeks from initiation of treatment; however, responses have occurred up to 12 weeks after treatment initiation.

Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.10) ].

2.4Recommended Dosage for Polyarticular Juvenile Idiopathic Arthritis The recommended starting dosage of methotrexate tablets is 10 mg/m 2 orally once weekly with escalation to achieve optimal response. Dosages of more than 30 mg/m 2 once weekly result in an increased risk of serious adverse reactions, including myelosuppression. When responses are observed, the majority occurred between 3 and 6 weeks from initiation of treatment; however, responses have occurred up to 12 weeks after treatment initiation.

Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions [see Warnings and Precautions (5.10) ].

2.5 Recommended Dosage for Psoriasis The recom…

💊 Dosage Forms and Strengths 63 words ▾

3 DOSAGE FORMS AND STRENGTHS Methotrexate Tablets, USP are available containing 2.5 mg methotrexate, USP equivalent to 2.74 mg methotrexate sodium. • The 2.5 mg tablets are orange, round, scored tablets debossed with M above the score and 14 below the score on one side of the tablet and blank on the other side of the tablet. Tablets: 2.5 mg ( 3 )

⛔ Contraindications 74 words ▾

4 CONTRAINDICATIONS Methotrexate tablets are contraindicated in: • Pregnant women receiving methotrexate tablets for treatment of non-neoplastic diseases [see Warnings and Precautions (5.1) , and Use in Specific Populations (8.1 , 8.3) ] . • Patients with a history of a severe hypersensitivity reactions, including anaphylaxis, to methotrexate [see Warnings and Precautions (5.2) ] . • In pregnancy for non-neoplastic diseases ( 4 ) • History of severe hypersensitivity to methotrexate ( 4 )

⚠️ Warnings and Cautions ~3 min read ▾

5 WARNINGS AND PRECAUTIONS • Serious Infections : Monitor patients for infection during and after treatment with methotrexate tablets. Withhold or discontinue methotrexate tablets for serious infections as appropriate. ( 5.11 ) • Neurotoxicity : Monitor patients for neurotoxicity and withhold or discontinue methotrexate tablets as appropriate.

( 5.12 ) • Secondary Malignancies : Can occur with methotrexate. ( 5.13 ) • Tumor Lysis Syndrome : Institute appropriate prophylactic measures in patients at risk for tumor lysis syndrome prior to initiation of methotrexate tablets. ( 5.14 ) • Immunizations and Risk Live Vaccines : Immunizations with live vaccines is not recommended.

Follow current vaccination practice guidelines. ( 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 tablets can cause fetal harm, including fetal death, when administered to a pregnant woman. Methotrexate tablets are contraindicated for use in pregnant women receiving methotrexate tablets for the treatment of non-malignant diseases. Advise pregnant women with neoplastic diseases of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment with methotrexate tablets and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during methotrexate tablets treatment and for 3 months after the final dose [see Contraindications (4) , Use in Specific Populations (8.1 , 8.3) ].

5.2Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, can occur with methotrexate [see Contraindications (4) , Adverse Reactions (6.1) ] . If anaphylaxis or other serious hypersensitivity reaction occurs, immediately and permanently discontinue methotrexate tablets [see Dosage and Administration (2.6) ].

5.3Myelosuppression Methotrexate suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia [see Adverse Reactions (6.1) ] . Obtain blood counts at baseline, periodically during treatment, and as clinically indicated. Monitor patients for clinical complications of myelosuppression.

Withhold, dose reduce, or discontinue methotrexate tablets taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy [see Dosage and Administration (2.6) ].

5.4Gastrointestinal Toxicity Diarrhea, vomiting, nausea, and stomatitis occurred in up to 10% of patients receiving methotrexate for treatment of non-neoplastic diseases. Hemorrhagic enteritis and fatal intestinal perforation have been reported [see Adverse Reactions (6.1 , 6.2) ] . Patients with peptic ulcer disease or ulcerative colitis are at a greater risk of developing severe gastrointestinal adverse reactions [see Drug Interactions (7.1) ] .

Withhold or discontinue methotrexate tablets for severe gastrointestinal toxicity taking into account the importance of methotrexate tablet treatment in the context of the severity of the disease being treated, the severity of the adverse drug reaction, and availability of alternative therapy [see Dosage and Administration (2.6) ].

5.5Hepatotoxicity Methotrexate can cause severe and potentially irreversible hepatotoxicity, including fibrosis, cirrhosis, and fatal liver failure [see Adverse Reactions (6.1) ]. The safety of methotrexate tablets in patients with hepatic disease is unknown. The risk of hepatotoxicity is increased with heavy alcohol consumption.

In patients with psoriasis, fibrosis or cirrhosis may occur in the absence of symptoms or abnormal liver tests; the risk of hepatotoxicity appears to increase with total cumulative dose and generally occurs after receipt of a…

🤒 Adverse Reactions ~3 min read ▾

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hypersensitivity Reactions [see Warnings and Precautions (5.2) ] • Myelosuppression [see Warnings and Precautions (5.3) ] • Gastrointestinal Toxicity [see Warnings and Precautions (5.4) ] • Hepatotoxicity [see Warnings and Precautions (5.5) ] • Pulmonary Toxicity [see Warnings and Precautions (5.6) ] • Dermatologic Reactions [see Warnings and Precautions (5.7) ] • Renal Toxicity [see Warnings and Precautions (5.8) ] • Serious Infections [see Warnings and Precautions (5.11) ] • Neurotoxicity [see Warnings and Precautions (5.12) ] • 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, abdominal distress.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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. Common adverse reactions were: ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other clinically relevant adverse reactions were infection, malaise, fatigue, chills, fever, and dizziness.

Rheumatoid Arthritis The most common adverse reactions of methotrexate that exceeded the rate of placebo in 12- to 18-week double-blind studies in patients (n = 128) with rheumatoid arthritis are listed below. Patients received methotrexate 7.5 to 15 mg orally once weekly. Most patients received concomitant nonsteroidal anti-inflammatory drugs (NSAIDs) and some also received corticosteroids.

Hepatic histology was not examined in these short-term studies. Incidence ≥ 10%: Elevated liver tests 15%, nausea/vomiting 10% Incidence 3% to < 10%: Stomatitis, thrombocytopenia (platelet count < 100,000/mm 3 ) Incidence 1% to < 3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (white blood cell count < 3000/mm 3 ), pancytopenia, dizziness Two other controlled trials of patients (n = 680) with rheumatoid arthritis who received methotrexate 7.5 mg to 15 mg orally once weekly showed the following serious adverse reaction: Incidence 1%: Interstitial pneumonitis Other less common adverse reactions were: anemia, 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 most common adverse reactions reported in patients 2 to 18 years of age with pJIA treated with methotrexate 5 mg/m 2 to 20 mg/m 2 orally once weekly or 0.1 to 0.65 mg/kg orally once weekly were as follows: elevated liver 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%. Most patients received concomitant NSAIDs and some also received corticosteroids.

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

6.2Postmarketing Experience The following adverse reactions have been identified during postapproval use of methotrexate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency o…

🔄 Drug Interactions ~1 min read ▾

7 DRUG INTERACTIONS Refer to the full prescribing information for drug interactions with methotrexate. ( 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. In some cases, the coadministration of methotrexate with these products may also subsequently reduce active metabolite formation, which may decrease the clinical effectiveness of methotrexate. 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: • Oral antibiotics (including neomycin) • Oral or intravenous penicillin or sulfonamide antibiotics • Highly protein-bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines) • Probencid • Antifolate drugs (e.g., dapsone, pemetrexed, pyrimethamine and sulfonamides) • Aspirin and other nonsteroidal anti-inflammatory drugs • Hepatotoxic products • Proton pump inhibitors • Weak acids (e.g., salicylates) • Nephrotoxic products 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 (5.10) ].

👥 Use in Specific Populations ~3 min read ▾

8 USE IN SPECIFIC POPULATIONS Lactation : Instruct not to breastfeed. ( 8.2 )

8.1Pregnancy Risk Summary Methotrexate tablets are contraindicated in pregnant women with non-neoplastic diseases [see Contraindications (4) ]. Based on published reports and its mechanism of action [see Clinical Pharmacology (12.1) ], methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. 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. 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, central nervous system 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/week after conception. The rate of spontaneous abortion and miscarriage in pregnant women exposed to methotrexate was 42% (95% confidence interval [95% CI] 29, 59), which was higher than in unexposed patients with autoimmune disease (22%; 95% CI: 17, 30) and unexposed patients with nonautoimmune disease (17%; 95% CI: 13, 23). 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, 6]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI: 1, 10]) (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 report the presence of methotrexate in human milk in low amounts, with the highest breast milk to plasma concentration ratio reported to be 0.08:1. There are no data on the effects of methotrexate or its metabolites on the breastfed child or their effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, instruct women not to breastfeed during treatment with methotrexate tablets and for 1 week after the final 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 tablets [see Contraindications (4) , Use in Specific Populations (8.1) ]. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with methotrexate tablets and for 6 months after the final dose.

Males Methotrexate can cause chromosomal damage to sperm cells. Advise males with female partners of reproductive potential to use effective contraception during treatment with methotrexate tablets and for 3 months after the final dose. Infertility Females Based on published reports of female…

🤰 Pregnancy ~2 min read ▾

8.1Pregnancy Risk Summary Methotrexate tablets are contraindicated in pregnant women with non-neoplastic diseases [see Contraindications (4) ]. Based on published reports and its mechanism of action [see Clinical Pharmacology (12.1) ], methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. 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. 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, central nervous system 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/week after conception. The rate of spontaneous abortion and miscarriage in pregnant women exposed to methotrexate was 42% (95% confidence interval [95% CI] 29, 59), which was higher than in unexposed patients with autoimmune disease (22%; 95% CI: 17, 30) and unexposed patients with nonautoimmune disease (17%; 95% CI: 13, 23). 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, 6]) and unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI: 1, 10]) (2.9%).

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

🧒 Pediatric Use 87 words ▾

8.4Pediatric Use The safety and effectiveness of methotrexate tablets in pediatric patients have been established for the treatment of ALL as part of the combination chemotherapy maintenance regimen and the treatment of pJIA [see Indications and Usage (1) , Dosage and Administration (2) ]. No new safety signals have been observed in pediatric patients in clinical studies [see Adverse Reactions (6.1) ]. The safety and effectiveness of methotrexate tablets have not been established in pediatric patients for the other indications [see Indications and Usage (1) ].

🧓 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 189 words ▾

10 OVERDOSAGE Overdosage, including fatal overdosage, has occurred with methotrexate [see Warnings and Precautions (5.9) ]. Manifestations: Manifestations of methotrexate 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.

Management: Leucovorin and levoleucovorin are indicated for diminishing the methotrexate adverse reactions of methotrexate overdosage. Administer leucovorin or levoleucovorin as soon as possible after methotrexate overdosage). Monitor serum creatinine and methotrexate levels to guide leucovorin or levoleucovorin therapy.

Refer to the leucovorin or levoleucovorin prescribing information for additional dosage information. Glucarpidase is indicated for the treatment of toxic plasma methotrexate concentrations (> 1 micromole per liter) in patients with delayed methotrexate clearance due to impaired renal function. Refer to the glucarpidase prescribing information for additional dosage information.

Administer concomitant hydration and urinary alkalinization. Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination; however, methotrexate has been effectively cleared 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 and in psoriasis is unknown.

12.3Pharmacokinetics Absorption At doses of 30 mg/m 2 or less, the mean bioavailability is approximately 60%. Peak plasma concentrations are reached within 0.75 to 6 hours following oral administration. Methotrexate may undergo enterohepatic recirculation; however, this pathway has not been fully characterized.

Effect of Food Food has been shown to delay absorption and reduce peak concentration. Distribution Methotrexate in serum is approximately 50% protein bound. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier at concentrations achieved with the recommended dosages.

Elimination The elimination half-life of methotrexate is approximately 3 to 10 hours. 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.

Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in studies of patients with psoriasis receiving methotrexate doses between 7.5 mg and 30 mg. Metabolism Methotrexate is partially metabolized by intestinal flora after oral administration. Methotrexate primarily undergoes hepatic and intracellular metabolism to active polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes.

Methotrexate also undergoes minor metabolism to active 7-hydroxymethotrexate. Excretion Methotrexate primarily undergoes renal excretion by glomerular filtration and active tubular secretion that is dependent upon dosage and route of administration. Biliary excretion accounts for ≤ 10% of the methotrexate dose.

Specific Populations The effect of hepatic impairment on the pharmacokinetics of methotrexate is unknown. Pediatric Patients In pediatric patients with leukemia, oral absorption (23% to 95%) of methotrexate is variable and dose-dependent. The difference between highest and lowest peak methotrexate concentrations (C max 0.11 to 2.3 micromolar after a 20 mg/m 2 dose) was 20-fold.

The time to peak concentration (T max 0.67 to 4 hours after a 15 mg/m 2 dose) and fraction of dose absorbed is variable. The absorption of doses greater than 40 mg/m 2 is significantly less than that of lower doses. In pediatric patients with pJIA, plasma concentrations of methotrexate are variable.

Following oral administration of methotrexate 6.4 mg/m 2 /week to 11.2 mg/m 2 /week, mean serum concentrations were 0.59 micromolar (0.03 to 1.40) at 1 hour, 0.44 micromolar (0.01 to 1.00) at 2 hours, and 0.29 micromolar (0.06 to 0.58) at 3 hours. In pediatric patients receiving methotrexate for acute lymphoblastic leukemia (6.3 mg/m 2 to 30 mg/m 2 ) or for JIA (3.75 mg/m 2 to 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. Patients with Renal impairment The elimination half-life of methotrexate is variable and increases with the severity of renal impairment.

🧬 Mechanism of Action 89 words ▾

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 and in psoriasis is unknown.

📦 How Supplied / Storage and Handling 121 words ▾

16 HOW SUPPLIED/STORAGE AND HANDLING Methotrexate Tablets, USP are available containing 2.5 mg methotrexate, USP equivalent to 2.74 mg methotrexate sodium. The 2.5 mg tablets are orange, round, scored tablets debossed with M above the score and 14 below the score on one side of the tablet and blank on the other side of the tablet. They are available as follows: NDC 0378-0014-01 bottles of 100 tablets Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.] Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Methotrexate tablets are a cytotoxic drug. Follow applicable special handling and disposal procedures.

1

📋 Description 103 words ▾

11 DESCRIPTION Methotrexate is dihydrofolate reductase inhibitor with the chemical name of N-[4-[[(2,4 diamino-6-pteridinyl) methyl]methylamino]benzoyl]-L glutamic acid. The molecular formula is C 20 H 22 N 8 O 5 and the molecular weight is 454.4 g/mol. The structural formula is: Methotrexate Tablets, USP for oral use are available in bottles of 100 tablets.

Each methotrexate tablet contains 2.5 mg methotrexate equivalent to 2.74 mg methotrexate sodium and the following inactive ingredients: colloidal silicon dioxide, FD&C Red No. 40 Aluminum Lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn), sodium carbonate (monohydrate), sodium lauryl sulfate and sodium starch glycolate (potato). Methotrexate 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) , Use in Specific Populations (8.1) ]. • Advise females of reproductive potential to use effective contraception during treatment with methotrexate tablets and for 6 months after the final dose [see Use in Specific Populations (8.3) ]. • Advise males of reproductive potential to use effective contraception during treatment with methotrexate tablets and for 3 months after the final dose [see Use in Specific Populations (8.3) ].

Hypersensitivity Reactions: Advise patients and their caregivers of the potential risk of hypersensitivity and that methotrexate tablets are contraindicated in patients with a history of hypersensitivity reactions to methotrexate. Instruct patients to seek immediate medical attention for signs of a hypersensitivity reaction [see Warnings and Precautions (5.2) ]. Myelosuppression and Serious Infections: Inform patients and their caregivers that methotrexate tablets can cause myelosuppression and the need for frequent monitoring of blood cell counts.

Advise patients and their caregivers to immediately report new onset fever, symptoms of infection, easy bruising or persistent bleeding to their healthcare provider [see Warnings and Precautions (5.3 , 5.11) ]. Gastrointestinal Toxicity: Advise patients and their caregivers to report new or worsening diarrhea, vomiting, or stomatitis to their healthcare provider. 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 (5.4) ].

Hepatotoxicity: Advise patients and their caregivers to report signs or symptoms of hepatic toxicity to their healthcare provider [see Warnings and Precautions (5.5) ]. Pulmonary Toxicity: Advise patients and their caregivers to report new or worsening cough, fever, or dyspnea to their healthcare provider [see Warnings and Precautions (5.6) ]. Dermatologic Reactions: Advise patients and their caregivers that methotrexate tablets can cause serious skin rash and to immediately contact their healthcare provider for new or worsening skin rash.

Advise patients and their caregivers to avoid excessive sun exposure and use sun protection measures [see Warnings and Precautions (5.7) ]. Renal Toxicity: Advise patients and their caregivers 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 (5.8) ]. Risk of Fatal Adverse Reactions with Medication Error: For patients who are prescribed a once weekly dosing regimen, advise patients and caregivers that the recommended dosage is to be taken once weekly as a single dose and that mistakenly taking the recommended weekly dosage once daily has led to fatal adverse reactions [see Warnings and Precautions (5.9) ].

Neurotoxicity: Advise patients and their caregivers to report new neurological signs or symptoms to their healthcare provider [see Warnings and Precautions (5.12) ]. Secondary Malignancies: Advise patients on the risk of second primary malignancies during treatment with methotrexate tablets [see Warnings and Precautions (5.13) ]. Lactation: Instruct women not to breastfeed during treatment with methotrexate tablets and for 1 week after the final dose [see Use in Specific Populations (8.2) ].

Infertility: Advise females and males of reproductive potential that methotrexate may impair fertility [see Warnings and Precautions (5.16) , Use in Specific Populations (8.3) ]. Drug Interactions: Advise patients and caregivers to inform their healthcare provider of all concomitant medications, includi…

Source: FDA Structured Product Labeling, mirrored from DailyMed / openFDA. Prefer the government’s original formatting? View this label on DailyMed ↗
← 00374-5080-01 · Lyne 00378-0018-01 · Mylan →
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.