There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
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=====Condition1=====
* Dosing Information
:* Dosage
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There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
<!--Pediatric Indications and Dosage-->
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|fdaLIADPed=
=====Condition1=====
* Dosing Information
:* Dosage
=====Condition2=====
There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.
<!--Off-Label Use and Dosage (Pediatric)-->
<!--Guideline-Supported Use (Pediatric)-->
|offLabelPedGuideSupport=
=====Condition1=====
* Developed by:
* Class of Recommendation:
* Strength of Evidence:
* Dosing Information
:* Dosage
=====Condition2=====
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
<!--Non–Guideline-Supported Use (Pediatric)-->
|offLabelPedNoGuideSupport=
=====Condition1=====
* Dosing Information
:* Dosage
=====Condition2=====
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
<!--Contraindications-->
|contraindications=
* Condition1
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|warnings=
* Description
====Precautions====
* Description
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<!--Clinical Trials Experience-->
|clinicalTrials=
There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.
=====Body as a Whole=====
=====Cardiovascular=====
=====Digestive=====
=====Endocrine=====
=====Hematologic and Lymphatic=====
=====Metabolic and Nutritional=====
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=====Neurologic=====
=====Respiratory=====
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=====Special Senses=====
=====Urogenital=====
=====Miscellaneous=====
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|postmarketing=
There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
=====Body as a Whole=====
=====Cardiovascular=====
=====Digestive=====
=====Endocrine=====
=====Hematologic and Lymphatic=====
=====Metabolic and Nutritional=====
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=====Neurologic=====
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=====Skin and Hypersensitivy Reactions=====
=====Special Senses=====
=====Urogenital=====
=====Miscellaneous=====
<!--Drug Interactions-->
|drugInteractions=
* Drug
:* Description
<!--Use in Specific Populations-->
|useInPregnancyFDA=
* '''Pregnancy Category'''
|useInPregnancyAUS=
* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
|useInLaborDelivery=
There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInNursing=
There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.
|useInPed=
There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
|useInGeri=
There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
|useInGender=
There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInRace=
There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRenalImpair=
There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.
|useInHepaticImpair=
There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
|useInReproPotential=
There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
|useInImmunocomp=
There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
<!--Administration and Monitoring-->
|administration=
* Oral
* Intravenous
|monitoring=
There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.
* Description
<!--IV Compatibility-->
|IVCompat=
There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
<!--Overdosage-->
|overdose=
===Acute Overdose===
====Signs and Symptoms====
* Description
====Management====
* Description
===Chronic Overdose===
There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.
<!--Pharmacology-->
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*
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|structure=
*
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
<!--Pharmacodynamics-->
|PD=
There is limited information regarding <i>Pharmacodynamics</i> of {{PAGENAME}} in the drug label.
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|PK=
There is limited information regarding <i>Pharmacokinetics</i> of {{PAGENAME}} in the drug label.
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|nonClinToxic=
There is limited information regarding <i>Nonclinical Toxicology</i> of {{PAGENAME}} in the drug label.
<!--Clinical Studies-->
|clinicalStudies=
There is limited information regarding <i>Clinical Studies</i> of {{PAGENAME}} in the drug label.
==Overview==
<!--How Supplied-->
'''Methotrexate''' ([[International Nonproprietary Name|rINN]]) ([[International Phonetic Alphabet|IPA]]: {{IPA|[mɛθəˈtrɛkseɪt]}}), abbreviated '''MTX''' and formerly known as '''amethopterin''', is an [[antimetabolite]] and antifolate drug used in treatment of [[cancer]] and [[autoimmune disease]]s. It acts by inhibiting the metabolism of [[folic acid]]. Methotrexate replaced the more powerful and toxic antifolate [[aminopterin]], and the two should not be confused with each other.
==History==
Methotrexate originated in the 1940s when [[Sidney Farber]] at [[Children's Hospital Boston]] was testing the effects of [[folic acid]] on cancer. This inspired chemists at the drug company Lederle to start looking for antimetabolites resembling folate. The result was methotrexate, which was developed in 1948 by [[Yellapragada Subbarao]] from Lederle. Methotrexate gained [[Food and Drug Administration]] (FDA) approval as an oncology drug in 1953.
==Uses==
|howSupplied=
===In chemotherapy===
Methotrexate was originally used, as part of combination chemotherapy regimens, to treat many kinds of [[cancer]]s. It is still the mainstay for the treatment of many [[neoplasm|neoplastic]] disorders including [[acute lymphoblastic leukemia]].
===Other uses===
*
More recently it has come into use as a treatment for some [[autoimmune diseases]], including [[ankylosing spondylitis]], [[Crohn's disease]], [[psoriasis]], [[psoriatic arthritis]], and [[rheumatoid arthritis]] (see [[disease-modifying antirheumatic drug]]s). A parallel use with [[Tumor necrosis factor-alpha|TNFα]] blockers as [[infliximab]] or [[etanercept]] has been shown to markedly improve symptoms.<ref>{{cite journal | author=Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, Martin Mola E, Pavelka K, Sany J, Settas L, Wajdula J, Pedersen R, Fatenejad S, Sanda M | title=Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial | journal=Lancet | year=2004 | pages=675-81 | volume=363 | issue=9410 | id=PMID 15001324}}</ref>
Although not indicated for this use, methotrexate is also sometimes used (generally in combination with [[misoprostol]]) to terminate early [[pregnancy|pregnancies]], particularly [[ectopic pregnancy|ectopic pregnancies]].
<!--Patient Counseling Information-->
==Pharmacokinetics==
|fdaPatientInfo=
Methotrexate is a weak dicarboxylic acid with [[Acid dissociation constant|pKa]] 4.8 and 5.5, and thus it is mostly [[Ionization|ionized]] at physiologic pH. Oral absorption is saturatable and thus dose-dependent, with doses less than 40mg/M2 having 42% bioavailability and doses greater than 40mg/M2 only 18%. Mean oral bioavailability is 33% (13-76% range), and there is no clear benefit to subdividing an oral dose. Mean intramuscular bioavailability is 76%.
Methotrexate is metabolized by intestinal bacteria to the inactive metabolite 4-amino-4-deoxy-N-methylpteroic acid (DAMPA) and accounts for less than 5% loss of the oral dose.
There is limited information regarding <i>Patient Counseling Information</i> of {{PAGENAME}} in the drug label.
Factors that decrease absorption include food, oral non-absorbable antibiotics (e.g. vancomycin, neomycin, and bacitracin), and more rapid transit through the Gastrointestinal (GI) tract such as diarrhea, while slower transit time in the GI tract from constipation will increase absorption.
<!--Precautions with Alcohol-->
==Administration==
|alcohol=
It can be taken orally or administered by injection (subcutaneous, [[intramuscular]], [[intravenous]] or [[intrathecal]]). Although daily preparations are occasionally used, most patients take weekly doses, which decreases the risk of certain side-effects.
==Adverse effects==
* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Possible side effects can include [[anemia]], [[neutropenia]], increased risk of [[bruising]], [[nausea]] and [[vomiting]], [[dermatitis]] and [[diarrhea]]. A small percentage of patients develop [[hepatitis]], and there is an increased risk of [[pulmonary fibrosis]].
<!--Brand Names-->
The higher doses of methotrexate often used in cancer chemotherapy can cause toxic effects to the rapidly-dividing cells of [[bone marrow]] and [[gastrointestinal]] [[mucosa]]. The resulting myelosuppression and [[mucositis]] are often prevented (termed methotrexate "rescue") by using [[folinic acid]] supplements (not to be confused with [[folic acid]]).
|brandNames=
Methotrexate is a highly [[teratogenic]] drug and categorized in [[Pregnancy category|Pregnancy Category X]] by the FDA. Women must not take the drug during pregnancy, if there is a risk of becoming pregnant, or if they are breastfeeding. Men who are trying to get their partner pregnant must also not take the drug. To engage in any of these activities (after discontinuing the drug), women must wait until the end of a full ovulation cycle and men must wait three months.
* ®<ref>{{Cite web | title = | url = }}</ref>
There is a risk of a severe adverse reaction if [[penicillin]] is prescribed alongside methotrexate.
<!--Look-Alike Drug Names-->
Interestingly, there have also been some reports of central nervous system reactions to methotrexate especially when given via the intrathecal route which include myelopathies and leucoencephalopathies.
|lookAlike=
==Mode of action==
* A® — B®<ref name="www.ismp.org">{{Cite web | last = | first = | title = http://www.ismp.org | url = http://www.ismp.org | publisher = | date = }}</ref>
Methotrexate competitively and reversibly inhibits [[dihydrofolate reductase]] (DHFR), an [[enzyme]] that is part of the [[folate]] synthesis metabolic pathway. The affinity of methotrexate for DHFR is about one thousand-fold that of folate for DHFR. Dihydrofolate reductase catalyses the conversion of [[dihydrofolate]] to the active [[tetrahydrofolate]]. Folic acid is needed for the ''de novo'' synthesis of the [[nucleoside]] [[thymidine]], required for [[DNA synthesis]]. Also, folate is needed for purine base synthesis, so all purine synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of [[DNA]], [[RNA]], thymidylates, and [[protein]]s.
Methotrexate acts specifically during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the [[cell cycle]]. Logically, it therefore has a greater toxic effect on rapidly dividing cells (such as [[malignant]] and [[myeloid]] cells, and GI & oral mucosa), which replicate their DNA more frequently, and thus inhibits the growth and proliferation of these non-cancerous cells as well causing side effects listed above.
<!--Drug Shortage Status-->
Lower doses of methotrexate have been shown to be very effective for the management of [[rheumatoid arthritis]] and [[psoriasis]]. In these cases inhibition of [[dihydrofolate reductase]] (DHFR) is not thought to be the main mechanism, rather the inhibition of [[enzyme]]s involved in purine metabolism, leading to accumulation of [[adenosine]], or the inhibition of [[T cell]] activation and suppression of [[intercellular adhesion molecule]] expression by [[T cell]]s.<ref>{{cite journal | author=Johnston A, Gudjonsson JE, Sigmundsdottir H, Ludviksson BR, Valdimarsson H; | title=The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules | journal=Clin Immunol. | volume=114 | issue=Feb. | year=2005 | pages=154-163 | id=PMID 15639649}}</ref>
|drugShortage=
}}
==References==
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{{Chemotherapeutic agents}}
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[[Category:Drugs]]
{{LabelImage
[[Category:Chemotherapeutic agents]]
|fileName={{PAGENAME}}11.png|This image is provided by the National Library of Medicine.
[[Category:Immunosuppressive agents]]
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[[Category:Dihydrofolate reductase inhibitors]]
{{LabelImage
|fileName={{PAGENAME}}11.png|This image is provided by the National Library of Medicine.
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Black Box Warning
Title
See full prescribing information for complete Boxed Warning.
ConditionName:
Content
Overview
Methotrexate (injection) is a that is FDA approved for the {{{indicationType}}} of . There is a Black Box Warning for this drug as shown here. Common adverse reactions include .
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Condition1
Dosing Information
Dosage
Condition2
Dosing Information
Dosage
Condition3
Dosing Information
Dosage
Condition4
Dosing Information
Dosage
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Methotrexate (injection) in adult patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Methotrexate (injection) in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding FDA-Labeled Use of Methotrexate (injection) in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Methotrexate (injection) in pediatric patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Methotrexate (injection) in pediatric patients.
Contraindications
Condition1
Warnings
Title
See full prescribing information for complete Boxed Warning.
ConditionName:
Content
Description
Precautions
Description
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Methotrexate (injection) in the drug label.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Methotrexate (injection) in the drug label.
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