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Methotrexate information from DrugsUpdate  

See Available Brands of Methotrexate in India

P - Contraindicated in pregnancy
L - Contraindicated in lactation
FI - Food *

Methotrexate, abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug used in treatment of cancer and autoimmune diseases. It acts by inhibiting the metabolism of folic acid. Methotrexate began to replace the more powerful and toxic antifolate aminopterin starting in the 1950s, and the two should not be confused with each other.

Pharmacodynamics

Pharmacokinetics

Methotrexate is a folic acid antagonist that inhibits DNA synthesis. It irreversibly binds to dihydrofolate reductase, inhibiting the formation of reduced folates, and thymidylate synthetase, resulting in inhibition of purine and thymidylic acid synthesis.

Absorption

Rapidly absorbed from the GI tract at low doses, higher doses are less well absorbed. Rapidly and completely absorbed after IM doses. Peak plasma concentrations after 1-2 hours (oral), 30-60 minutes (IM).

Distribution

Tissues and extracellular fluids; crosses the blood-brain barrier and placenta; enters breast milk. Small amounts in saliva and breastmilk. 50% bound to plasma proteins. Bound as polyglutamate conjugates, bound drug may remain in the body for several months, particularly in the liver .

Metabolism
Partly by intestinal flora. Does not undergo significant metabolism at low dose therapy; 7-hydroxy metabolite is detected at high-doses.

Excretion

Primarily via urine; small amounts in bile, faeces. Some evidence of enterohepatic recirculation. Interindividual variation exists, patients with delayed clearance are at an increased risk of toxicity.

Methotrexate Indications / Methotrexate Uses

Information Not Available

Methotrexate Adverse Reactions / Methotrexate Side Effects

Ulceration of the mouth and GI disturbances (e.g. stomatitis and diarrhoea), bone marrow depression, hepatotoxicity, renal failure, skin reactions, alopecia, ocular irritation, arachnoiditis in intrathecal use, megaloblastic anaemia, osteoporosis, precipitation of diabetes, arthralgias, necrosis of soft tissue and bone, anaphylaxis, impaired fertility.

Potentially Fatal: Pulmonary reactions (e.g. interstitial lung disease); neurotoxicity (e.g. leukoencephalopathy, paresis, demyelination) with intrathecal use; foetal deaths.

Precautions

Methotrexate has the potential for serious toxicity. Toxic effects may be related in frequency and severity to dose or frequency of administration but have been seen at all doses. Because they can occur at any time during therapy, it is necessary to follow patients on Methotrexate closely. Most adverse reactions are reversible if detected early. When such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If necessary, this could include the use of leucovorin calcium and/or acute, intermittent hemodialysis with a high-flux dialyzer. If Methotrexate therapy is reinstituted, it should be carried out with caution, with adequate consideration of further need for the drug and with increased alertness as to possible recurrence of toxicity.

The clinical pharmacology of Methotrexate has not been well studied in older individuals. Due to diminished hepatic and renal function as well as decreased folate stores in this population, relatively low doses should be considered, and these patients should be closely monitored for early signs of toxicity.


Overdosage
Nausea, vomiting, alopecia, melena, and renal failure.

Special Precautions

Hepatic or renal impairment, bone marrow depression, elderly, neonates. Ulcerative disorders of the GI tract. Monitor haematological, renal and hepatic function, and GI toxicity regularly.

Other Drug Interactions

Decreased effectiveness with folic acid and its derivatives.

Potentially Fatal: Increased toxicity with NSAIDs and salicylates; probenecid; some penicillins; aminoglycosides neomycin and paromomycin; sulfonamides such as sulfafurazole and sulfamethoxazole; co-trimoxazole or trimethoprim; nephrotoxic agents (e.g. cisplatin); ciclosporin; etretinate. Synergistic enhancement of effects with fluorouracil. Increased bioavailability of mercaptopurine. Reduces serum-valproate concentrations. Reduced serum concentrations with colestyramine. Increased serum concentrations with omeprazole.

Other Interactions

May be given with meals to minimise GI discomfort. Serum levels may be decreased if taken with food. Decreased absorption in milk-rich food, decreased drug response with folate. Avoid ethanol (may be associated with increased liver injury). Avoid echinacea (has immunostimulant properties).

Dosage

Oral
Burkitt's lymphoma
Adult: 10-25 mg daily for 4-8 days, repeated after 7-10 days.

CrCl (ml/min)    Dosage Recommendation
61-80               75% of dose
51-60               70% of dose
10-50               30-50% of dose
<10                  Avoid use
Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.

Oral
Acute lymphoblastic leukaemia
Adult: Maintenance: 15 mg/m2 once or twice wkly, with other agents.

CrCl (ml/min)    Dosage Recommendation
61-80               75% of dose
51-60               70% of dose
10-50               30-50% of dose
<10                  Avoid use
Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.

Oral
Choriocarcinoma
Adult: 15-30 mg daily for 5 days, repeat after an interval of ≥1 week for 3-5 courses.

CrCl (ml/min)    Dosage Recommendation
61-80               75% of dose
51-60               70% of dose
10-50               30-50% of dose
<10                  Avoid use
Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.

Oral
Mycosis fungoides
Adult: 2.5-10 mg daily to induce remission.
CrCl (ml/min)    Dosage Recommendation
61-80               75% of dose
51-60               70% of dose
10-50               30-50% of dose
<10                  Avoid use
Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.

Oral
Psoriasis
Adult: 10-25 mg weekly as a single dose, adjust subsequent doses based on response.

CrCl (ml/min)    Dosage Recommendation
61-80               75% of dose
51-60               70% of dose
10-50               30-50% of dose
<10                  Avoid use
Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.

Oral
Rheumatoid arthritis
Adult: 7.5 mg once wkly, adjust by response. Not more than 20 mg/week.

CrCl (ml/min)    Dosage Recommendation
61-80               75% of dose
51-60               70% of dose
10-50               30-50% of dose
<10                  Avoid use
Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.

Oral
Crohn's disease
Adult: 12.5-22.5 mg once wkly for up to1 year.

CrCl (ml/min)    Dosage Recommendation
61-80               75% of use
51-60               70% of use
10-50               30-50% of use
<10                  Avoid use
Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.

Intravenous
Osteosarcoma
Adult: Initial recommended dose: 12 g/m2 as a 4-hours infusion, followed by folinic acid, as part of combined therapy. May increase dose to 15 g/m2 in subsequent treatments if initial dosage is insufficient to achieve peak serum methotrexate levels of 454 mcg/mL at the end of the infusion. Methotrexate infusion is administered on postoperative wk 4, 5, 6, 7, 11, 12, 15, 16, 29, 30, 44 and 45; in combination with other chemotherapy agents. Folinic acid can be given orally, IM or IV injection starting 24 hour after the beginning of the methotrexate infusion. Give via parenteral routes If patient experiences GI toxicity (e.g., nausea, vomiting). Usual dosage of folinic acid: 15 mg every 6 hour for a total of 60 hours or a total of 10 doses.

CrCl (ml/min)    Dosage Recommendation
61-80               75% of dose
51-60               70% of dose
10-50               30-50% of dose
<10                  Avoid use
Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.

Intravenous
Breast cancer
Adult: 10-60 mg/m2 often with cyclophosphamide and fluorouracil.

CrCl (ml/min)    Dosage Recommendation
61-80               75% of dose
51-60               70% of dose
10-50               30-50% of dose
<10                  Avoid use
Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.

Intravenous
Advanced lymphosarcoma
Adult: Up to 30 mg/kg, followed by folinic acid rescue.
CrCl (ml/min)    Dosage Recommendation
61-80               75% of dose
51-60               70% of dose
10-50               30-50% of dose
<10                  Avoid use
Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.

Intravenous
Acute lymphoblastic leukaemia
Adult: Maintenance: 2.5 mg/kg every 14 days.
CrCl (ml/min)    Dosage Recommendation
61-80               75% of dose
51-60               70% of dose
10-50               30-50% of dose
<10                  Avoid use
Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.

Intramuscular
Choriocarcinoma
Adult: 15-30 mg daily for 5 days. Repeat after at least 1 week for 3-5 courses. Alternatively, 0.25-1 mg/kg (max: 60 mg) every 48 hours for 4 doses followed by folinic acid rescue, repeat at intervals of 7 days for 4 or more courses.
CrCl (ml/min)    Dosage Recommendation
61-80               75% of dose
51-60               70% of dose
10-50               30-50% of dose
<10                  Avoid use
Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.

Intramuscular
Acute lymphoblastic leukaemia
Adult: Maintenance: 15 mg/m2 once or twice weekly, with other agents.

CrCl (ml/min)    Dosage Recommendation
61-80               75% of dose
51-60               70% of dose
10-50               30-50% of dose
<10                  Avoid use
Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.

Intramuscular
Mycosis fungoides
Adult: 50 mg weekly as a single dose or 2 divided doses.
CrCl (ml/min)    Dosage Recommendation
61-80               75% of dose
51-60               70% of dose
10-50               30-50% of dose
<10                  Avoid use
Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.

Intramuscular
Crohn's disease
Adult: 25 mg once weekly for 16 weeks. Maintenance: 15 mg weekly.

CrCl (ml/min)    Dosage Recommendation
61-80               75% of dose
51-60               70% of dose
10-50               30-50% of dose
<10                  Avoid use
Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.

Parenteral
Psoriasis
Adult: 10-25 mg weekly as a single dose. Adjust subsequent doses based on response. May be given via IV/IM admin.

CrCl (ml/min)    Dosage Recommendation
61-80               75% of dose
51-60               70% of dose
10-50               30-50% of dose
<10                  Avoid use
Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.

Intrathecal
Meningeal leukaemia
Adult: 12 mg/m2 (max 15 mg) once weekly for 2-3 weeks, then once mthly. Alternatively, 200-500 mcg/kg every 2-5 day until CSF cell count is normalised.
Child: <1 year: 6 mg, 1 year: 8 mg, 2 years: 10 mg, >3 years: 12 mg. Patients <3 years should be treated in accordance with combination chemotherapy protocols. Admin is at weekly intervals and repeated until the CSF cell count is normal.

CrCl (ml/min)    Dosage Recommendation
61-80               75% of dose
51-60               70% of dose
10-50               30-50% of dose
<10                  Avoid use
Hepatic impairment: Bilirubin 3.1-5 mg/dl: Administer 75% of dose; Bilirubin >5 mg/dl: Avoid use.

Reconstitution
Reconstitute to 2.5-5 mg/ml with normal saline, D5W, lactated Ringer's, or Elliott's B solution. Use preservative-free preparations.

Food(before/after)

May be taken with or without food. (May be taken w/ meals to minimise GI discomfort.)

List of Contraindications

Methotrexate and Pregnancy

Contraindicated in pregnancy

Category X: Studies in animals or human beings have demonstrated foetal abnormalities or there is evidence of foetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

Methotrexate and Lactation

Contraindicated in lactation

Methotrexate and Children

Safety and effectiveness in pediatric patients have been established only in cancer chemotherapy and in polyarticular-course juvenile rheumatoid arthritis.

Published clinical studies evaluating the use of Methotrexate in children and adolescents (ie, patients 2 to 16 years of age) with JRA demonstrated safety comparable to that observed in adults with rheumatoid arthritis.

Methotrexate and Geriatic

Clinical studies of Methotrexate did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic and renal function, decreased folate stores, concomitant disease or other drug therapy (ie, that interfere with renal function, Methotrexate or folate metabolism) in this population.

Methotrexate and Other Contraindications

Severe renal or hepatic impairment, pre-existing profound bone marrow suppression in patients with psoriasis or rheumatoid arthritis, alcoholic liver disease, AIDS, pre-existing blood dyscrasias, pregnancy (in patients with psoriasis or rheumatoid arthritis), breast-feeding.

Storage

Intramuscular
Store intact vials at room temperature (15-25°C). Protect from light. Solutions diluted in D5W or normal saline are stable at room temperature (21-25°C) for 24 hours. Reconstituted solutions with a preservative may be stored under refrigeration for up to 3 months, and up to 4 weeks at room temperature.

Intrathecal
Store intact vials at room temperature (15-25°C). Protect from light. Solutions diluted in D5W or normal saline are stable at room temperature (21-25°C) for 24 hours. Reconstituted solutions with a preservative may be stored under refrigeration for up to 3 months, and up to 4 weeks at room temperature. Dilutions are stable for 7 days at room temperature, but are recommended to be used within 4-8 hours.


Intravenous
Store intact vials at room temperature (15-25°C). Protect from light. Solutions diluted in D5W or normal saline are stable at room temperature (21-25°C) for 24 hours. Reconstituted solutions with a preservative may be stored under refrigeration for up to 3 mth, and up to 4 weeks at room temperature.

Oral

Store tablets at room temperature (15-25°C). Protect from light.


Parenteral
Store intact vials at room temperature (15-25°C). Protect from light. Solutions diluted in D5W or normal saline are stable at room temperature (21-25°C) for 24 hours. Reconstituted solutions with a preservative may be stored under refrigeration for up to 3 months, and up to 4 weeks at room temperature.

Lab interference

Intramuscular
Store intact vials at room temperature (15-25°C). Protect from light. Solutions diluted in D5W or normal saline are stable at room temperature (21-25°C) for 24 hours. Reconstituted solutions with a preservative may be stored under refrigeration for up to 3 months, and up to 4 weeks at room temperature.

Intrathecal
Store intact vials at room temperature (15-25°C). Protect from light. Solutions diluted in D5W or normal saline are stable at room temperature (21-25°C) for 24 hours. Reconstituted solutions with a preservative may be stored under refrigeration for up to 3 months, and up to 4 weeks at room temperature. Dilutions are stable for 7 days at room temperature, but are recommended to be used within 4-8 hours.


Intravenous
Store intact vials at room temperature (15-25°C). Protect from light. Solutions diluted in D5W or normal saline are stable at room temperature (21-25°C) for 24 hours. Reconstituted solutions with a preservative may be stored under refrigeration for up to 3 mth, and up to 4 weeks at room temperature.

Oral

Store tablets at room temperature (15-25°C). Protect from light.


Parenteral
Store intact vials at room temperature (15-25°C). Protect from light. Solutions diluted in D5W or normal saline are stable at room temperature (21-25°C) for 24 hours. Reconstituted solutions with a preservative may be stored under refrigeration for up to 3 months, and up to 4 weeks at room temperature.

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