METHOTREXATE ACCORD

Methotrexate is a folate derivative that inhibits several enzymes responsible for nucleotide synthesis.

This inhibition leads to suppression of inflammation as well as prevention of cell division.

Because of these effects, methotrexate is often used to treat inflammation caused by arthritis or to control cell division in neoplastic diseases such as breast cancer and non-Hodgkin's lymphoma. 1, 4, 5, 6, 7 Due to the toxic effects of methotrexate, it is indicated for treatment of some forms of arthritis and severe psoriasis only if first line treatment has failed or patients are intolerant of those treatments.

Methotrexate was granted

FDA approval on 7 December 1953.

Methotrexate oral solution is indicated for pediatric acute lymphoblastic leukemia and pediatric polyarticular juvenile idiopathic arthritis.

Methotrexate injections for subcutaneous use are indicated for severe active rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and severe, recalcitrant, disabling psoriasis. 5, 6, 10 It has also been approved by the EMA for the treatment of adult patients requiring systemic therapy for moderate-to-severe plaque psoriasis.

Other formulations are indicated to treat gestational choriocarcinoma, chorioadenoma destruens, hydatiform mole, breast cancer, epidermoid cancer of the head and neck, advanced mycosis fungoides, lung cancer, and advanced non-Hodgkin's lymphoma.

It is also used in the maintenance of acute lymphocytic leukemia.

Methotrexate is also given before treatment with leucovorin to prolong relapse-free survival following surgical removal of a tumour in non-metastatic osteosarcoma.

Methotrexate inhibits enzymes responsible for nucleotide synthesis which prevents cell division and leads to anti-inflammatory actions.

It has a long duration of action and is generally given to patients once weekly. 1, 4, 5, 6 Methotrexate has a narrow therapeutic index.

Do not take methotrexate daily. 5, 6.

Thymidylate synthase Inhibitor Bifunctional purine biosynthesis protein ATIC Inhibitor Dihydrofolate reductase Inhibitor.

Methotrexate has a bioavailability of 64-90%, though this decreases at oral doses above 25 mg due to saturation of the carrier mediated transport of methotrexate. 1.

Methotrexate has a

T max of 1-2 hours. 1 oral doses of 10-15 µg reach serum levels of 0.01-0.1µM.

The volume of distribution of methotrexate at steady state is approximately 1 L/kg.

Methotrexate is metabolized by folylpolyglutamate synthase to methotrexate polyglutamate in the liver as well as in tissues. 1, 7 Gamma-glutamyl hydrolase hydrolyzes the glutamyl chains of methotrexate polyglutamates converting them back to methotrexate. 1, 7 A small amount of methotrexate is also converted to 7-hydroxymethotrexate. 1, 7 Hover over products below to view reaction partners Methotrexate 7-hydroxymethotrexate.

Methotrexate is >80% excreted as the unchanged drug and approximately 3% as the 7-hydroxylated metabolite.

Methotrexate is primarily excreted in the urine with 8.7-26% of an intravenous dose appearing in the bile.

The half life of low dose methotrexate is 3-10 hours in adults.

The half life for high dose methotrexate is 8-15 hours.

Pediatric patients taking methotrexate for acute lymphoblastic anemia experience a terminal half life of 0.7-5.8 hours.

Pediatric patients taking methotrexate for juvenile idiopathic arthritis experience a half life of 0.9-2.3 hours.

Methotrexate clearance varies widely between patients and decreases with increasing doses.

Currently, predicting clearance of methotrexate is difficult and exceedingly high serum levels of methotrexate can still occur when all precautions are taken.

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The oral

LD in rats is 135 mg/kg and in mice is 146 mg/kg.

Symptoms of overdose include hematologic and gastrointestinal reactions like leukopenia, thombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, and gastrointestinal bleeding.

In the event of an overdose, patients should be treated with glucarpidase and not be given leucovorin for 2 hours before or after glucarpidase.

• Pregnant women receiving methotrexate tablets for treatment of non-neoplastic diseases.

• Patients with a history of severe hypersensitivity reactions, including anaphylaxis, to methotrexate. .

• In pregnancy for non-neoplastic diseases.

• History of severe hypersensitivity to methotrexate.

• Instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to deaths.

• Verify pregnancy status in females of reproductive potential before starting methotrexate tablets.

• ALL: The recommended dosage is 20 mg/m 2 orally once weekly as a part of a combination chemotherapy maintenance regimen.

• Mycosis fungoides: The recommended dosage is to 75 mg orally once weekly as monotherapy; 10 mg/m 2 orally twice weekly as part of combination chemotherapy.

• 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.

• Rheumatoid Arthritis: The recommended starting dosage is 7.5 mg orally once weekly; adjust dose to achieve an optimal response.

• pJIA: The recommended starting dosage is 10 mg/m 2 orally once weekly; adjust dose to achieve an optimal response.

• Psoriasis: The recommended dosage is to 25 mg orally once weekly until adequate response is achieved. 2.1 Important Dosage and Safety Information Verify pregnancy status in females of reproductive potential before starting methotrexate tablets.

Instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to deaths.

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 2.2 Recommended 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.

The recommended dosage of methotrexate tablets is 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.

The recommended dosage of methotrexate tablets is 2.5 mg orally to 4 times per week (maximum 10 mg per week) as part of a metronomic combination chemotherapy regimen. 2.3 Recommended 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 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. 2.4 Recommended 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.

Administer folic acid or folinic acid to reduce the risk of methotrexate adverse reactions. 2.5 Recommended Dosage for Psoriasis The recommended dosage of methotrexate tablets is to 25 mg orally once weekly until an adequate response is achieved.

Adjust the dose gradually to achieve optimal clinical response; do not exceed a dose of 30 mg per week.

Once optimal clinical response has been achieved, reduce the dosage to the lowest possible dosing regimen.

• Anaphylaxis or other severe hypersensitivity reactions.

• Severe gastrointestinal toxicity.

• Pulmonary toxicity.

• Severe dermatologic reactions.

• Severe renal toxicity.

• Serious infections.

Methotrexate tablets

USP, 2.5 mg having functional scoring are supplied as pale yellow to yellow, round, uncoated tablets with debossing “C7” on one side and scoring on other side.

• 36 count bottle with child-resistant closure, NDC 62332-730-36.

• 100 count bottle with child-resistant closure, NDC 62332-730-31 Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

Methotrexate tablet, USP is a cytotoxic drug.

Follow applicable special handling and disposal procedures.

Methotrexate is contraindicated in pregnant women with non-neoplastic diseases.

Based on published reports and its mechanism of action, methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman.

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.

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.

The safety and effectiveness of methotrexate in pediatric patients have been established for the treatment of ALL as part of the combination chemotherapy maintenance regimen and the treatment of pJIA.

No new safety signals have been observed in pediatric patients in clinical studies.

The safety and effectiveness of methotrexate have not been established in pediatric patients for the other indications.

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