Methotrexate (methotrexate sodium)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Methotrexate, a folic acid antagonist, is an antineoplastic agent and immunosuppressant.
Methotrexate and its polyglutamate metabolites reversibly inhibit dihydrofolate reductase, the enzyme that reduces folic acid to tetrahydrofolic acid. Inhibition of tetrahydrofolate formation limits the availability of one-carbon fragments necessary for synthesis of purines and pyrimidines and various other reactions necessary for the synthesis of DNA and cell reproduction. In cancer, malignant cells are unable to synthesize DNA and RNA without these purine and pyrimidine precursors and thus, are unable to proliferate.
Tissues with high rates of cellular proliferation, such as neoplasms, buccal and intestinal mucosa, bone marrow, the bladder, and fetal cells are most sensitive to the effects of methotrexate. The mechanism by which methotrexate works for the treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, and psoriasis is not known; however, it may have effects on the immune system.
Resistance to methotrexate may develop and has been associated with decreased cellular uptake of the drug, increased dihydrofolate reductase activity (associated with increased synthesis of the enzyme), decreased binding of methotrexate to dihydrofolate reductase (because of mutated dihydrofolate reductase protein), increased enzymatic hydrolysis of methotrexate polyglutamates, and decreased intracellular concentrations of polyglutamylated metabolites of methotrexate; however, the precise mechanism of this resistance development has not been established.
Oral absorption of methotrexate appears to be highly variable and dose dependent. At lower oral doses (i.e., <=30 mg/m2), methotrexate is well absorbed with a mean bioavailability of approximately 60%. The bioavailability of methotrexate decreases with increasing oral doses (suggesting the presence of a saturable absorption process) and absorption is substantially reduced at doses exceeding 80 mg/m2.
Food delays absorption and decreases peak serum concentrations of the drug. Methotrexate appears to be completely absorbed following parenteral administration. Peak serum concentrations are achieved within 0.75-6 hours after oral administration and 30-60 minutes after IM administration of the drug.
Methotrexate is actively transported across cell membranes. At serum methotrexate concentrations exceeding 0.1 mcmol/mL, passive diffusion becomes a major means of intracellular transport of the drug. According to the manufacturer, the drug does not reach therapeutic concentrations in the CSF when given orally or parenterally.
However, high CSF concentrations can be attained following intrathecal administration. In the serum, about 50% of the drug is bound to plasma proteins.
In adults receiving methotrexate for the treatment of psoriasis or rheumatoid arthritis, or as low-dose antineoplastic therapy (i.e., <30 mg/m2), a terminal half-life of about 3-10 hours has been reported. Higher IV doses of methotrexate have been associated with a longer elimination half-life of about 8-15 hours in adults. In pediatric patients, terminal half-life ranges from 0.7-5.8 hours in those with acute lymphoblastic leukemia or 0.9-2.3 hours in those with polyarticular juvenile idiopathic arthritis.
After absorption, methotrexate undergoes hepatic and intracellular metabolism to form methotrexate polyglutamates, metabolites which may be converted back to methotrexate by hydrolysis. Methotrexate polyglutamates inhibit dihydrofolate reductase and thymidylate synthetase. Small amounts of these polyglutamate metabolites may remain in tissues for extended periods; the retention and prolonged action of these active metabolites vary among different cells, tissues, and tumors.
In addition, small amounts of methotrexate polyglutamates may be converted to 7-hydroxymethotrexate; accumulation of this metabolite may become substantial following administration of high doses of methotrexate, since the aqueous solubility of 7-hydroxymethotrexate is threefold to fivefold lower than that of the parent compound. Following oral administration of methotrexate, the drug is also partially metabolized by the intestinal flora.
The drug is excreted primarily by the kidneys via glomerular filtration and active transport;. 80-90% of an IV dose is excreted unchanged in the urine within 24 hours of administration. Small amounts (<=10%) are excreted in the feces via the bile.
Enterohepatic recirculation of methotrexate may occur. Methotrexate excretion is impaired and accumulation occurs more rapidly in patients with impaired renal function, pleural effusions, or those with other third-space compartments (e.g., ascites); in such patients, methotrexate levels may remain elevated for prolonged periods, leading to toxicity. Rates of clearance are highly variable and typically lower with higher doses of methotrexate.
USES: Methotrexate is used to treat certain types of cancer (such as acute lymphoblastic leukemia, non-Hodgkin's lymphoma), severe psoriasis that has not responded to other treatments, or rheumatoid arthritis. It may also be used to treat a certain type of arthritis in children (polyarticular juvenile idiopathic arthritis - pJIA). Methotrexate belongs to a class of drugs known as antimetabolites.
It works by slowing or stopping the growth of cancer cells and blocking the immune system from attacking healthy tissue. Early treatment of rheumatoid arthritis with methotrexate helps to reduce further joint damage and to preserve joint function.
Generic name: methotrexate sodium
Pronunciation: (METH-oh-TREX-ate)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Methotrexate
Indications
The following indications are listed for Methotrexate:
- Acute Lymphoid Leukemia
- Mycosis Fungoides
- Non-Hodgkin's Lymphoma
- Polyarticular Juvenile Idiopathic Arthritis
- Rheumatoid Arthritis
- Severe Recalcitrant Psoriasis
Also known as: Acute Lymphatic Leukemia, Acute Lymphocytic Leukemia, Acute Lymphogenous Leukemia, Arthritis Deformans, Arthrosis Deformans, Lymphoblastic Leukemia, Nodose Rheumatism, Non-Hodgkin's Type Lymphoma, Polyarticular Jia, Polyarticular Jra, Polyarticular Juvenile Chronic Arthritis, Polyarticular Juvenile Rheumatoid Arthritis, Rheumatic Arthritis, Rheumatic Gout, Severe Intractable Psoriasis, Severe Refractory Psoriasis.
Dosing
Dosage of methotrexate sodium is expressed in terms of methotrexate.
Methotrexate is administered orally as tablets or an oral solution. Methotrexate sodium is administered by IM, IV, sub-Q, or intrathecal injection; methotrexate powder for injection may also be administered intraarterially. Some injectable preparations of methotrexate sodium (Rasuvo(R) and Otrexup(R)) are only administered sub-Q. Rasuvo(R) is only available in doses between 7.5-30 mg in 2.5 mg increments; use a different formulation of methotrexate for alternative dosing via the oral, IM, IV, intraarterial, or intrathecal routes, for dosages <7.5 mg per week, dosages >30 mg per week, high-dose regimens, or dosage adjustments in increments that are <2.5 mg. Otrexup(R) is only available in doses between 10-25 mg in 2.5 mg increments; use a different formulation of methotrexate for alternative dosing via the oral, IM, IV, intraarterial, or intrathecal routes, for dosages <10 mg per week, dosages >25 mg per week, high-dose regimens, or dosage adjustments between the available doses.
Methotrexate sodium powder for injection should be reconstituted according to the manufacturers' directions. Methotrexate sodium injection is available as a single-dose vial that is ready for use. Rasuvo(R) and Otrexup(R) (methotrexate sodium injection for sub-Q use) are commercially available in single-use, prefilled auto-injectors.
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Drug interactions
Methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms that can then be hydrolyzed back to methotrexate.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*History of hypersensitivity to methotrexate.
*Pregnancy (in patients with non-neoplastic diseases).
*Lactation (powder for injection formulation only).
*Alcoholism, alcoholic liver disease, or other chronic liver disease in patients with psoriasis or rheumatoid arthritis.
*Overt laboratory evidence of immunodeficiency syndromes in patients with psoriasis or rheumatoid arthritis.
*Preexisting blood dyscrasias (i.e., bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia) in patients with psoriasis or rheumatoid arthritis.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
The most common adverse effects reported in patients receiving methotrexate injection, powder for injection, oral solution, and tablets include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Elevated liver function tests are also commonly reported in patients receiving Xatmep(R) oral solution.
The most common adverse effects reported in patients receiving methotrexate injection for sub-Q use include nausea, abdominal pain, dyspepsia, stomatitis/mouth sores, rash, nasopharyngitis, diarrhea, liver function test abnormalities, vomiting, headache, bronchitis, thrombocytopenia, alopecia, leukopenia, pancytopenia, dizziness, photosensitivity, and "burning of skin lesions."
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
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The safety and efficacy of methotrexate (all formulations) have been established in pediatric patients for the treatment of polyarticular juvenile idiopathic arthritis.
The safety and efficacy of methotrexate injection and powder for injection have been established in pediatric patients for the treatment of acute lymphoblastic leukemia (ALL), meningeal leukemia prophylaxis and treatment, non-Hodgkin lymphoma, and osteosarcoma. Severe neurotoxic effects, manifested mainly by focal or generalized seizures, have been reported with increased frequency in pediatric patients with ALL who were receiving intermediate-dose IV methotrexate (1 g/m2). The safety and efficacy of methotrexate injection and powder for injection have not been established in pediatric patients for the treatment of other types of cancer, including breast cancer, squamous cell carcinoma of the head and neck, and gestational trophoblastic diseases.
The safety and efficacy of methotrexate oral solution and tablets have also been established in pediatric patients for the treatment of ALL, but have not been established for the treatment of other neoplastic diseases. The safety and efficacy of Rasuvo(R) and Otrexup(R) (methotrexate injection for sub-Q use) have not been established in pediatric patients for the treatment of any neoplastic diseases.
The safety and efficacy of methotrexate (all formulations) have not been established in pediatric patients for the treatment of rheumatoid arthritis or psoriasis.
Abortion, fetal death, and/or congenital anomalies have occurred in pregnant women receiving methotrexate, especially during the first trimester of pregnancy. Methotrexate is contraindicated in the management of all non-neoplastic disorders (i.e., psoriasis or rheumatoid arthritis (including polyarticular juvenile idiopathic arthritis)) in pregnant women. Verify pregnancy status in female patients of reproductive potential prior to initiating treatment with methotrexate. Advise female patients of reproductive potential to use effective contraception during treatment with methotrexate and for 6 months following the final dose; advise male patients with such female partners to use effective contraception during treatment with methotrexate and for 3 months following the final dose. Women of childbearing potential should be fully informed of the potential hazard to the fetus should they become pregnant during methotrexate therapy.
Benzyl alcohol is present in certain formulations of methotrexate injection and powder for injection and can cross the placenta. If methotrexate injection is administered to treat a neoplastic disease in a pregnant patient, use a preservative-free formulation when possible.
Methotrexate is distributed into breast milk, with a reported breast milk to plasma concentration ratio as high as 0.08:1. The potential effects of methotrexate on the breast-fed infant or on milk production are not known. Methotrexate powder for injection is contraindicated in nursing mothers due to the potential for serious adverse reactions in breast-fed infants exposed to methotrexate. Advise patients taking all other formulations of methotrexate not to breast-feed during treatment and for 1 week after the final dose.
The manufacturer makes no specific dosage recommendations for geriatric patients. Due to the reduced hepatic and renal function, decreased folate stores, and possibility of concomitant diseases or drug therapies in this population, consider relatively low doses and closely monitor for early signs of renal, hepatic, and bone marrow toxicity.
Clinical studies of methotrexate did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently from younger patients. Post-marketing reports have suggested that the risk of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with age. Due to the reduced hepatic and renal function, decreased folate stores, and possibility of concomitant diseases or drug therapies in this population, consider relatively low doses and closely monitor for early signs of renal, hepatic, and bone marrow toxicity.
ICD codes
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Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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