Trexall Information
Trexall (Methotrexate sodium)
Trexall (Methotrexate sodium) Description:
Each tablet contains methotrexate sodium in an amount equivalent to the labeled amount of methotrexate, and contains the following inactive ingredients: anhydrous lactose, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, sodium carbonate monohydrate, talc and titanium dioxide.
The 5 mg also contains: D&C yellow no. 10 aluminum lake, FD&C blue no. 1 aluminum lake and FD&C yellow no. 6 aluminum lake.
The 7.5 mg also contains: FD&C blue no.1 aluminum lake.
The 10 mg also contains: FD&C red no. 40 aluminum lake.
The 15 mg also contains: FD&C blue no. 2 aluminum lake and FD&C red no. 40 aluminum lake.
Trexall (Methotrexate sodium) Clinical Pharmacology:
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. When cellular proliferation in malignant tissues is greater than in most normal tissues, methotrexate may impair malignant growth without irreversible damage to normal tissues.
The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function. Two reports describe methotrexate inhibition of DNA precursor uptake by stimulated mononuclear cells, and another describes, in animal polyarthritis partial correction by methotrexate of spleen cell hyporesponsiveness and suppressed IL 2 production. Other laboratories, however, have been unable to demonstrate similar effects. Clarification of methotrexate’s effect on immune activity and its relation to rheumatoid immunopathogenesis await further studies.
In patients with rheumatoid arthritis, effects of methotrexate on articular swelling and tenderness can be seen as early as 3 to 6 weeks. Although methotrexate clearly ameliorates symptoms of inflammation (pain, swelling, stiffness), there is no evidence that it induces remission of rheumatoid arthritis nor has a beneficial effect been demonstrated on bone erosions and other radiologic changes which result in impaired joint use, functional disability, and deformity.
Most studies of methotrexate in patients with rheumatoid arthritis are relatively short term (3 to 6 months). Limited data from long-term studies indicate that an initial clinical improvement is maintained for at least two years with continued therapy.
In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This differential in proliferation rates is the basis for the use of methotrexate to control the psoriatic process.
In a 6-month, double-blind, placebo-controlled trial of 127 pediatric patients with juvenile rheumatoid arthritis (JRA) (mean age, 10.1 years; age range, 2.5 to 18 years; mean duration of disease, 5.1 years) on background nonsteroidal anti-inflammatory drugs (NSAIDs) and/or prednisone, methotrexate given weekly at an oral dose of 10 mg/m provided significant clinical improvement compared to placebo as measured by either the physician’s global assessment, or by a patient composite (25% reduction in the articular-severity score plus improvement in parent and physician global assessments of disease activity.) Over two-thirds of the patients in this trial had polyarticular-course JRA, and the numerically greatest response was seen in this subgroup treated with 10 mg/m/wk methotrexate. The overwhelming majority of the remaining patients had systemic-course JRA.
All patients were unresponsive to NSAIDs; approximately one-third were using low dose corticosteroids. Weekly methotrexate at a dose of 5 mg/m was not significantly more effective than placebo in this trial.
Trexall (Methotrexate sodium) Indications And Usage:
Trexall (Methotrexate sodium) ™
Methotrexate is used alone or in combination with other anticancer agents in the treatment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides, (cutaneous T cell lymphoma), and lung cancer, particularly squamous cell and small cell types. Methotrexate is also used in combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin’s lymphomas.
Trexall (Methotrexate sodium) ™
Aspirin, NSAIDs, and/or low dose steroids may be continued, although the possibility of increased toxicity with concomitant use of NSAIDs including salicylates has not been fully explored (see PRECAUTIONS, Drug Interactions). Steroids may be reduced gradually in patients who respond to methotrexate. Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has not been studied and may increase the incidence of adverse effects. Rest and physiotherapy as indicated should be continued.
Trexall (Methotrexate sodium) Contraindications:
Methotrexate can cause fetal death or teratogenic effects when administered to a pregnant woman. Methotrexate is contraindicated in pregnant women with psoriasis or rheumatoid arthritis and should be used in the treatment of neoplastic diseases only when the potential benefit outweighs the risk to the fetus. Women of childbearing potential should not be started on methotrexate until pregnancy is excluded and should be fully counseled on the serious risk to the fetus (see PRECAUTIONS) should they become pregnant while undergoing treatment. Pregnancy should be avoided if either partner is receiving methotrexate; during and for a minimum of three months after therapy for male patients, and during and for at least one ovulatory cycle after therapy for female patients. (See Boxed WARNINGS.)
Because of the potential for serious adverse reactions from methotrexate in breast fed infants, it is contraindicated in nursing mothers.
Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver disease should not receive methotrexate.
Patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence of immunodeficiency syndromes should not receive methotrexate.
Patients with psoriasis or rheumatoid arthritis who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anemia, should not receive methotrexate.
Patients with a known hypersensitivity to methotrexate should not receive the drug.
Trexall (Methotrexate sodium) Precautions:
Methotrexate has the potential for serious toxicity. (See Boxed WARNINGS.) 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. (See OVERDOSAGE.) 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.
Patients should be informed of the early signs and symptoms of toxicity, of the need to see their physician promptly if they occur, and the need for close follow-up, including periodic laboratory tests to monitor toxicity.
Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken weekly in rheumatoid arthritis and psoriasis, and that mistaken daily use of the recommended dose has led to fatal toxicity.
Prescriptions should not be written or refilled on a PRN basis.
Patients should be informed of the potential benefit and risk in the use of methotrexate. The risk of effects on reproduction should be discussed with both male and female patients taking methotrexate.
Patients undergoing methotrexate therapy should be closely monitored so that toxic effects are detected promptly. Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests, and a chest X-ray. During therapy of rheumatoid arthritis and psoriasis, monitoring of these parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months. More frequent monitoring is usually indicated during antineoplastic therapy. or during periods of increased risk of elevated methotrexate blood levels (e.g., dehydration), more frequent monitoring may also be indicated.
Transient liver function test abnormalities are observed frequently after methotrexate administration and are usually not cause for modification of methotrexate therapy. Persistent liver function test abnormalities, and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation. (See PRECAUTIONS, Organ System Toxicity, Hepatic.)
A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver has not been established for patients with psoriasis. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.
Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available.
Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity.
Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal model and may enhance its toxicity.
Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in rheumatoid arthritis (7.5 to 15 mg/week) are somewhat lower than those used in psoriasis and that larger doses could lead to unexpected toxicity.
Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. Renal tubular transport is also diminished by probenecid; use of methotrexate with this drug should be carefully monitored.
Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria.
Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with high and low dose methotrexate. Use of methotrexate with penicillins should be carefully monitored.
The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with methotrexate and other potential hepatotoxins (e.g., azathioprine, retinoids, sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity.
Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate.
Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. Preliminary animal and human studies have shown that small quantities of intravenously administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1-3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate.
Folate deficiency states may increase methotrexate toxicity.
Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by an additive antifolate effect.
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 (i.e., patients 2 to 16 years of age) with JRA demonstrated safety comparable to that observed in adults with rheumatoid arthritis. (See CLINICAL PHARMACOLOGY, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION.)
Trexall (Methotrexate sodium) Adverse Reactions:
The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse effects are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection.
Other adverse reactions that have been reported with methotrexate are listed below by organ system. In the oncology setting, concomitant treatment and the underlying disease make specific attribution of a reaction to methotrexate difficult.
Gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis.
Other rarer reactions related to or attributed to the use of methotrexate such as nodulosis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis, sudden death, reversible lymphomas, tumor lysis syndrome, soft tissue necrosis and osteonecrosis. Anaphylactoid reactions have been reported.
Trexall (Methotrexate sodium) Overdosage:
Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Leucovorin administration should begin as promptly as possible. As the time interval between methotrexate administration and leucovorin initiation increases, the effectiveness of leucovorin in counteracting toxicity decreases. Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin.
In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules. Generally speaking, neither hemodialysis nor peritoneal dialysis have been shown to improve methotrexate elimination. However, effective clearance of methotrexate has been reported with acute, intermittent hemodialysis using a high-flux dialyzer. (Wall, SM et al: 28(6):846-854, 1996).
Trexall (Methotrexate sodium) Handling And Disposal:
Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Trexall (Methotrexate sodium) How Supplied:
Dispense with a child-resistant closure in a well-closed container.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Protect from light.
Trexall (Methotrexate sodium) References:
1.Controlling occupational exposure to hazardous drugs (OSHA Work-Practice Guidelines). 1996; 53:1669-1685.
2.Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, US Government Printing Office, Washington, DC 20402.
3.AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. 1985; 253(11):1590-1592.
4.National Study Commission on Cytotoxic Exposure - Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc D, Chairman, National Study Commisssion on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston Massachusetts 02115.
5.Clinical Oncological Society of Australia: Guidelines and recommendations for safe handling of antineoplastic agents. 1983; 1:426-428.
6.Jones RB, et al. Safe handling of chemotherapeutic agents: A report from the Mount Sinai Medical Center. Ca - Sept/Oct 1983; 258-263.
7.American Society of Hospital Pharmacists technical assistance bulletin on handling cytotoxic and hazardous drugs. 1990; 47:1033-1049.
8.OSHA Work-Practice Guidelines for Personnel Dealing with Cytotoxic (Antineoplastic) Drugs. 1986; 43:1193-1204.
Revised OCTOBER 2005
BR-927, 928, 929, 945
Trexall (Methotrexate sodium) Principal Display Panel
Trexall (Methotrexate sodium) ™
(methotrexate tablets, USP)
5 mg
30 Tablets
Duramed
Rx only
Trexall (Methotrexate sodium) Principal Display Panel
Trexall (Methotrexate sodium) ™
(methotrexate tablets, USP)
7.5 mg
30 Tablets
Duramed
Rx only
Trexall (Methotrexate sodium) Principal Display Panel
Trexall (Methotrexate sodium) ™
(methotrexate tablets, USP)
10 mg
30 Tablets
Duramed
Rx only
Trexall (Methotrexate sodium) Principal Display Panel
Trexall (Methotrexate sodium) ™
(methotrexate tablets, USP)
15 mg
30 Tablets
Duramed
Rx only
