Side Effects of Trexall (methotrexate)

Trexall (methotrexate) is an antimetabolite drug used to treat cancer, psoriasis, inflammatory diseases of the skin, rheumatoid arthritis in adults and children, psoriatic arthritis, polymyositis, lupus, and to induce miscarriage in women with ectopic pregnancies.

It is capable of blocking the metabolism of cells. (Metabolism consists of the production and destruction of important components of the cell as well as the production of energy for use by the cell.) As a result of this effect, it has been found helpful in treating certain diseases associated with abnormally rapid cell growth, such as breast cancer and psoriasis. 

Trexall has been shown to be effective in inducing miscarriage, for example, in patients with ectopic pregnancy. This effect of Trexall is attributed to its action of killing rapidly growing cells such as those of the placenta. It also has been found very helpful in treating rheumatoid arthritis, although its mechanism of action in this illness is not known. It seems to work, in part, by altering immunity which may play a role in causing rheumatoid arthritis.

Common side effects of Trexall include

• mouth sores,
• stomach upset,
• headache,
• drowsiness,
• itching,
• skin rash,
• dizziness, and
• hair loss. 

Serious side effects of Trexall include low white blood counts and severe toxicity of the liver, kidneys and bone marrow, which require regular monitoring with blood tests. A dry, non-productive cough can be a result of rare lung toxicity.

Drug interactions of Trexall include

• azathioprine,
• chloramphenicol,
• hydroxychloroquine,
• retinol,
• tretinoin,
• isotretinoin,
• steroids,
• sulfa drugs,
• phenytoin,
• probenecid,
• tetracycline,
• theophylline,
• gold treatments,
• oral diabetes medications,
• penicillin antibiotics,
• stomach acid reducers,
• nonsteroidal anti-inflammatory drugs (NSAIDs), and
• salicylates such as aspirin. 

Trexall should not be used in pregnancy, as it can be toxic to the embryo and can cause fetal defects and spontaneous abortion (miscarriage). It should be discontinued prior to conception if used in either partner. 

Male patients should stop taking Trexall at least 3 months prior to a planned conception in order to avoid the theoretical risk of Trexall-induced abnormal sperm. Women should discontinue Trexall use for at least one ovulatory cycle before conception to reduce exposure of a developing ovarian follicle to Trexall. 

Trexall is excreted in breast milk and should not be used by breastfeeding mothers.

Methotrexate can cause severe toxicity which usually is related to the dose taken. The most frequent reactions include:

• mouth sores,
• stomach upset;
• low white blood counts;
• severe toxicity of the liver, kidneys and bone marrow, which require regular monitoring with blood tests;
• headache
• drowsiness

Methotrexate can cause itching, skin rash, dizziness, and hair loss. A dry, non-productive cough can be a result of rare lung toxicity.

IN GENERAL, THE INCIDENCE AND SEVERITY OF ACUTE SIDE EFFECTS ARE RELATED TO DOSE AND FREQUENCY OF ADMINISTRATION. THE MOST SERIOUS REACTIONS ARE DISCUSSED ABOVE UNDER ORGAN SYSTEM TOXICITY IN THE PRECAUTION SECTION. THAT SECTION SHOULD ALSO BE CONSULTED WHEN LOOKING FOR INFORMATION ABOUT ADVERSE REACTIONS WITH METHOTREXATE.

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.

Alimentary System: gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis.

Blood and Lymphatic System Disorders: suppressed hematopoiesis causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia and/or thrombocytopenia, lymphadenopathy and lymphoproliferative disorders (including reversible). Hypogammaglobulinemia has been reported rarely.

Cardiovascular: pericarditis, pericardial effusion, hypotension, and thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus).

Central Nervous System: headaches, drowsiness, blurred vision, transient blindness, speech impairment including dysarthria and aphasia, hemiparesis, paresis and convulsions have also occurred following administration of methotrexate. Following low doses, there have been occasional reports of transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy.

Patientdisorders, hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, decrease in serum albumin, liver enzyme elevations.

Infection: There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases. Pneumocystis carinii pneumonia was the most common opportunistic infection. There have also been reports of infections, pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis, herpes zoster, H. simplex hepatitis, and disseminated H. simplex.

Musculoskeletal System: stress fracture.

Ophthalmic: conjunctivitis, serious visual changes of unknown etiology.

Pulmonary System: respiratory fibrosis, respiratory failure, interstitial pneumonitis; deaths have been reported, and chronic interstitial obstructive pulmonary disease has occasionally occurred.

Skin: erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson Syndrome, skin necrosis, skin ulceration, and exfoliative dermatitis.

Urogenital System: severe nephropathy or renal failure, azotemia, cystitis, hematuria; defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, vaginal discharge, and gynecomastia; infertility, abortion, fetal defects.

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.

Adverse Reactions In Double-Blind Rheumatoid Arthritis Studies

The approximate incidences of methotrexate attributed (i.e., placebo rate subtracted) adverse reactions in 12 to 18 week double-blind studies of patients (n=128) with rheumatoid arthritis treated with lowdose oral (7.5 to 15 mg/week) pulse methotrexate, are listed below.

Virtually all of these patients were on concomitant nonsteroidal anti-inflammatory drugs and some were also taking low dosages of corticosteroids. Hepatic histology was not examined in these short-term studies.

Incidence greater than 10%: Elevated liver function tests 15%, nausea/vomiting 10%.

Incidence 3% to 10%: Stomatitis, thrombocytopenia, (platelet count less than 100,000/mm³).

Incidence 1% to 3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (WBC less than 3000/mm³), pancytopenia, dizziness.

Two other controlled trials of patients (n=680) with Rheumatoid Arthritis on 7.5 mg to 15 mg/wk oral doses showed an incidence of interstitial pneumonitis of 1%.

Other less common reactions included

• decreased hematocrit,
• headache,
• upper respiratory infection,
• anorexia,
• arthralgias,
• chest pain,
• coughing,
• dysuria,
• eye discomfort,
• epistaxis,
• fever,
• infection,
• sweating,
• tinnitus, and
• vaginal discharge.

Adverse Reactions In Psoriasis

There are no recent placebo-controlled trials in patients with psoriasis. There are two literature reports (Roenigk, 1969 and Nyfors, 1978) describing large series (n=204, 248) of psoriasis patients treated with methotrexate. Dosages ranged up to 25 mg per week and treatment was administered for up to four years. With the exception of alopecia, photosensitivity, and “burning of skin lesions” (each 3% to 10%), the adverse reaction rates in these reports were very similar to those in the rheumatoid arthritis studies. Rarely, painful plaque erosions may appear.

Adverse Reactions In JRA Studies

The approximate incidences of adverse reactions reported in pediatric patients with JRA treated with oral, weekly doses of methotrexate (5 to 20 mg/m²/wk or 0.1 to 0.65 mg/kg/wk) were as follows (virtually all patients were receiving concomitant nonsteroidal anti-inflammatory drugs, and some also were taking low doses of corticosteroids):

• elevated liver function tests, 14%;
• gastrointestinal reactions  (e.g., nausea, vomiting, diarrhea), 11%;
• stomatitis, 2%;
• leukopenia, 2%;
• headache, 1.2%;
• alopecia, 0.5%;
• dizziness, 0.2%; and
• rash, 0.2%.

Although there is experience with dosing up to 30 mg/m²/wk in JRA, the published data for doses above 20 mg/m²/wk are too limited to provide reliable estimates of adverse reaction rates.

• 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 20 mg/wk) 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 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, sulfa-salazine) 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.
• Certain side effects such as mouth sores may be reduced by folate supplementation with methotrexate.
• Trimethoprim/sulfa-methoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by an additive antifolate effect.