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General: Because of the possibility of serious toxic reactions (which can be fatal), methotrexate should be used only in neoplastic diseases (as indicated), or in patients with severe, recalcitrant, disabling psoriasis or rheumatoid arthritis that is not adequately responsive to other forms of therapy. The patient should be informed by the physician of the risks involved and should be under a physician's constant supervision. Refer to Use in the Elderly and Use in Children as follows for specific warnings.
It should be emphasized to the patient treated for rheumatoid arthritis and psoriasis that the recommended dose must be taken weekly, and that mistaken daily use of the recommended dose has led to fatal toxicity (see Dosage & Administration and Overdosage).
Methotrexate has been reported to cause fetal death and/or congenital anomalies. It is not recommended for the treatment of neoplastic diseases in women of childbearing potential.
Like other cytotoxic drugs, methotrexate may induce "tumor lysis syndrome" in patients with rapidly growing tumors. Appropriate supportive and pharmacologic measures may prevent or alleviate this complication.
Severe, occasionally fatal, skin reactions such as Stevens-Johnson Syndrome, toxic epidermal necrolysis (Lyell's syndrome), have been reported following single or multiple doses of methotrexate.
Methotrexate causes hepatotoxicity, liver fibrosis, and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. Periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.
Methotrexate has caused reactivation of hepatitis B infection or worsening of hepatitis C infections, in some cases resulting in death. Some cases of hepatitis B reactivation have occurred after discontinuation of methotrexate. Clinical and laboratory evaluation should be performed to evaluate preexisting liver disease in patients with prior hepatitis B or C infections. Based on these evaluations, treatment with methotrexate may not be appropriate for some patients.
Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis and pleural effusion, may occur at any time during therapy and has been reported at low doses. It is not always fully reversible, and fatalities have been reported. Rheumatoid arthritis patients are at risk to develop rheumatoid lung disease, which is often associated with interstitial pulmonary disease. Methotrexate may exacerbate this underlying lung disease. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.
Diarrhea and ulcerative stomatitis require interruption of therapy, otherwise, hemorrhagic enteritis and death from intestinal perforation may occur. Methotrexate should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis.
Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
Methotrexate exits slowly from third space compartments (e.g., pleural effusions, ascites). This results in a prolonged terminal half-life and unexpected toxicity. In patients with significant third space accumulations, it is advisable to evacuate the fluid before treatment and to monitor plasma methotrexate levels.
Methotrexate therapy in patients with impaired renal function should be undertaken with extreme caution, and at reduced doses, because impairment of renal function will decrease methotrexate elimination.
It is necessary to follow patients on methotrexate closely. Methotrexate has the potential for serious toxicity. Toxic effects may be related in frequency and severity to dose or frequency of administration, but has been seen at all doses and can occur at any time during therapy. Most adverse reactions are reversible if detected early. When such reactions do occur, the dosing should be reduced or discontinued and appropriate corrective measures should be taken. 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.
Patients should be informed of the potential benefits and risks in the use of methotrexate (including the early signs and symptoms of toxicity), the need to see their physician promptly if they occur, and of the need for close follow-up, including periodic laboratory tests, to monitor toxicity.
The use of methotrexate high-dose regimens (≥500 mg/m2) recommended for osteosarcoma requires meticulous care (see Dosage & Administration). High dosing regimens for other neoplastic diseases are investigational and a therapeutic advantage has not been established.
Malignant lymphomas, may occur in patients receiving low-dose methotrexate. These lymphomas may regress following withdrawal of methotrexate without requiring treatment.
Folate deficiency states may increase methotrexate toxicity.
Organ system toxicity: Gastrointestinal: If vomiting, diarrhea, or stomatitis occur, resulting in dehydration, supportive therapy should be instituted and methotrexate discontinuation until recovery occurs, should be considered.
Hematologic: Methotrexate can suppress hematopoiesis and cause anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. Methotrexate should be used with caution in patients with preexisting hematopoietic impairment (see Interactions). The nadir of circulating leukocytes, neutrophils and platelets usually occurs between 5 to 13 days after an IV bolus dose (with recovery between 14 to 28 days). Leukocytes and neutrophils may occasionally show two depressions, the first occurring in 4 to 7 days and a second nadir after 12 to 21 days, followed by recovery. Clinical sequelae such as fever, infections and hemorrhage from various sites may be expected. In the treatment of neoplastic diseases, methotrexate should be continued only if the potential benefit outweighs the risk of severe myelosuppression. In psoriasis and rheumatoid arthritis, methotrexate should be stopped immediately if there is a significant drop in blood cell counts.
Hepatic: Methotrexate has the potential for acute hepatitis and chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal; it generally has occurred after prolonged use (generally two years or more) and after a total cumulative dose of at least 1.5 grams. In studies in psoriatic patients, hepatotoxicity appeared to be a function of total cumulative dose and appeared to be enhanced by alcoholism, obesity, diabetes and advanced age.
Transient abnormalities of liver parameters are observed frequently after methotrexate administration and are usually not a reason for modification of methotrexate therapy. Persistent liver abnormalities, and/or decrease of serum albumin may be indicators of serious liver toxicity.
In psoriasis, liver damage and function tests, including serum albumin and prothrombin time, should be performed several times prior to dosing. Liver function tests are often normal in developing fibrosis or cirrhosis. These lesions may be detectable only by biopsy. It is recommended to obtain a liver biopsy at: 1) before start of therapy or shortly after initiation of therapy (2-4 months); 2) after a total cumulative dose of 1.5 grams; and 3) after each additional 1.0 to 1.5 grams. In case of moderate fibrosis or any cirrhosis, discontinue the drug; mild fibrosis normally suggests a repeat biopsy in 6 months. Milder histologic findings, such as fatty change and low grade portal inflammation are relatively common before the start of therapy. Although these mild changes are usually not a reason to avoid or discontinue methotrexate therapy, the drug should be used with caution.
In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid population. Liver function tests should be performed at baseline and at 4 to 8 week intervals in patients receiving methotrexate for rheumatoid arthritis. Pretreatment liver biopsy should be performed for patients with a history of excessive alcohol consumption, persistently abnormal baseline liver function test values, or chronic hepatitis B or C infection. During therapy, liver biopsy should be performed if there are persistent liver function test abnormalities, or there is a decrease in serum albumin below the normal range (in the setting of well controlled rheumatoid arthritis).
If the results of a liver biopsy show mild changes (Roenigk grades I, II, IIIa), methotrexate may be continued and the patient monitored according to the recommendations listed previously. Methotrexate should be discontinued in any patient who displays persistently abnormal liver function tests and refuses liver biopsy, or in any patient whose liver biopsy shows moderate to severe changes (Roenigk grade IIIb or IV).
Infection or immunologic states: Methotrexate should be used with extreme caution in the presence of active infection, and is usually contraindicated in patients with overt or laboratory evidence of immunodeficiency syndromes.
Potentially fatal opportunistic infections, including Pneumocystis carinii pneumonia, may occur with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered.
Immunization: Vaccinations may be less immunogenic when given during methotrexate therapy. Immunization with live virus vaccines is generally not recommended. There have been reports of disseminated vaccinia infections after smallpox immunization in patients receiving methotrexate therapy.
Neurologic: There have been reports of leukoencephalopathy following intravenous administration of methotrexate to patients who have had craniospinal irradiation. Refer to Use in Children as follows for specific warnings. Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic calcifications on diagnostic imaging studies.
Chronic leukoencephalopathy has also been reported in patients who received repeated doses of high-dose methotrexate with folinic acid rescue even without cranial irradiation. There are also reports of leukoencephalopathy in patients who received oral methotrexate.
Discontinuation of methotrexate does not always result in complete recovery.
A transient acute neurologic syndrome has been observed in patients treated with high dosing regimens. Manifestations of this neurologic syndrome may include behavioral abnormalities, focal sensorimotor signs, including transient blindness, and abnormal reflexes. The exact cause is unknown.
Cases of severe neurological adverse reactions that ranged from headache to paralysis, coma and stroke-like episodes have been reported mostly in juveniles and adolescents given methotrexate in combination with cytarabine.
Pulmonary: Pulmonary signs and symptoms, e.g., a dry nonproductive cough, fever, cough, chest pain, dyspnea, hypoxemia, and an infiltrate on chest X-ray, or a nonspecific pneumonitis occurring during methotrexate therapy, may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Methotrexate induced pneumonitis can occur at all doses. Infection (including pneumonia) needs to be excluded.
Renal: Methotrexate may cause renal damage that may lead to acute renal failure. Close attention to renal function including adequate hydration, urine alkalinization, and measurement of serum methotrexate and renal function are recommended.
Concomitant use of proton pump inhibitors (PPIs) and high dose methotrexate should be avoided, especially in patients with renal impairment.
Skin: Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis (Lyell's Syndrome), Stevens-Johnson syndrome, and erythema multiforme, have been reported within days of oral methotrexate administration.
Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Radiation dermatitis and sunburn may be "recalled" by the use of methotrexate.
Laboratory monitoring: General: 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, hepatitis B or C infection testing, renal function tests; and a chest X-ray.
During therapy of rheumatoid arthritis and psoriasis, monitoring of the following parameters is recommended: hematology at least monthly, hepatic enzyme levels and renal function every 1 to 2 months. More frequent monitoring is usually indicated during antineoplastic therapy. During initial or change in dosing, or during periods of increased risk of elevated methotrexate blood levels (e.g., dehydration), more frequent monitoring may also be indicated.
Pulmonary function tests: Pulmonary function tests may be useful if lung disease (e.g., interstitial pneumonitis) is suspected, especially if baseline measurements are available.
Methotrexate level: Serum methotrexate level monitoring can significantly reduce toxicity and mortality by allowing the adjustment of methotrexate dosing and the implementation of appropriate rescue measures.
Patients subject to the following conditions are predisposed to developing elevated or prolonged methotrexate levels and benefit from routine monitoring of levels: e.g., pleural effusion, ascites, gastrointestinal tract obstruction, previous cisplatin therapy, dehydration, aciduria, impaired renal function.
Some patients may have delayed methotrexate clearance in the absence of these features. It is important that patients be identified within 48 hours since methotrexate toxicity may not be reversible if adequate folinic acid rescue is delayed for more than 42 to 48 hours.
The method of monitoring methotrexate concentrations varies from institution to institution. Monitoring of methotrexate concentrations should include determination of a methotrexate level at 24, 48, or 72 hours, and assessment of the rate of decline in methotrexate concentrations (to determine how long to continue folinic acid rescue).
Effects on ability to drive and use machines: Some of the effects reported in Adverse Reactions (e.g., dizziness, fatigue) may have an influence on the ability to drive and use machines.
Use in Children: Safety and effectiveness in pediatric patients have been established only in cancer chemotherapy.
Use in the Elderly: Fatal toxicities related to inadvertent daily rather than weekly dosing have been reported, particularly in elderly patients. It should be emphasized to the patient that the recommended dose is taken weekly for rheumatoid arthritis and psoriasis (see Dosage & Administration).
