Rheumatrex (Methotrexate)

RHEUMATREX™

Wyeth-Ayerst

Methotrexate Sodium

Antirheumatic

Caution: Methotrexate should be used only by physicians whose knowledge and experience includes the use of antimetabolite therapy.

Because of the possibility of serious toxic reactions the patient should be informed by the physician of the risks involved and should be under a physician’s constant supervision.

Deaths have been reported with the use of methotrexate in the treatment of rheumatoid arthritis.

In the treatment of rheumatoid arthritis, methotrexate use should be restricted to patients with severe, recalcitrant, disabling disease, which is not adequately responsive to other forms of therapy, and only when the diagnosis has been established and after appropriate consultation.

Action And Clinical Pharmacology: Methotrexate has as its mechanism of action the competitive inhibition of the enzyme folic acid reductase. Folic acid must be reduced to tetrahydrofolic acid by this enzyme in the process of DNA synthesis and cellular replication. Methotrexate inhibits the reduction of folic acid and interferes with tissue-cell reproduction. In rheumatoid arthritis, the mechanism of action is unknown; it may affect immune function.

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). Data from long-term studies indicate that an initial clinical improvement is maintained for at least 2 years with continued therapy.

Absorption: In adults, oral absorption of methotrexate appears to be dose dependent. Peak serum levels are reached within 1 to 2 hours. At doses of 30 mg/mor less, methotrexate is generally well absorbed with a mean bioavailability of about 60%.

Distribution: Methotrexate is rapidly distributed throughout the body. In a study in oncology patients, methotrexate was distributed to total body water within 1 hour following i.v. or small oral doses. Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein bound. Laboratory studies demonstrate that it may be displaced from plasma albumin by various compounds including sulfonamides, salicylates, tetracyclines, chloramphenicol and phenytoin.

Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given orally.

In dogs, synovial fluid concentrations after oral dosing were higher in inflamed than uninflamed joints. Although salicylates did not interfere with this penetration, prior prednisone treatment reduced penetration into inflamed joint to the level of normal joints.

Metabolism: After absorption, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthase. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolite(s) vary among different cells and tissues. Methotrexate is partially metabolized by intestinal flora after oral administration.

Excretion: The terminal half-life reported for methotrexate is approximately 3 to 10 hours for patients receiving treatment for psoriasis or rheumatoid arthritis or low dose antineoplastic therapy (less than 30 mg/m.

Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. With i.v. administration, 58 to 92% of a 0.1 mg/kg dose was excreted in the urine within 24 hours. Oral administration gave only slightly lower rates of excretion. Repeated doses daily result in more sustained serum levels and some retention of methotrexate over each 24-hour period, which may result in accumulation of the drug within tissues. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed.

Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 and 30 mg. Impaired renal function as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels. Excellent correlation has been reported between methotrexate clearance and endogenous creatinine clearance.

Methotrexate clearance rates vary widely and are generally decreased at higher doses. Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity. It has been postulated that the toxicity of methotrexate for normal tissues is more dependent upon the duration of exposure to the drug rather than the peak level achieved. When a patient has delayed drug elimination due to compromised renal function, a third space effusion, or other causes, methotrexate serum concentrations may remain elevated for prolonged periods.

The potential for toxicity from delayed excretion is reduced by the administration of leucovorin during the final phase of methotrexate plasma elimination. Pharmacokinetic monitoring of methotrexate serum concentrations may help identify those patients at high risk for methotrexate toxicity and aid in proper adjustment of leucovorin dosing.

Methotrexate has been detected in human breast milk. The highest breast milk to plasma concentration ratio reached was 0.08:1.

Indications And Clinical Uses: In the management of selected adults with severe, active, classical or definite rheumatoid arthritis (American Rheumatism Association criteria) who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first line therapy including full dose NSAIDs and usually a trial of at least one or more disease-modifying antirheumatic drugs.

ASA, 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.

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.

Methotrexate has a long history of clinical use as a folate antagonist and is the most widely used antimetabolite in chemotherapy, and severe psoriasis.

In 1951, the use of a folate antagonist to treat rheumatoid arthritis, a nonmalignant disease was reported. Moderate to marked improvement in patients with rheumatoid arthritis given methotrexate in intermittent dosage has been reported. As shown in many subsequent studies, methotrexate is effective in the treatment of rheumatoid arthritis at doses much lower than those used in chemotherapy. The use of methotrexate in severe active rheumatoid arthritis has been discussed in an increasing number of publications including several recent review articles.

Short-term, placebo-controlled trials have established the efficacy of methotrexate sodium in recalcitrant rheumatoid arthritis. In a placebo-controlled study, patients who crossed over to methotrexate showed significant improvement in all clinical variables. For those crossed over to placebo from methotrexate an increase in the mean number of tender/painful joints was evident as early as 3 weeks and deterioration in other clinical variables was observed within 6 weeks after crossover to placebo.

In several long-term studies patients have shown continued disease control with acceptable toxicity and few withdrawals from treatment.

The improvement in disease activity produced by methotrexate in clinical studies became maximal after 6 months of treatment and was maintained for a number of years. Several investigators observed a reduction in steroid dose during long-term therapy. However, in patients who discontinued methotrexate, a severe flare of rheumatoid arthritis occurred.

A short-term study showed an increased effect of methotrexate was evident at 10 mg/m(15 to 22 mg) compared with half this amount and placebo.

In clinical trials versus auranofin, the response with methotrexate was consistently greater than that with auranofin for all measures of efficacy. About 44% of patients in the auranofin group discontinued treatment, 12 (8%) due to lack of efficacy, 37 (26%) due to toxicity and 14 (10%) for administrative or other reasons. This dropout rate was higher than for the methotrexate group as only 25% of patients discontinued treatment; 4 (3%) due to lack of efficacy, 17 (12%) due to toxicity, and 14 (10%) for administrative or other reasons.

In long-term prospective studies, data up to January 1989 show that out of 47 patients followed for more than 1 year, only 2 have withdrawn due to lack of efficacy (4%) and 2 due to adverse reactions (4%).

The results obtained by a variety of investigators suggest that a higher percentage of patients may be able to continue treatment with methotrexate than with other agents like gold and other antirheumatic drugs. In a life-table analysis, 78.7% of patients with rheumatoid arthritis remained on treatment with methotrexate after 12 months, a higher percentage than with other antirheumatic drugs. Other studies have shown similar favorable results for methotrexate.

The most common adverse effects seen in clinical trials were gastrointestinal disturbances and transient elevations of serum liver enzymes. Pulmonary toxicity is uncommon and may represent a hypersensitivity reaction. Incidence and severity of adverse experiences were similar for younger and older patients.

In summary, methotrexate represents an effective therapy in appropriately selected patients with severe refractory rheumatoid arthritis. It has been used for many years for thousands of patients in the clinical practice setting and in carefully controlled clinical trials. In short-term trials it has proven effective and well tolerated in most patients, in long-term trials continuingly effective and acceptable, and in comparative trials comparable to or better than available conventional therapy.

Contra-Indications: Pregnancy: Methotrexate has caused fetal deaths and congenital anomalies.

Blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia; liver disease including fibrosis, cirrhosis, recent or active hepatitis; active infectious disease and during immunization procedures; hypersensitivity to methotrexate; nursing mothers; overt or laboratory evidence of immunodeficiency syndrome(s).

Manufacturers’ Warnings In Clinical States: Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue methotrexate first and, if the lymphoma does not regress, appropriate treatment should be instituted.

Methotrexate should be used only by physicians whose knowledge and experience includes the use of antimetabolite therapy.

Because of the possibility of serious toxic reactions the patient should be informed by the physician of the risks involved and should be under a physician’s constant supervision.

In the treatment of rheumatoid arthritis, methotrexate use should be restricted to patients with severe, recalcitrant, disabling disease, which is not adequately responsive to other forms of therapy, and only when the diagnosis has been established and after appropriate consultation.

Periodic monitoring for toxicity, including CBC with differential and platelet counts, and liver and renal function tests is a mandatory part of methotrexate therapy. Periodic liver biopsies may be indicated in some situations. Patients at increased risk for impaired methotrexate elimination (e.g., renal dysfunction, pleural effusions or ascites) should be monitored more frequently (see Precautions, Laboratory Tests).

Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen, these are usually transient and asymptomatic, and also 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 often are not preceded by symptoms or abnormal liver function tests.

Methotrexate-induced lung disease is a potentially dangerous lesion, which may occur acutely at any time during therapy and which has been reported at doses as low as 7.5 mg/week. It is not always fully reversible. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.

Concomitant use of drugs with hepatotoxic potential should be avoided.

Methotrexate therapy should not be initiated in subjects who have an excessive alcohol intake.

Methotrexate is toxic to the hematopoietic system and may produce depression of bone marrow, anemia, leukopenia, thrombocytopenia and bleeding.

Unexpectedly severe (sometimes fatal) marrow suppression and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs.

For men and women in the fertile age, appropriate steps should be taken to avoid conception during methotrexate therapy. Methotrexate has been reported to cause fetal deaths and/or congenital anomalies. After discontinuation of methotrexate therapy, the risk of genetic abnormalities may persist. Thus, both men and women are advised to avoid intercourse leading to conception for an undefined period (at least 8 weeks) after taking the drug to ensure the re-establishment of the normal production of germinal cells.

Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.

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 have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, i.m., i.v., or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy (see Precautions, Organ System Toxicity, Skin).

Potentially, fatal opportunistic infections, especially P. carinii pneumonia, may occur with methotrexate therapy.

Methotrexate therapy in patients with impaired renal function should be undertaken with extreme caution, and at reduced dosages, because renal dysfunction will prolong methotrexate elimination.

Interruption of methotrexate therapy should be considered as a result of toxicity in the following situations: pulmonary symptoms (especially a dry nonproductive cough) or a nonspecific pneumonitis, persistent evidence of impaired liver function, suppression of the hematopoietic system, ulcerative stomatitis, significant hepatic fibrosis or cirrhosis, impaired renal function, severe diarrhea, pregnancy.

Precautions: Methotrexate has a high potential toxicity, usually dose-related. The physician should be familiar with the various characteristics of the drug and its established clinical usage. Patients undergoing therapy should be subject to appropriate supervision so that signs or symptoms of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay. Pretreatment and periodic tests and hematologic studies are essential to the use of methotrexate. Hematopoietic suppression may occur abruptly and while on an apparent safe dosage. Any profound drop in blood-cell count indicates immediate stopping of the drug and appropriate therapy.

In all instances where the use of methotrexate is considered for therapy, the physician must evaluate the need and usefulness of the drug against the risks of toxic effects or adverse reaction. Most adverse reactions are reversible if detected early. When such effects or reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken, according to the clinical judgment of the physician. Reinstitution of methotrexate therapy should be carried out with caution, with adequate consideration of further need for the drug and alertness as to possible recurrence of toxicity.

The toxicity profile of methotrexate has been studied in older individuals. Due to the potential for diminished hepatic and renal function in this population, these patients should be closely monitored for early signs of toxicity.

When methotrexate is discontinued a ‘flare’ of arthritis usually occurs within 3 to 6 weeks.

Both the physician and the pharmacist should emphasize to the patient the importance of the weekly dosage regimens; mistaken daily use may cause serious and sometimes life-threatening or fatal toxicity.

Methotrexate is excreted principally by the kidneys. Its use in the presence of impaired renal function may result in accumulation of toxic amounts or even additional renal damage. The patient’s renal status should be determined prior to and during methotrexate therapy and proper caution exercised should significant renal impairment be disclosed. Drug dosage should be reduced or discontinued until renal function is improved or restored.

If stomatitis, vomiting, diarrhea, or decreased fluid intake occur which may result in dehydration, methotrexate should be discontinued until recovery ensues.

Methotrexate should be used with extreme caution in the presence of infection, peptic ulcer, ulcerative colitis, debility, in extreme youth and old age, and in the presence of a significant third space (e.g., pleural effusion).

Methotrexate should be stopped if there is a significant drop in blood counts. Patients with profound granulocytopenia and fever should be evaluated immediately and usually require parenteral broad-spectrum antibiotic therapy. In severe bone marrow depression, blood or platelet transfusions may be necessary.

Pulmonary symptoms (especially a dry, nonproductive cough) or a nonspecific pneumonitis occurring during methotrexate therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Although clinically variable, the typical patient with methotrexate-induced lung disease presents with fever, cough, dyspnea, hypoxemia and an infiltrate on chest x-ray; infection needs to be excluded. This lesion can occur at all dosages.

Since it is reported that methotrexate may have an immunosuppressive action, this factor must be taken into consideration in evaluating the use of the drug where immune responses in a patient may be important or essential. Therefore, immunization may be ineffective and immunization with live virus is contraindicated.

Laboratory Tests: 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, monitoring of these parameters is recommended: hematology at least monthly, and liver and renal function every 1 to 3 months. More frequent monitoring is usually indicated during antineoplastic therapy. During initial or changing doses, or during periods of increased risk of elevated methotrexate blood levels (e.g., dehydration), more frequent monitoring may also be indicated.

A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver has not been established. 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 just prior to dosing and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation (see Organ System Toxicity, Hepatic).

Liver function tests, including serum albumin, should be performed periodically prior to dosing but are often normal in the face of developing fibrosis or cirrhosis. These lesions may be detectable only by biopsy.

When to perform a liver biopsy in rheumatoid arthritis patients has not been established, either in terms of cumulative methotrexate dose or duration of therapy.

Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available.

Drug Interactions: Methotrexate may be displaced from its protein binding sites by phenylbutazone, salicylates, phenytoin and sulfonamides. Renal tubular transport is diminished by probenecid, salicylates, and weak organic acids such as some NSAIDs. Oral antibiotics such as tetracycline, chloramphenicol and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria. Trimethoprim/sulfamethoxazole has been reported to increase bone marrow depression in a few patients receiving methotrexate. Therefore, caution should be used when NSAIDs, salicylates, and the aforementioned drugs are administered concomitantly with methotrexate.

In patients with rheumatoid arthritis, the controlled clinical trials have included concurrent use of constant dosage regimens of NSAIDs without observed problems. Therefore, until more is known about the NSAIDs/methotrexate interaction, it is recommended that methotrexate dosage be carefully controlled during treatment with NSAIDs.

Vitamin preparations containing folic acid or its derivatives may alter responses to methotrexate.

Organ System Toxicity: Potentially fatal opportunistic infections, especially P. carinii pneumonia, may occur with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility of P. carinii pneumonia should be considered.

Gastrointestinal: If vomiting, diarrhea, or stomatitis occur, which may result in dehydration, methotrexate should be discontinued until recovery occurs. Methotrexate should be used with extreme caution in the presence of peptic ulcer disease or ulcerative colitis.

Hematologic: Methotrexate can suppress hematopoiesis and cause anemia, leukopenia, and/or thrombocytopenia. In patients with malignancy and pre-existing hematopoietic impairment, the drug should be used with caution, if at all. In controlled clinical trials in rheumatoid arthritis (n=128).

In psoriasis and rheumatoid arthritis, methotrexate should be stopped immediately if there is a significant drop in blood counts. In the treatment of neoplastic diseases, methotrexate should be continued only if the potential benefit warrants the risk of severe myelosuppression. Patients with profound granulocytopenia and fever should be evaluated immediately and usually require parenteral broad-spectrum antibiotic therapy.

Hepatic: Methotrexate has the potential for acute (elevated transaminases) and chronic (fibrosis and cirrhosis) hepatoxicity. Chronic toxicity is potentially fatal; it generally has occurred after prolonged use (generally 2 years or more) and after a total dose of at least 1.5 g. 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. An accurate incidence rate has not been determined; the rate of progression and reversibility of lesions is not known. Special caution is indicated in the presence of pre-existing liver damage or impaired hepatic function.

In psoriasis, liver function tests, including serum albumin, should be performed periodically prior to dosing but are often normal in the face of developing fibrosis or cirrhosis. These lesions may be detectable only by biopsy. The usual recommendation is to obtain a liver biopsy at 1) pretherapy or shortly after initiation of therapy (2 to 4 months), 2) a total cumulative dose of 1.5 g, and 3) after each additional 1.5 g. Moderate fibrosis or any cirrhosis normally leads to discontinuation of 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 pretherapy. 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; other risk factors, similar to those observed in psoriasis, may be present in rheumatoid arthritis but have not been confirmed to date. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this population. There is a combined reported experience in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 g) and 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for early fibrosis and its use may increase these figures. It is unknown whether even longer use will increase these risks.

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 as per recommendations listed above. 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. Immunization may be ineffective 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. Hypogammaglobulinemia has been reported rarely.

Potentially fatal opportunistic infections, especially P. carinii pneumonia, may occur with methotrexate therapy. When a patient presents with pulmonary symptoms, the possibility of P. carinii pneumonia should be considered.

Neurologic: There have been reports of leukoencephalopathy following i.v. administration of methotrexate to patients who have had craniospinal irradiation. Serious neurotoxicity, frequently manifested as generalized or focal seizures, has been reported with unexpectedly increased frequency among pediatric patients with acute lymphoblastic leukemia who were treated with intermediate-dose i.v. methotrexate (1 g/m. Symptomatic patients were commonly noted to have leukoencephalopathy and/or microangiopathic calcifications on diagnostic imaging studies. Chronic leukoencephalopathy has also been reported in patients with osteosarcoma who received repeated doses of high-dose methotrexate with leucovorin rescue even without cranial irradiation. Discontinuation of methotrexate does not always result in complete recovery.

A transient acute neurologic syndrome has been observed in patients treated with high dosage regimens. Manifestations of this neurologic disorder may include behavioral abnormalities, focal sensorimotor signs and abnormal reflexes. The exact cause is unknown.

Pulmonary: Pulmonary symptoms (especially a dry nonproductive cough) or a nonspecific pneumonitis occurring during methotrexate therapy may be indicative of a potentially dangerous lesion and require interruption of treatment and careful investigation. Although clinically variable, the typical patient with methotrexate induced lung disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray; infection needs to be excluded. This lesion can occur at all dosages.

Renal: High doses of methotrexate used in the treatment of osteosarcoma may cause renal damage leading to acute renal failure. Nephrotoxicity is due primarily to the precipitation of methotrexate and 7-hydroxymethotrexate in the renal tubules. Close attention to renal function including adequate hydration, urine alkalinization and measurement of serum methotrexate and creatinine levels are essential for safe administration.

Skin: Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have been reported in children and adults, within days of oral, i.m., i.v., or intrathecal methotrexate administration. Reactions were noted after single or multiple, low, intermediate or high doses of methotrexate in patients with neoplastic and nonneoplastic diseases.

Other Precautions: Methotrexate should be used with extreme caution in the presence of debility.

Methotrexate exits slowly from third space compartments (e.g., pleural effusions or ascites). This results in a prolonged terminal plasma 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.

Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Radiation dermatitis and sunburn may be “recalled” by the use of methotrexate.

Adverse Reactions: The most common adverse reactions reported in studies of rheumatoid arthritis patients involved the gastrointestinal system. Symptoms included nausea, stomatitis, gastrointestinal discomfort, diarrhea, vomiting and anorexia. Clinical laboratory findings included elevation of liver enzymes and, occasionally, decreased white-cell counts. In general, the incidence and severity of side effects are considered to be dose-related.

The incidence of adverse reactions in double-blind studies of patients with rheumatoid arthritis treated with low-dose oral (7.5 to 15 mg/week) pulse methotrexate are listed below. Virtually all of these patients were on concomitant NSAIDs and some were also taking low dosages of corticosteroids.

Incidence greater than 10%: liver enzymes 15%, nausea/vomiting.

Incidence between 3 and 10%: stomatitis, headache, and thrombocytopenia.

Incidence between 1 and 3%: alopecia, dizziness, leukopenia and pancytopenia.

Incidence less than 1%: chest pain, coughing, epistaxis, pruritus, tinnitus, decreased hematocrit, headache, upper respiratory infection, anorexia, arthralgias, chest pain, dysuria, eye discomfort, fever, infection, sweating and vaginal discharge.

Other reactions, usually reported at higher dosage in antineoplastic chemotherapy are as follows: Skin: urticaria, photosensitivity, depigmentation, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, exfoliative dermatitis. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation.

Infections: There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and nonneoplastic diseases. P. carinii pneumonia was the most common infection. Other reported infections included nocardiosis, histoplasmosis, cryptococcosis, Herpes zoster, H. simplex hepatitis, and disseminated H. simplex.

Blood: anemia, hypogammaglobulinemia, hemorrhage from various sites, septicemia.

Alimentary: pharyngitis, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, hepatic toxicity resulting in acute liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis, or hepatic cirrhosis, gingivitis.

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

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

Pulmonary: interstitial pneumonitis deaths have been reported and chronic interstitial obstructive pulmonary disease has occasionally occurred.

CNS: drowsiness, blurred vision, leukoencephalopathy or encephalopathy. Aphasia, hemiparesis, paresis, and convulsions have also occurred. Following low doses, occasional patients have reported transient subtle cognitive dysfunction, mood alteration or unusual cranial sensations.

Other reactions attributed to the use of methotrexate such as metabolic changes, precipitation of diabetes, osteoporotic effects, loss of libido/impotence and even sudden death have been reported. Radiation dermatitis and sunburn may be ‘recalled’. A few cases of anaphylactoid reactions have been reported.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Discontinue methotrexate at the first sign of ulceration or bleeding, diarrhea or marked depression of hematopoietic system.

As soon as possible after an inadvertent overdosage of methotrexate, leucovorin should be given at 10 mg/mi.v. or i.m. every 6 hours until the serum methotrexate levels are below 108M. If there is adequate gastrointestinal function, doses subsequent to the initial dose may be given orally. Concomitant hydration (3 L/day) and urinary alkalinization with sodium bicarbonate should be employed. The bicarbonate dose should be adjusted to maintain a urinary pH at 7 or greater. Serum samples should be assayed for creatinine levels and methotrexate levels at 24-hour intervals. If the 24-hour serum creatinine level has increased 50% over baseline or if the 24-hour methotrexate level is >5´106M or the 48-hour methotrexate level is 9´107M or higher, the doses of leucovorin should be increased to 100 mg/mi.v. every 3 hours.

Dosage And Administration: The patient should be fully informed of the risks involved and should be under constant supervision of the physician. Assessment of hematologic, hepatic, renal and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting methotrexate therapy. Appropriate steps should be taken in men and women to avoid conception during methotrexate therapy.

Both the physician and the pharmacist should emphasize to the patient the importance of the weekly dosage regimens; mistaken daily use may cause serious and sometimes life-threatening or fatal toxicity.

All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects. Complete blood count with platelets should be evaluated 7 to 10 days later.

Recommended starting dosage schedules are: single oral doses of 7.5 mg once weekly or divided oral doses of 2.5 mg at 12-hour intervals for 3 doses given as a course once weekly.

Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.

The dosage in each schedule may be increased to 15 mg/week after 6 weeks in nonresponsive patients. If necessary dosage may be gradually increased further to achieve optimal response but not ordinarily to exceed a total weekly dosage of 20 mg.

Once response has been achieved, each schedule should be reduced, if possible, to the lowest possible amount of drug and with the longest possible rest period. Although rare, some patients may be maintained on a dose of 2.5 mg/week.

The optimal duration of therapy is unknown. Limited data available from long-term studies indicate that the initial clinical improvement is maintained for at least 2 years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks.

Safe Handling and Disposal: Methotrexate is a potent antineoplastic drug. Good medical practice will minimize exposure of persons involved with frequent handling of this drug as outlined below.

Handling: Methotrexate or solutions of methotrexate have no vesicant properties and do not show acute toxicity on topical contact with the skin or mucous membranes. However, persons involved with handling cytotoxic drugs should avoid contact with skin and inhalation of airborne particles. Personnel regularly involved in the preparation and handling of antineoplastics should have biannual examinations.

Disposal: Avoid contact with skin and inhalation of airborne particles by use of PVC gloves and disposable gowns and masks. Tablets: Place container and tablets in a plastic bag, seal, and mark as hazardous waste. Incinerate at 1 000°C or higher. If incineration is not available, dissolve tablets in a suitable quantity of 1 normal sodium hydroxide solution, and autoclave the mixture for 1 hour. Discard in the sewer system with copious amounts of running water.

Cleaning: Nondisposable equipment that has come in contact with methotrexate solutions may be rinsed with water and washed thoroughly with soap and water.

Availability And Storage: Each round, yellow, scored tablet, engraved “LL” and “M1”, contains: methotrexate sodium equivalent to methotrexate 2.5 mg. Nonmedicinal ingredients: lactose, monohydrate, magnesium stearate, (food grade) and starch pregelatinized. Dye- and tartrazine-free. Bottles of 100. Store at 15 to 30°C.

RHEUMATREX™ Wyeth-Ayerst Methotrexate Sodium Antirheumatic Caution: Methotrexate should be used only by physicians whose knowledge and experience includes the use of antimetabolite therapy. Because of the possibility of serious toxic reactions the patient should be informed by the physician of the risks involved and should be under a physician’s constant supervision. Deaths have been reported with the use of methotrexate in the treatment of rheumatoid arthritis. In the treatment of rheumatoid arthritis, methotrexate use should be restricted to patients with severe, recalcitrant, disabling disease, which is not adequately responsive to other forms of therapy, and only when the diagnosis has been established and after appropriate consultation.

Connected Diseases :

Arthritis, Rheumatoid

General Illness Information Common Name: ARTHRITIS, RHEUMATOID Medical Term: None Specified Description: A chronic auto-immune disease characterized by inflammation, swelling and pain in the joints,…