METHOTREXATE TABLETS USP
Action And Clinical Pharmacology: Methotrexate is an antimetabolite which competitively inhibits the enzyme folic acid reductase. During DNA synthesis and cellular reproduction, folic acid is reduced to tetrahydrofolic acid by the enzyme folic acid reductase. By interfering with the reduction of folic acid, methotrexate interferes with tissue cell reproduction. Generally, the most sensitive cells to the antimetabolite effect of methotrexate are those cells which are most actively proliferating such as malignant cells, dermal epithelium, buccal and intestinal mucosa, bone marrow, fetal cells and cells of the urinary bladder. Because the proliferation of cells in malignant tissues is greater than in most normal tissues, methotrexate may impair the growth of the malignant tissues without causing irreversible damage to normal tissues.
The basis for the use of methotrexate in psoriasis lies in the fact that the rate of production of the epithelial cells in this skin condition are greatly increased over normal and thus methotrexate affects the psoriatic tissues which are reproducing at a greater rate than the normal skin cells.
The mechanism of action of methotrexate in rheumatoid arthritis has not been elucidated; it may affect immune function. In vitro studies suggest methotrexate may inhibit DNA precursor uptake by stimulated mononuclear cells. One report in an animal polyarthritis model has shown partial correction of spleen cell hyporesponsiveness and suppression of interleukin 2 production, as responses to methotrexate.
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.
Pharmacokinetics: The absorption of methotrexate orally administered in small doses (approximately 30 mg/m is rapid and complete, whereas with oral doses in excess of 80 mg/mabsorption is less than complete. About a third of an oral dose of methotrexate is metabolized by intestinal bacteria during absorption. Pretreatment with oral neomycin decreases and with kanamycin increases the gastrointestinal absorption of oral methotrexate.
The plasma disposition of methotrexate is multiexponential. Due to differences in sampling schedule and assay methods, widely varying estimates of elimination half-life (t 1/2b) of 6 to 69 hours of methotrexate have been reported. The long half-life may either be due to enterohepatic circulation of methotrexate and/or its metabolites or a slow elimination of dihydrofolate reductase (DHFR) bound methotrexate. The plasma clearance of methotrexate following small clinical doses is about 80 mL/min but may become saturated at high doses (20 g). During high dose infusions, the peak plasma level is proportional to dose up to 200 mg/kg. The pharmacokinetics of low doses of methotrexate in patients with rheumatoid arthritis closely resembles the pattern in patients receiving intermediate and high doses for the treatment of neoplasia.
Methotrexate is transported across cellular membranes via a carrier-mediated active process. At high concentrations, when the carrier route is saturated, passive diffusion assumes greater importance.
Methotrexate is not highly bound to plasma proteins (approximately 50%). However, being highly ionized at physiological pH, the drug does not accumulate in the cerebrospinal fluid to any appreciable extent, necessitating intrathecal administration in the treatment of cerebral and meningeal metastases.
Renal excretion is the major route of elimination of methotrexate (approximately 80%), the drug being actively secreted in the renal tubule by the general organic acid transport system. Hence, the renal clearance of methotrexate is decreased by the concomitant administration of organic acids, such as salicylate. The renal clearance of methotrexate is correlated with endogenous creatinine clearance.
Biliary excretion of methotrexate constitutes less than 10% of the administered dose. Other extrarenal routes of excretion such as secretion into human breast milk and saliva are negligible.
Methotrexate is extensively metabolized intracellularly to polyglutamate derivates. The major metabolite is 4-amino-4-deoxy-N0methylpteroic acid. Small amounts (approximately 11%) of 7-hydroxymethotrexate have also been found in urine of patients receiving high dose methotrexate therapy. Except for the poly-y-glutamates, all of the reported metabolites are less effective than methotrexate as an inhibitor of dihydrofolate reductase. As determined by inhibition of DNA synthesis, normal tissues are sensitive to low levels of methotrexate (108). Furthermore, toxicity with methotrexate is related to duration of exposure as well as to the dose or plasma concentration.
Resistance in tumor cells is related to one or more of the following biochemical phenomena: decreased membrane transport of methotrexate, altered dihydrofolate reductase, which has reduced affinity for methotrexate, increased levels of dihydrofolate reductase due to amplification of the gene controlling dihydrofolate reductase synthesis, decreased formation of methotrexate polyglutamates and decreased activity of thymidylate synthetase.
Indications And Clinical Uses: Neoplastic Diseases: For the treatment of gestational choriocarcinoma, and in patients with chorioadenoma destruens and hydatidiform mole.
For the palliation of acute and subacute lymphocytic leukemia. The greatest effect of methotrexate is in the palliation of acute lymphoblastic (stem-cell) leukemia.
Methotrexate is also effective in the treatment of the advanced stages (III and IV, Peters Staging System) of lymphosarcoma, especially in children, and in advanced stages of mycosis fungoides.
Psoriasis: For the symptomatic control of severe, recalcitrant, disabling disease which has not responded adequately to other therapies, following established diagnosis and after dermatologic consultation. It is important to determine that a psoriasis “flare” is not due to undiagnosed disease affecting immune response.
Rheumatoid Arthritis: In the management of selected adults with severe, active, classical or definite rheumatoid arthritis (American Rheumatism Association criteria), who have shown insufficient response to an adequate trial of first-line therapy with a nonsteroidal anti-inflammatory drug (NSAID), and usually a trial of at least one disease modifying antirheumatic drug (DMARD).
ASA, NSAIDs and/or low dose steroids may be continued, although increased toxicity with concomitant NSAIDs including salicylates may be expected (see Pharmacology, Pharmacokinetics and Precautions, Drug Interactions). Steroids must be reduced gradually in patients who respond to methotrexate. Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine, immunosuppressive therapy or cytotoxic agents has not been studied and may increase the risk of toxicity. Physiotherapy, where indicated, should be continued.
Contra-Indications: Methotrexate is contraindicated in the following conditions:
Pregnancy and Lactation: Methotrexate has caused fetal deaths and congenital abnormalities.
The presence of pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, anemia. Kidney disease. Liver disease including fibrosis, cirrhosis, recent or active hepatitis, or known alcoholism in patients with rheumatoid arthritis or psoriasis. Active infectious disease and during immunization procedures. Active peptic ulcer. Ulcerative colitis. Overt or laboratory evidence of immunodeficiency syndromes in patients with psoriasis or rheumatoid arthritis. Known hypersensitivity to methotrexate.
Manufacturers’ Warnings In Clinical States: Caution: Methotrexate is a potent and potentially fatal drug and should be used only by physicians experienced with cancer chemotherapeutic drugs (see Precautions). Renal and hepatic function must be assessed prior to therapy and frequently during therapy. Blood counts should be taken once or twice weekly. Patients 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.
Because of the possibility of serious toxicity, the use of methotrexate in psoriasis and rheumatoid arthritis is indicated only in the symptomatic control of severe, recalcitrant, disabling disease, which is not adequately responsive to other forms of therapy, and only after the diagnosis has been established and the need for therapy has been confirmed by appropriate consultation.
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.
Methotrexate therapy is not recommended in patients who are known to ingest excessive quantities of alcohol. The concomitant use of hepatotoxic drugs and alcohol should be avoided.
During the treatment of psoriasis with methotrexate, deaths have been reported. Although the reasons for the sudden deaths have not been completely explained, it appears that they may be due to hypersensitivity reactions.
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.
Methotrexate is toxic to the hematopoietic system and may produce depression of the 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.
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.
The concomitant use of nonsteroidal anti-inflammatory drugs may potentiate methotrexate toxicity.
In men and women of fertile age, steps should be taken to avoid conception during methotrexate therapy. The risk of genetic abnormalities may persist after discontinuing methotrexate therapy. Thus, it is advised that both men and women avoid intercourse leading to conception for an indefinite period (at least 8 weeks) after taking methotrexate to ensure the reestablishment of normal germinal cells.
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).
Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.
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 as a result of toxicity is indicated in the following situations: ulcerative stomatitis, severe diarrhea, hemorrhagic enteritis, hepatic fibrosis or cirrhosis, impaired liver function, impaired renal function, suppression of the hematopoietic system, pulmonary symptoms (especially a dry non-productive cough) or a non-specific pneumonitis, pregnancy.
Precautions: General: Methotrexate has a high potential for toxicity which is usually dose related. 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.
Methotrexate patients should be kept under appropriate supervision so that signs and symptoms of toxicity or adverse effects may be detected and evaluated as early as possible.
The use of methotrexate requires pretreatment and periodic hematologic evaluations as a result of its hematopoietic suppressive effects. Hematopoietic suppression may occur abruptly and while on an apparently safe dosage. In severe bone marow depression, blood or platelet transfusions may be necessary.
In rheumatoid arthritis and psoriasis, 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 risks of severe myelosuppression. Patients with profound granulocytopenia and fever should be evaluated immediately and usually require parenteral broad-spectrum antibiotic therapy.
The drug should be used with caution, if at all, in patients with malignant disease in which there is pre-existing bone marrow aplasia, leukopenia, thrombocytopenia or anemia.
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, these patients should be closely monitored for early signs of toxicity and relatively low doses should be considered.
Because methotrexate is excreted primarily by the kidneys, impaired renal function can lead to drug accumulation with resultant toxicity or even additional renal damage. Therefore, pre-existing kidney disease is considered a contraindication to methotrexate therapy. It is recommended that the renal status of the patients proposed for methotrexate therapy be determined prior to beginning therapy and at appropriate intervals during therapy. Caution should be taken if significant renal damage is present, and 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.
Use methotrexate with extreme caution when infection is present and in patients with peptic ulcer, ulcerative colitis or general debilitation. Also exercise caution with the use of methotrexate in young children, the elderly and in the presence of a significant third space (e.g. pleural effusion).
Bacterial infection may be a threat or may occur if profound leukopenia occurs during therapy. In this instance the drug should be discontinued and appropriate antibiotic therapy instituted. If severe bone marrow depression occurs, blood or platelet transfusions may be required.
The possible immunosuppressant action of methotrexate should be taken into consideration when considering the use of the drug in patients where immune responses are important or essential. Therefore, immunization may be ineffective and immunization with live virus is contraindicated.
When considering the use of methotrexate for chemotherapy, clinicians must evaluate the need and potential value of the drug against risks, adverse reactions or toxic effects.
The physician and pharmacist should emphasize to the patient with rheumatoid arthritis, that the recommended dose is taken weekly, and that mistaken daily use of the recommended dose has led to fatal toxicity (see Information for the Patient). When methotrexate is discontinued, a “flare” of arthritis usually occurs within 3 to 6 weeks.
Laboratory Tests: The following laboratory tests should be carried out as part of the clinical evaluation and monitoring of patients on methotrexate therapy: complete hemogram, hematocrit, urinalysis, renal function tests and liver function tests. Periodic liver biopsy may be indicated in some situations. A chest x-ray is recommended.
Tests should be performed prior to, during and after termination of therapy. If high-dose, long-term therapy is used, it is imperative that liver biopsy and bone marrow aspiration studies be completed.
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 causes 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.
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.
Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if baseline measurements are available.
Drug Interactions: Methotrexate is bound in part to serum albumin after absorption, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, sulfonamides and phenytoin. These drugs, especially salicylates and sulfonamides, whether hypoglycemic or diuretic, should not be given concurrently until the significance of these findings is established.
Nonsteroidal anti-inflammatory drugs should not be administered prior to or concomitantly with the high doses of methotrexate used in the treatment of osteosarcoma. Concomitant administration of some NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, thereby enhancing 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 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.
Vitamin preparations containing folic acid or its derivatives may alter responses to methotrexate.
Oral antibiotics such as tetracycline, chloramphenicol and non-absorbable 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.
Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by an additive antifolate effect.
Adverse Reactions: The most common adverse reactions include ulcerative stomatitis, leukopenia, nausea and abdominal distress. Others reported are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection. In general, the incidence and severity of side effects are considered to be dose-related. Adverse reactions as reported for the various systems are as follows: Skin: erythematous rashes, pruritus, urticaria, photosensitivity, depigmentation, alopecia, ecchymosis, telangiectasia, acne, furunculosis. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Radiation dermatitis and sunburn may be reactivated by methotrexate.
Blood: bone marrow depression, leukopenia, thrombocytopenia, anemia, hypogammaglobulinemia, hemorrhage from various sites, septicemia.
Alimentary: gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, significant elevation of liver enzymes, hepatic toxicity resulting in acute liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis or hepatic cirrhosis.
Urogenital: renal failure, azotemia, cystitis, hematuria, defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, infertility, abortion, fetal defects, severe nephropathy.
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.
CNS: headaches, drowsiness, blurred vision, dizziness, tinnitus. Aphasia, hemiparesis, paresis and convulsions have occurred, possibly related to hemorrhage or to complications from intra-arterial catheterization. Convulsion, paresis and Guillain-Barre syndrome, and increased cerebrospinal fluid pressure have followed intrathecal administration. Following low doses, occasional patients have reported transient subtle cognitive dysfunction, mood alteration or unusual cranial sensations.
Other reactions related to or attributed to the use of methotrexate, such as pneumonitis, metabolic changes, precipitating diabetes, osteoporotic effects, loss of libido/impotence, abnormal tissue cell changes and even sudden death have been reported. Although not completely explained as yet, the sudden death would appear to point to the possibility of hypersensitivity reactions. A few cases of anaphylactoid reactions have been reported.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Discontinue or reduce dosage at the first sign of ulceration or bleeding, diarrhea or marked depression of hematopoietic system. 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. The bicarbonate dose should be adjusted to maintain a urinary pH at 7 or greater.
Leucovorin (citrovorum factor) is a potent agent for neutralizing the immediate toxic effects of methotrexate on the hematopoietic system. When large doses or overdoses are given, calcium leucovorin may be administered by i.v. infusion in doses up to 75 mg within 12 hours, followed by 12 mg i.m. every 6 hours for 4 doses. Where average doses of methotrexate appear to have an adverse effect, 6 to 12 mg of leucovorin calcium may be given i.m. every 6 hours for 4 doses. In general, where overdosage is suspected, the dose of leucovorin should be equal to or higher than the dose of methotrexate and is best administered within the first hours. Use of leucovorin calcium after an hour’s delay is much less effective.
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 ´ 106 or the 48 hour methotrexate level is 9 ´ 107 or higher, the doses of leucovorin should be increased to 100 mg/mi.v. every 3 hours until the methotrexate level is
Dosage And Administration: Neoplastic Disease: Absorption of methotrexate tablets is rapid, and effective serum levels are obtained in 1 to 2 hours. Alternatively, methotrexate sodium parenteral may be given by i.m., i.v. intra-arterial or intrathecal route (see package insert or product monograph for Methotrexate Sodium Injection Faulding).
A guideline ratio of 1:30 is given for the conversion of mg/kg body weight to mg/mof body surface area. The conversion factor actually varies between 1:20 and 1:40, depending on age and body build.
Choriocarcinoma and Similar Trophoblastic Diseases: Methotrexate is administered in doses of 15 to 30 mg daily for a 5-day course. Such courses are usually repeated for 3 to 5 times, as required, with rest periods of 1 or more weeks interposed between courses until any manifesting toxic symptoms subside. The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotrophin (CGH), which should return to normal or less than 50 IU/24 hours, usually after the third or fourth course, with a complete resolution of measurable lesions in 4 to 6 weeks. One to 2 courses of methotrexate after normalization of CGH are usually recommended. Before each course of the drug, careful clinical assessment is essential. Cyclic combination therapy of methotrexate with other anti-tumor drugs has been reported as being useful.
Since hydatidiform mole may precede or be followed by choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended. Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole. Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma.
Leukemia: Acute lymphatic (lymphoblastic) leukemia in children and young adolescents is the most responsive. In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common. In chronic lymphatic leukemia, the prognosis for adequate response is less encouraging.
Methotrexate alone or in combination with steroids was used initially for induction of remission of lymphoblastic leukemia. More recently, corticosteroid therapy in combination with other antileukemic drugs or in cyclic combinations with methotrexate appears to produce rapid and effective remissions. When used for induction, methotrexate in doses of 3.3 mg/min combination with prednisone 60 mg/m given daily, produced remission in 50% of patients treated, usually within a period of 4 to 6 weeks. Methotrexate alone or in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions. When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated as follows: Methotrexate is administered 2 times weekly in doses of 30 mg/m If and when relapse occurs, reinduction of remission can usually be obtained by repeating the initial induction regime. A variety of dosage schedules for both induction and maintenance of remission with various combinations of alkylating and antifolic agents, have been proposed. Multiple drug therapy with several agents, including methotrexate, given concomitantly is gaining increasing support in both the acute and chronic forms of leukemia. The physician should familiarize himself with new advances in antileukemia therapy.
Acute granulocytic leukemia is rare in children but common in adults. This form of leukemia responds poorly to chemotherapy and remissions are short with relapses common, and resistance to therapy develops rapidly.
Lymphomas: In Burkitt’s tumor, stages I to II, methotrexate has produced prolonged remissions in some cases. Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days. In stage III, methotrexate is commonly given concomitantly with other antitumor agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods. Lymphosarcomas in stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 mg to 2.5 mg/kg daily. Hodgkin’s disease responds poorly to methotrexate and to most types of chemotherapy.
Mycosis Fungoides: Therapy with methotrexate appears to produce clinical remission in one-half of the cases treated. Dosage is usually 2.5 to 10 mg daily by mouth for weeks or months. Dose levels of drug and adjustment of dose regimen with reduction or cessation of drug are guided by patient response and hematologic monitoring.
Psoriasis Chemotherapy: The patient should be fully informed of the risks involved and should be under constant supervision of the physician.
Methotrexate therapy should be restricted to patients whose psoriasis is so extensive or severe that it seriously interferes with physical, emotional or economic well being and is not adequately controlled by standard, topically applied antipsoriatic therapy. Methotrexate therapy has been widely used for patients and has provided effective therapy. Most studies indicate that about three quarters of patients benefit from the treatment. Methotrexate tablets may be used for the treatment of psoriasis. Either of the following are dosage schedules recommended: 1. Weekly intermittent large doses. 2. Divided doses, intermittent over 36 hours. These schedules should be continually tailored to the individual patient. Example dose schedules cited below pertain to an average 70 kg adult. An initial test dose 1 week prior to initiation of therapy is recommended to detect any idiosyncrasy.
Recommended Starting Dose Schedules: Weekly Single Oral Dose Schedule: 10 to 25 mg/week until adequate response is achieved. With this dosage schedule, 50 mg/week should ordinarily not be exceeded.
Divided Oral Dose Schedule: 2.5 mg at 12-hour intervals for 3 doses or at 8-hour intervals for 4 doses each week. With this dosage schedule, 30 mg/week should not be exceeded.
Dosage may be gradually adjusted to achieve optimal clinical response, but not to exceed the maximum stated for each schedule. Once optimal clinical response has been achieved, the dosage should be reduced to the lowest amount of drug and to the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy, which should be encouraged.
Assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests (such as CBC, urinalysis, serum creatinine, liver function studies and liver biopsy) before beginning methotrexate therapy and before re-instituting methotrexate therapy after a rest period. Appropriate steps should be taken to avoid conception during and for at least 8 weeks following methotrexate therapy.
Rheumatoid Arthritis: The patient should be fully informed of the risks involved and should be under constant supervision by 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 berfore reinstituting methotrexate therapy (see Precautions). Appropriate measures should be taken to avoid conception during methotrexate therapy (see Contraindications and Precautions).
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: 1. Single doses of 7.5 mg (3 ´ 2.5 mg tablets) once weekly or 2. Divided dosages of 2.5 mg at 12-hour intervals for 3 doses given as a course once weekly.
Dosages in each schedule may be increased to 15 mg/week after 6 weeks in non-responsive patients. If necessary dosage may be gradually increased further to achieve optimal response, but not ordinarily to exceed a total weekly dose of 20 mg. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg.
Once response has been achieved, each schedule should be reduced, if possible, to the lowest possible effective dose. Although rare, some patients may be maintained on a dose of 2.5 mg/week. Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.
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 outlined below.
Handling: 1. Methotrexate does not show acute toxicity on topical contact with the skin and mucous membrane. However, persons involved with handling cytotoxic drugs should avoid contact with skin and inhalation of airborne particles.
2. Personnel regularly involved in preparation and handling of antineoplastics should have bi-annual blood examinations.
Disposal: 1. Avoid contact with skin and inhalation of airborne particles by use of PVC gloves and disposable gowns and masks.
2. Tablets: Place container and tablets in a plastic bag, seal, and mark as hazardous waste. Incinerate at 1 000°C or higher.
3. If incineration is not available, dissolve tablets in a suitable quantity of 1N sodium hydroxide solution, and autoclave the mixture for 1 hour. Discard in the sewer system with copious amounts of running water.
Cleaning: Non-disposable equipment that has come in contact with methotrexate may be rinsed with water and washed thoroughly with soap and water.
Availability And Storage: Each small, round, yellow, uncoated tablet, engraved with M2.5/F, contains: methotrexate USP 2.5 mg. No preservatives or coloring agents. Bottles of 100. Store at room temperature 15 to 25°C).
Patients with rheumatoid arthritis should receive the 2.5 mg dosage form and should be informed of the Information for the Patient.
METHOTREXATE TABLETS USP Faulding Antimetabolite
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