`Rx only
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`WARNINGS
`METHOTREXATE SHOULD BE USED ONLY BY PHYSICIANS WHOSE KNOWLEDGE AND
`EXPERIENCE INCLUDE THE USE OF ANTIMETABOLITE THERAPY.
`BECAUSE OF THE POSSIBILITY OF SERIOUS TOXIC REACTIONS (WHICH CAN BE FATAL):
`
`METHOTREXATE SHOULD BE USED ONLY IN LIFE THREATENING NEOPLASTIC
`DISEASES, OR IN PATIENTS WITH PSORIASIS OR RHEUMATOID ARTHRITIS WITH
`SEVERE, RECALCITRANT, DISABLING DISEASE WHICH IS NOT ADEQUATELY
`RESPONSIVE TO OTHER FORMS OF THERAPY.
`DEATHS HAVE BEEN REPORTED WITH THE USE OF METHOTREXATE IN THE
`TREATMENT OF MALIGNANCY, PSORIASIS, AND RHEUMATOID ARTHRITIS.
`PATIENTS SHOULD BE CLOSELY MONITORED FOR BONE MARROW, LIVER, LUNG
`AND KIDNEY TOXICITIES. (See PRECAUTIONS).
`PATIENTS SHOULD BE INFORMED BY THEIR PHYSICIAN OF THE RISKS INVOLVED
`AND BE UNDER A PHYSICIAN’S CARE THROUGHOUT THERAPY.
`THE USE OF METHOTREXATE HIGH DOSE REGIMENS RECOMMENDED FOR
`OSTEOSARCOMA REQUIRES METICULOUS CARE. (See DOSAGE AND ADMINISTRATION.)
`HIGH DOSE REGIMENS FOR OTHER NEOPLASTIC DISEASES ARE INVESTIGATIONAL AND
`A THERAPEUTIC ADVANTAGE HAS NOT BEEN ESTABLISHED. METHOTREXATE
`FORMULATIONS AND DILUENTS CONTAINING PRESERVATIVES MUST NOT BE USED FOR
`INTRATHECAL OR HIGH DOSE METHOTREXATE THERAPY.
`1.
`Methotrexate has been reported to cause fetal death and/or congenital anomalies.Therefore, it is
`not recommended for women of childbearing potential unless there is clear medical evidence that
`the benefits can be expected to outweigh the considered risks. Pregnant women with psoriasis or
`rheumatoid arthritis should not receive methotrexate. (See CONTRAINDICATIONS).
`Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural
`effusions. Such patients require especially careful monitoring for toxicity, and require dose
`reduction or, in some cases, discontinuation of methotrexate administration.
`Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and
`gastrointestinal toxicity have been reported with concomitant administration of methotrexate
`(usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs). (See
`PRECAUTIONS, Drug Interactions).
`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 may not be preceded by symptoms or abnormal liver function tests in the psoriasis
`population. For this reason, 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. (See PRECAUTIONS,
`Organ System Toxicity, Hepatic).
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`2.
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`3.
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`4.
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`5.
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`6.
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`7.
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`Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a
`potentially dangerous lesion, which may occur acutely at any time during therapy and has been
`reported at low doses. It is not always fully reversible and fatalities have been reported. 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.
`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.
`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, intramuscular, intravenous, or
`intrathecal methotrexate administration. Recovery has been reported with discontinuation of
`therapy. (See PRECAUTIONS, Organ System Toxicity, Skin.)
`Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia, may occur
`with methotrexate therapy.
`11. Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis
`and osteonecrosis.
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`8.
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`9.
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`10.
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`DESCRIPTION
`Methotrexate (formerly Amethopterin) is an antimetabolite used in the treatment of certain neoplastic
`diseases, severe psoriasis, and adult rheumatoid arthritis.
`Chemically methotrexate is N-[4-[[(2,4-diamino-6-pteridinyl) methyl]methylamino]benzoyl]-L-glutamic
`acid.
`The structural formula is:
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`
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`C20H22N8O5
`
`Molecular weight: 454.45
`Methotrexate Injection, USP is sterile and non-pyrogenic and may be given by the intramuscular,
`intravenous or intra-arterial route. (See DOSAGE AND ADMINISTRATION.) However, the preserved
`formulation contains Benzyl Alcohol and must not be used for intrathecal or high dose therapy.
`Methotrexate Injection, USP Isotonic Liquid, Contains Preservative is available in 25 mg/mL, 2 mL
`(50 mg) vials.
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`Each 25 mg/mL, 2 mL vial contains methotrexate sodium equivalent to 50 mg methotrexate, 0.9% w/v of
`Benzyl Alcohol as a preservative, and the following inactive ingredients: Sodium Chloride 0.260% w/v
`and Water for Injection qs ad 100% v. Sodium Hydroxide and, if necessary, Hydrochloric Acid are added
`to adjust the pH to approximately 8.5.
`Methotrexate Injection, USP, Isotonic Liquid, Preservative Free, for single use only, is available in
`10 mg/mL, 2 mL (20 mg) vials and 25 mg/mL, 20 mL (500 mg), 40 mL (1 g) and 100 mL (2.5 g) vials.
`Each 10 mg/mL, 2 mL vial contains methotrexate sodium equivalent to 20 mg methotrexate, and the
`following inactive ingredients: Sodium Chloride 0.70% w/v. Sodium Hydroxide and, if necessary,
`Hydrochloric Acid are added to adjust the pH to approximately 8.5.
`Each 25 mg/mL, 20 mL, 40 mL and 100 mL vial contains methotrexate sodium equivalent to 500 mg, 1 g
`and 2.5 g methotrexate, respectively, and the following inactive ingredients: Sodium Chloride 0.490%
`w/v. Sodium Hydroxide and, if necessary, Hydrochloric Acid are added to adjust the pH to approximately
`8.5.
`
`CLINICAL PHARMACOLOGY
`Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by
`this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine
`nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular
`replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and
`intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of
`methotrexate. When cellular proliferation in malignant tissues is greater than in most normal tissues,
`methotrexate may impair malignant growth without irreversible damage to normal tissues.
`The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function. Two reports
`describe in vitro methotrexate inhibition of DNA precursor uptake by stimulated mononuclear cells, and
`another describes in animal polyarthritis partial correction by methotrexate of spleen cell
`hyporesponsiveness and suppressed IL 2 production. Other laboratories, however, have been unable to
`demonstrate similar effects. Clarification of methotrexate’s effect on immune activity and its relation to
`rheumatoid immunopathogenesis await further studies.
`In patients with rheumatoid arthritis, effects of methotrexate on articular swelling and tenderness can be
`seen as early as 3 to 6 weeks. Although methotrexate clearly ameliorates symptoms of inflammation
`(pain, swelling, stiffness), there is no evidence that it induces remission of rheumatoid arthritis nor has a
`beneficial effect been demonstrated on bone erosions and other radiologic changes which result in
`impaired joint use, functional disability, and deformity.
`Most studies of methotrexate in patients with rheumatoid arthritis are relatively short term (3 to 6
`months). Limited data from long-term studies indicate that an initial clinical improvement is maintained
`for at least two years with continued therapy.
`In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This
`differential in proliferation rates is the basis for the use of methotrexate to control the psoriatic process.
`Methotrexate in high doses, followed by leucovorin rescue, is used as a part of the treatment of patients
`with non-metastatic osteosarcoma. The original rationale for high dose methotrexate therapy was based on
`the concept of selective rescue of normal tissues by leucovorin. More recent evidence suggests that high
`dose methotrexate may also overcome methotrexate resistance caused by impaired active transport,
`decreased affinity of dihydrofolic acid reductase for methotrexate, increased levels of dihydrofolic acid
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`reductase resulting from gene amplification, or decreased polyglutamation of methotrexate. The actual
`mechanism of action is unknown.
`In a 6-month double-blind, placebo-controlled trial of 127 pediatric patients with juvenile rheumatoid
`arthritis (JRA) (mean age, 10.1 years; age range, 2.5 to 18 years; mean duration of disease, 5.1 years) on
`background nonsteroidal anti-inflammatory drugs (NSAIDs) and/or prednisone, methotrexate given
`weekly at an oral dose of 10 mg/m2 provided significant clinical improvement compared to placebo as
`measured by either the physician’s global assessment, or by a patient composite (25% reduction in the
`articular-severity score plus improvement in parent and physician global assessments of disease activity).
`Over two-thirds of the patients in this trial had polyarticular-course JRA, and the numerically greatest
`response was seen in this subgroup treated with 10 mg/m2/wk methotrexate. The overwhelming majority
`of the remaining patients had systemic-course JRA. All patients were unresponsive to NSAIDs;
`approximately one-third were using low dose corticosteroids. Weekly methotrexate at a dose of 5 mg/m2
`was not significantly more effective than placebo in this trial.
`Two Pediatric Oncology Group studies (one randomized and one non-randomized) demonstrated a
`significant improvement in relapse-free survival in patients with nonmetastatic osteosarcoma, when high
`dose methotrexate with leucovorin rescue was used in combination with other chemotherapeutic agents
`following surgical resection of the primary tumor. These studies were not designed to demonstrate the
`specific contribution of high dose methotrexate/leucovorin rescue therapy to the efficacy of the
`combination. However, a contribution can be inferred from the reports of objective responses to this
`therapy in patients with metastatic osteosarcoma, and from reports of extensive tumor necrosis following
`preoperative administration of this therapy to patients with non-metastatic osteosarcoma.
`Pharmacokinetics
`Absorption- In adults, oral absorption appears to be dose dependent. Peak serum levels are reached within
`one to two hours. At doses of 30 mg/m2 or less, methotrexate is generally well absorbed with a mean
`bioavailability of about 60%. The absorption of doses greater than 80 mg/m2 is significantly less, possibly
`due to a saturation effect.
`In leukemic pediatric patients, oral absorption of methotrexate also appears to be dose dependent and has
`been reported to vary widely (23% to 95%). A twenty fold difference between highest and lowest peak
`levels (Cmax: 0.11 to 2.3 micromolar after a 20 mg/m2 dose) has been reported. Significant interindividual
`variability has also been noted in time to peak concentration (Tmax: 0.67 to 4 hrs after a 15 mg/m2 dose)
`and fraction of dose absorbed. The absorption of doses greater than 40 mg/m2 has been reported to be
`significantly less than that of lower doses. Food has been shown to delay absorption and reduce peak
`concentration. Methotrexate is generally completely absorbed from parenteral routes of injection. After
`intramuscular injection, peak serum concentrations occur in 30 to 60 minutes. As in leukemic pediatric
`patients, a wide interindividual variability in the plasma concentrations of methotrexate has been reported
`in pediatric patients with JRA. Following oral administration of methotrexate in doses of 6.4 to
`11.2 mg/m2/week in pediatric patients with JRA, mean serum concentrations were 0.59 micromolar
`(range, 0.03 to 1.40) at 1 hour, 0.44 micromolar (range, 0.01 to 1.00) at 2 hours, and 0.29 micromolar
`(range, 0.06 to 0.58) at 3 hours. In pediatric patients receiving methotrexate for acute lymphocytic
`leukemia (6.3 to 30 mg/m2), or for JRA (3.75 to 26.2 mg/m2), the terminal half-life has been reported to
`range from 0.7 to 5.8 hours or 0.9 to 2.3 hours, respectively.
`Distribution- After intravenous administration, the initial volume of distribution is approximately
`0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg
`(40 to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell
`membranes by means of a single carrier-mediated active transport process. At serum concentrations
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`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 or parenterally. High CSF concentrations of the drug may be attained by intrathecal administration.
`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 joints 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 synthetase. Small amounts of
`methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged
`drug action of these active metabolites vary among different cells, tissues and tumors. A small amount of
`metabolism to 7-hydroxymethotrexate may occur at doses commonly prescribed. Accumulation of this
`metabolite may become significant at the high doses used in osteogenic sarcoma. The aqueous solubility
`of 7-hydroxymethotrexate is 3 to 5 fold lower than the parent compound. Methotrexate is partially
`metabolized by intestinal flora after oral administration.
`Half-Life - The terminal half-life reported for methotrexate is approximately three to ten hours for patients
`receiving treatment for psoriasis, or rheumatoid arthritis or low dose antineoplastic therapy (less than
`30 mg/m2). For patients receiving high doses of methotrexate, the terminal half-life is eight to 15 hours.
`Excretion - Renal excretion is the primary route of elimination and is dependent upon dosage and route of
`administration. With IV administration, 80% to 90% of the administered dose is excreted unchanged in
`the urine within 24 hours. 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 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 high dose regimens or delayed excretion is reduced by the administration
`of leucovorin calcium 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 adjustments of leucovorin dosing. Guidelines for
`monitoring serum methotrexate levels, and for adjustment of leucovorin dosing to reduce the risk of
`methotrexate toxicity, are provided below in DOSAGE AND ADMINISTRATION.
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`Methotrexate has been detected in human breast milk. The highest breast milk to plasma concentration
`ratio reached was 0.08:1.
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`INDICATIONS AND USAGE
`Neoplastic Diseases
`Methotrexate is indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens and
`hydatidiform mole.
`In acute lymphocytic leukemia, methotrexate is indicated in the prophylaxis of meningeal leukemia and is
`used in maintenance therapy in combination with other chemotherapeutic agents. Methotrexate is also
`indicated in the treatment of meningeal leukemia.
`Methotrexate is used alone or in combination with other anticancer agents in the treatment of breast
`cancer, epidermoid cancers of the head and neck, advanced mycosis fungoides (cutaneous T cell
`lymphoma), and lung cancer, particularly squamous cell and small cell types. Methotrexate is also used in
`combination with other chemotherapeutic agents in the treatment of advanced stage non-Hodgkin’s
`lymphomas.
`Methotrexate in high doses followed by leucovorin rescue in combination with other chemotherapeutic
`agents is effective in prolonging relapse-free survival in patients with non-metastatic osteosarcoma who
`have undergone surgical resection or amputation for the primary tumor.
`Psoriasis
`Methotrexate is indicated in the symptomatic control of severe, recalcitrant, disabling psoriasis that is not
`adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by
`biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis “flare” is not due
`to an undiagnosed concomitant disease affecting immune responses.
`Rheumatoid Arthritis including Polyarticular-Course Juvenile Rheumatoid Arthritis
`Methotrexate is indicated in the management of selected adults with severe, active rheumatoid arthritis
`(ACR criteria), or children with active polyarticular-course juvenile rheumatoid arthritis, who have had an
`insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including
`full dose non-steroidal anti-inflammatory agents (NSAIDs).
`Aspirin, (NSAIDs), and/or low dose steroids may be continued, although the possibility of increased
`toxicity with concomitant use of NSAIDs including salicylates has not been fully explored. (See
`PRECAUTIONS, Drug Interactions.) Steroids may be reduced gradually in patients who respond to
`methotrexate. Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, sulfasalazine,
`or cytotoxic agents, has not been studied and may increase the incidence of adverse effects. Rest and
`physiotherapy as indicated should be continued.
`
`CONTRAINDICATIONS
`Methotrexate can cause fetal death or teratogenic effects when administered to a pregnant woman.
`Methotrexate is contraindicated in pregnant women with psoriasis or rheumatoid arthritis and should be
`used in the treatment of neoplastic diseases only when the potential benefit outweighs the risk to the fetus.
`Women of childbearing potential should not be started on methotrexate until pregnancy is excluded and
`should be fully counseled on the serious risk to the fetus (see PRECAUTIONS) should they become
`pregnant while undergoing treatment. Pregnancy should be avoided if either partner is receiving
`methotrexate; during and for a minimum of three months after therapy for male patients, and during and
`for at least one ovulatory cycle after therapy for female patients. (See Boxed WARNINGS).
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`Because of the potential for serious adverse reactions from methotrexate in breast fed infants, it is
`contraindicated in nursing mothers.
`Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic
`liver disease should not receive methotrexate.
`Patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence of
`immunodeficiency syndromes should not receive methotrexate.
`Patients with psoriasis or rheumatoid arthritis who have preexisting blood dyscrasias, such as bone
`marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia, should not receive
`methotrexate.
`Patients with a known hypersensitivity to methotrexate should not receive the drug.
`
`WARNINGS - SEE BOXED WARNINGS.
`Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitor (PPI)
`therapy. Case reports and published population pharmacokinetic studies suggest that concomitant use of
`some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high
`dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate,
`possibly leading to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was
`observed when high-dose methotrexate was co-administered with PPIs, but was not observed when
`methotrexate was co-administered with ranitidine. However, no formal drug interaction studies of
`methotrexate with ranitidine have been conducted.
`Methotrexate formulations and diluents containing preservatives must not be used for intrathecal or high
`dose methotrexate therapy.
`
`PRECAUTIONS
`General
`Methotrexate has the potential for serious toxicity (See Boxed WARNINGS). Toxic effects may be
`related in frequency and severity to dose or frequency of administration but have been seen at all doses.
`Because they can occur at any time during therapy, it is necessary to follow patients on methotrexate
`closely. Most adverse reactions are reversible if detected early. When such reactions do occur, the drug
`should be reduced in dosage or discontinued and appropriate corrective measures should be taken. If
`necessary, this could include the use of leucovorin calcium and/or acute, intermittent hemodialysis with a
`high-flux dialyzer. (See OVERDOSAGE). If methotrexate therapy is reinstituted, it should be carried out
`with caution, with adequate consideration of further need for the drug and increased alertness as to
`possible recurrence of toxicity.
`The clinical pharmacology of methotrexate has not been well studied in older individuals. Due to
`diminished hepatic and renal function as well as decreased folate stores in this population, relatively low
`doses should be considered, and these patients should be closely monitored for early signs of toxicity.
`Some of the effects mentioned under ADVERSE REACTIONS, such as dizziness and fatigue, may
`affect the ability to drive or operate machinery.
`Information for Patients
`Patients should be informed of the early signs and symptoms of toxicity, of the need to see their physician
`promptly if they occur, and the need for close follow-up, including periodic laboratory tests to monitor
`toxicity.
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`Both the physician and pharmacist should emphasize to the patient that the recommended dose is taken
`weekly in rheumatoid arthritis and psoriasis, and that mistaken daily use of the recommended dose has led
`to fatal toxicity. Prescriptions should not be written or refilled on a PRN basis.
`Patients should be informed of the potential benefit and risk in the use of methotrexate. The risk of effects
`on reproduction should be discussed with both male and female patients taking methotrexate.
`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
`and psoriasis, monitoring of these parameters is recommended: hematology at least monthly, renal
`function and liver function every 1 to 2 months. More frequent monitoring is usually indicated during
`antineoplastic therapy. 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.
`Transient liver function test abnormalities are observed frequently after methotrexate administration and
`are usually not cause for modification of methotrexate therapy. Persistent liver function test abnormalities,
`and/or depression of serum albumin may be indicators of serious liver toxicity and require evaluation.
`(See PRECAUTIONS, Organ System Toxicity, Hepatic).
`A relationship between abnormal liver function tests and fibrosis or cirrhosis of the liver has not been
`established for patients with psoriasis. Persistent abnormalities in liver function tests may precede
`appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.
`Pulmonary function tests may be useful if methotrexate-induced lung disease is suspected, especially if
`baseline measurements are available.
`Drug Interactions
`Nonsteroidal anti-inflammatory drugs should not be administered prior to or concomitantly with the high
`doses of methotrexate, such as 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, resulting in deaths from severe hematologic and gastrointestinal toxicity.
`Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of
`methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate in an animal
`model and may enhance its toxicity.
`Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have
`usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It
`should be appreciated, however, that the doses used in rheumatoid arthritis (7.5 to 15 mg/week) are
`somewhat lower than those used in psoriasis and that larger doses could lead to unexpected toxicity.
`Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement
`by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. Renal tubular
`transport is also diminished by probenecid; use of methotrexate with this drug should be carefully
`monitored.
`In the treatment of patients with osteosarcoma, caution must be exercised if high-dose methotrexate is
`administered in combination with a potentially nephrotoxic chemotherapeutic agent (e.g., cisplatin).
`Methotrexate increases the plasma levels of mercaptopurine. The combination of methotrexate and
`mercaptopurine may therefore require dose adjustment.
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`Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may
`decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting
`bowel flora and suppressing metabolism of the drug by bacteria.
`Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of
`methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with high
`and low dose methotrexate. Use of methotrexate with penicillins should be carefully monitored.
`The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic
`agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore,
`patients receiving concomitant therapy with methotrexate and other potential hepatotoxins (e.g.,
`azathioprine, retinoids, sulfasalazine) should be closely monitored for possible increased risk of
`hepatotoxicity.
`Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when
`used concurrently with methotrexate.
`Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically
`administered methotrexate. Preliminary animal and human studies have shown that small quantities of
`intravenously administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in
`humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following
`intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally
`administered methotrexate.
`Folate deficiency states may increase methotrexate toxicity. Trimethoprim/sulfamethoxazole has been
`reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by
`decreased tubular secretion and/or an additive antifolate effect.
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`No controlled human data exist regarding the risk of neoplasia with methotrexate. Methotrexate has been
`evaluated in a number of animal studies for carcinogenic potential with inconclusive results. Although
`there is evidence that methotrexate causes chromosomal damage to animal somatic cells and human bone
`marrow cells, the clinical significance remains uncertain. Non-Hodgkin’s lymphoma and other tumors
`have been reported in patients receiving low-dose oral methotrexate. However, there have been instances
`of malignant lymphoma arising during treatment with low-dose oral methotrexate, which have regressed
`completely following withdrawal of methotrexate, without requiring active anti-lymphoma treatment.
`Benefits should be weighed against the potential risk before using methotrexate alone or in combination
`with other drugs, especially in pediatric patients or young adults. Methotrexate causes embryotoxicity,
`abortion, and fetal defects in humans. It has also been reported to cause impairment of fertility,
`oligospermia and menstrual dysfunction in humans, during and for a short period after cessation of
`therapy.
`Pregnancy
`Psoriasis and rheumatoid arthritis: Methotrexate is in Pregnancy Category X. See
`CONTRAINDICATIONS.
`Nursing Mothers
`See CONTRAINDICATIONS.
`Pediatric Use
`Safety and effectiveness in pediatric patients have been established only in cancer chemotherapy and in
`polyarticular-course juvenile rheumatoid arthritis.
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`Published clinical studies evaluating the use of methotrexate in children and adolescents (i.e., patients 2 to
`16 years of age) with JRA demonstrated safety comparable to that observed in adults with rheumatoid
`arthritis (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS and DOSAGE AND
`ADMINISTRATION.)
`Methotrexate injectable formulations containing the preservative benzyl alcohol are not recommended for
`use in neonates. There have been reports of fatal ‘gasping syndrome’ in neonates (children less than one
`month of age) foll