Rheumatrex Package Insert 10/30/03 12:36 PM Page 1
Methotrexate Sodium Tablets for oral administration are available in bottles of 100 and
In dogs, synovial fluid concentrations after oral dosing were higher in inflamed than
after therapy for male patients, and during and for at least one ovulatory cycle after
in a packaging system designated as the RHEUMATREX® Methotrexate Sodium Dose
uninflamed joints. Although salicylates did not interfere with this penetration, prior pred-
therapy for female patients. (See Boxed WARNINGS.) (METHOTREXATE SODIUM TABLETS)
Pack for therapy with a weekly dosing schedule of 5 mg, 7.5 mg, 10 mg, 12.5 mg and
nisone treatment reduced penetration into inflamed joints to the level of normal joints.
Because of the potential for serious adverse reactions from methotrexate in breast fed
15 mg. Methotrexate Sodium Tablets contain an amount of methotrexate sodium
Metabolism - After absorption, methotrexate undergoes hepatic and intracellular
infants, it is contraindicated in nursing mothers.
equivalent to 2.5 mg of methotrexate and the following inactive ingredients: Lactose,
metabolism to polyglutamated forms which can be converted back to methotrexate by
Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease
Magnesium Stearate and Pregelatinized Starch. May also contain Corn Starch.
hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase
or other chronic liver disease should not receive methotrexate. WARNINGS CLINICAL PHARMACOLOGY
and thymidylate synthetase. Small amounts of methotrexate polyglutamates may
METHOTREXATE SHOULD BE USED ONLY BY PHYSICIANS WHOSE KNOWL-
Patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence
remain in tissues for extended periods. The retention and prolonged drug action of
EDGE AND EXPERIENCE INCLUDE THE USE OF ANTIMETABOLITE THERAPY
Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to
of immunodeficiency syndromes should not receive methotrexate.
these active metabolites vary among different cells, tissues and tumors. A small
BECAUSE OF THE POSSIBILITY OF SERIOUS TOXIC REACTIONS (WHICH CAN BE
tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon
Patients with psoriasis or rheumatoid arthritis who have preexisting blood dyscrasias,
amount of metabolism to 7-hydroxymethotrexate may occur at doses commonly pre-
groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate
such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anemia,
scribed. Accumulation of this metabolite may become significant at the high doses
interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tis-
METHOTREXATE SHOULD BE USED ONLY IN LIFE THREATENING NEOPLASTIC
used in osteogenic sarcoma. The aqueous solubility of 7-hydroxymethotrexate is 3 to
sues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa,
DISEASES, OR IN PATIENTS WITH PSORIASIS OR RHEUMATOID ARTHRITIS
5 fold lower than the parent compound. Methotrexate is partially metabolized by
Patients with a known hypersensitivity to methotrexate should not receive the drug.
and cells of the urinary bladder are in general more sensitive to this effect of
WITH SEVERE, RECALCITRANT, DISABLING DISEASE WHICH IS NOT ADE-
intestinal flora after oral administration.
methotrexate. When cellular proliferation in malignant tissues is greater than in most
WARNINGS - SEE BOXED WARNINGS.
QUATELY RESPONSIVE TO OTHER FORMS OF THERAPY.
normal tissues, methotrexate may impair malignant growth without irreversible dam-
Half-Life - The terminal half-life reported for methotrexate is approximately three to
Methotrexate formulations and diluents containing preservatives must not be used for
DEATHS HAVE BEEN REPORTED WITH THE USE OF METHOTREXATE IN THE
ten hours for patients receiving treatment for psoriasis, or rheumatoid arthritis or low
intrathecal or high dose methotrexate therapy.
TREATMENT OF MALIGNANCY, PSORIASIS, AND RHEUMATOID ARTHRITIS.
dose antineoplastic therapy (less than 30 mg/m2). For patients receiving high doses of
The mechanism of action in rheumatoid arthritis is unknown; it may affect immune
PATIENTS SHOULD BE CLOSELY MONITORED FOR BONE MARROW, LIVER,
methotrexate, the terminal half-life is eight to 15 hours.
function. Two reports describe in vitro methotrexate inhibition of DNA precursor
LUNG AND KIDNEY TOXICITIES. (See PRECAUTIONS.)
uptake by stimulated mononuclear cells, and another describes in animal polyarthritis
Excretion - Renal excretion is the primary route of elimination and is dependent upon
Methotrexate has the potential for serious toxicity. (See Boxed WARNINGS.) Toxic
PATIENTS SHOULD BE INFORMED BY THEIR PHYSICIAN OF THE RISKS
partial correction by methotrexate of spleen cell hyporesponsiveness and suppressed
dosage and route of administration. With IV administration, 80% to 90% of the admin-
effects may be related in frequency and severity to dose or frequency of administration
INVOLVED AND BE UNDER A PHYSICIAN’S CARE THROUGHOUT THERAPY.
IL 2 production. Other laboratories, however, have been unable to demonstrate similar
istered dose is excreted unchanged in the urine within 24 hours. There is limited biliary
but have been seen at all doses. Because they can occur at any time during therapy, it is
effects. Clarification of methotrexate’s effect on immune activity and its relation to
excretion amounting to 10% or less of the administered dose. Enterohepatic recircula-
necessary to follow patients on methotrexate closely. Most adverse reactions are
1. Methotrexate has been reported to cause fetal death and/or congenital anom-
rheumatoid immunopathogenesis await further studies.
tion of methotrexate has been proposed.
reversible if detected early. When such reactions do occur, the drug should be reduced
alies. Therefore, it is not recommended for women of childbearing potential
In patients with rheumatoid arthritis, effects of methotrexate on articular swelling and
Renal excretion occurs by glomerular filtration and active tubular secretion. Nonlinear
in dosage or discontinued and appropriate corrective measures should be taken. If
unless there is clear medical evidence that the benefits can be expected to out-
tenderness can be seen as early as 3 to 6 weeks. Although methotrexate clearly ame-
elimination due to saturation of renal tubular reabsorption has been observed in psori-
necessary, this could include the use of leucovorin calcium and/or acute, intermittent
weigh the considered risks. Pregnant women with psoriasis or rheumatoid
liorates symptoms of inflammation (pain, swelling, stiffness), there is no evidence that
atic patients at doses between 7.5 and 30 mg. Impaired renal function, as well as con-
hemodialysis with a high-flux dialyzer. (See OVERDOSAGE.) If methotrexate therapy is
arthritis should not receive methotrexate. (See CONTRAINDICATIONS.)
it induces remission of rheumatoid arthritis nor has a beneficial effect been demon-
current use of drugs such as weak organic acids that also undergo tubular secretion,
reinstituted, it should be carried out with caution, with adequate consideration of further
2. Methotrexate elimination is reduced in patients with impaired renal function,
strated on bone erosions and other radiologic changes which result in impaired joint
can markedly increase methotrexate serum levels. Excellent correlation has been
need for the drug and with increased alertness as to possible recurrence of toxicity.
ascites, or pleural effusions. Such patients require especially careful monitoring
use, functional disability, and deformity.
reported between methotrexate clearance and endogenous creatinine clearance.
The clinical pharmacology of methotrexate has not been well studied in older individu-
for toxicity, and require dose reduction or, in some cases, discontinuation of
Most studies of methotrexate in patients with rheumatoid arthritis are relatively short
Methotrexate clearance rates vary widely and are generally decreased at higher doses.
als. Due to diminished hepatic and renal function as well as decreased folate stores in
term (3 to 6 months). Limited data from long-term studies indicate that an initial clini-
Delayed drug clearance has been identified as one of the major factors responsible for
this population, relatively low doses should be considered, and these patients should
3. Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic
cal improvement is maintained for at least two years with continued therapy.
methotrexate toxicity. It has been postulated that the toxicity of methotrexate for nor-
be closely monitored for early signs of toxicity.
anemia, and gastrointestinal toxicity have been reported with concomitant
mal tissues is more dependent upon the duration of exposure to the drug rather than
In psoriasis, the rate of production of epithelial cells in the skin is greatly increased
Information for Patients
administration of methotrexate (usually in high dosage) along with some non-
the peak level achieved. When a patient has delayed drug elimination due to compro-
over normal skin. This differential in proliferation rates is the basis for the use of
Patients should be informed of the early signs and symptoms of toxicity, of the need to
steroidal anti-inflammatory drugs (NSAIDs). (See PRECAUTIONS, Drug
mised renal function, a third space effusion, or other causes, methotrexate serum
methotrexate to control the psoriatic process.
see their physician promptly if they occur, and the need for close follow-up, including
concentrations may remain elevated for prolonged periods.
In a 6-month, double-blind, placebo-controlled trial of 127 pediatric patients with juve-
periodic laboratory tests to monitor toxicity.
4. Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only
The potential for toxicity from high dose regimens or delayed excretion is reduced by
nile rheumatoid arthritis (JRA) (mean age, 10.1 years; age range 2.5 to 18 years, mean
Both the physician and pharmacist should emphasize to the patient that the recom-
after prolonged use. Acutely, liver enzyme elevations are frequently seen. These
the administration of leucovorin calcium during the final phase of methotrexate plasma
duration of disease, 5.1 years) on background non-steroidal anti-inflammatory drugs
mended dose is taken weekly in rheumatoid arthritis and psoriasis, and that mistaken
are usually transient and asymptomatic, and also do not appear predictive of
elimination. Pharmacokinetic monitoring of methotrexate serum concentrations may
(NSAIDs) and/or prednisone, methotrexate given weekly at an oral dose of 10 mg/m2
daily use of the recommended dose has led to fatal toxicity. Patients should be encour-
subsequent hepatic disease. Liver biopsy after sustained use often shows his-
provided significant clinical improvement compared to placebo as measured by either
help identify those patients at high risk for methotrexate toxicity and aid in proper
aged to read the Patient Instructions sheet within the Dose Pack. Prescriptions should
tologic changes, and fibrosis and cirrhosis have been reported; these latter
the physician’s global assessment, or by a patient composite (25% reduction in the
adjustment of leucovorin dosing. Guidelines for monitoring serum methotrexate levels,
not be written or refilled on a PRN basis.
lesions may not be preceded by symptoms or abnormal liver function tests in
articular-severity score plus improvement in parent and physician global assessments
and for adjustment of leucovorin dosing to reduce the risk of methotrexate toxicity, are
Patients should be informed of the potential benefit and risk in the use of methotrexate.
the psoriasis population. For this reason, periodic liver biopsies are usually
of disease activity.) Over two-thirds of the patients in this trial had polyarticular-course
provided below in DOSAGE AND ADMINISTRATION.
The risk of effects on reproduction should be discussed with both male and female
recommended for psoriatic patients who are under long-term treatment.
JRA, and the numerically greatest response was seen in this subgroup treated with
Methotrexate has been detected in human breast milk. The highest breast milk to
Persistent abnormalities in liver function tests may precede appearance of
10 mg/m2/wk methotrexate. The overwhelming majority of the remaining patients had
plasma concentration ratio reached was 0.08:1.
fibrosis or cirrhosis in the rheumatoid arthritis population. (See
systemic-course JRA. All patients were unresponsive to NSAIDs; approximately one-
Laboratory Tests INDICATIONS AND USAGE PRECAUTIONS, Organ System Toxicity, Hepatic.)
third were using low dose corticosteroids. Weekly methotrexate at a dose of 5 mg/m2
Patients undergoing methotrexate therapy should be closely monitored so that toxic
5. Methotrexate-induced lung disease is a potentially dangerous lesion, which
was not significantly more effective than placebo in this trial.
effects are detected promptly. Baseline assessment should include a complete blood
Methotrexate is indicated in the treatment of gestational choriocarcinoma, chorio-
may occur acutely at any time during therapy and which has been reported at
count with differential and platelet counts, hepatic enzymes, renal function tests, and a
adenoma destruens and hydatidiform mole.
doses as low as 7.5 mg/week. It is not always fully reversible. Pulmonary
chest X-ray. During therapy of rheumatoid arthritis and psoriasis, monitoring of these
Absorption - In adults, oral absorption appears to be dose dependent. Peak serum lev-
Methotrexate is used in maintenance therapy in combination with other chemothera-
symptoms (especially a dry, nonproductive cough) may require interruption of
parameters is recommended: hematology at least monthly, renal function and liver
els are reached within one to two hours. At doses of 30 mg/m2 or less, methotrexate is
treatment and careful investigation.
function every 1 to 2 months. More frequent monitoring is usually indicated during
generally well absorbed with a mean bioavailability of about 60%. The absorption of
Methotrexate is used alone or in combination with other anticancer agents in the treat-
antineoplastic therapy. During initial or changing doses, or during periods of increased
6. Diarrhea and ulcerative stomatitis require interruption of therapy; otherwise,
doses greater than 80 mg/m2 is significantly less, possibly due to a saturation effect. RHEUMATREX®
ment of breast cancer, epidermoid cancers of the head and neck, advanced mycosis
risk of elevated methotrexate blood levels (eg, dehydration), more frequent monitoring
hemorrhagic enteritis and death from intestinal perforation may occur.
In leukemic pediatric patients, oral absorption of methotrexate also appears to be dose
(METHOTREXATE SODIUM TABLETS)
fungoides (cutaneous T cell lymphoma), and lung cancer, particularly squamous cell
7. Malignant lymphomas, which may regress following withdrawal of methotrex-
dependent and has been reported to vary widely (23% to 95%). A twenty fold differ-
and small cell types. Methotrexate is also used in combination with other chemothera-
Transient liver function test abnormalities are observed frequently after methotrexate
ate, may occur in patients receiving low-dose methotrexate and, thus, may not
ence between highest and lowest peak levels (Cmax: 0.11 to 2.3 micromolar after a
peutic agents in the treatment of advanced stage non-Hodgkin’s lymphomas.
administration and are usually not cause for modification of methotrexate therapy.
require cytotoxic treatment. Discontinue methotrexate first and, if the lym-
20 mg/m2 dose) has been reported. Significant interindividual variability has also been
Persistent liver function test abnormalities, and/or depression of serum albumin may
phoma does not regress, appropriate treatment should be instituted. Psoriasis
noted in time to peak concentration (Tmax: 0.67 to 4 hrs after a 15 mg/m2 dose) and
Methotrexate is indicated in the symptomatic control of severe, recalcitrant, disabling
be indicators of serious liver toxicity and require evaluation. (See PRECAUTIONS,
8. Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome”
fraction of dose absorbed. The absorption of doses greater than 40 mg/m2 has been
psoriasis that is not adequately responsive to other forms of therapy, but only whenOrgan System Toxicity, Hepatic.)
in patients with rapidly growing tumors. Appropriate supportive and pharmaco-
reported to be significantly less than that of lower doses. Food has been shown to
the diagnosis has been established, as by biopsy and/or after dermatologic consulta-
A relationship between abnormal liver function tests and fibrosis or cirrhosis of the
logic measures may prevent or alleviate this complication.
delay absorption and reduce peak concentration. Methotrexate is generally completely
tion. It is important to ensure that a psoriasis “flare” is not due to an undiagnosed
liver has not been established for patients with psoriasis. Persistent abnormalities in
9. Severe, occasionally fatal, skin reactions have been reported following single or
absorbed from parenteral routes of injection. After intramuscular injection, peak
concomitant disease affecting immune responses.
liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid
multiple doses of methotrexate. Reactions have occurred within days of oral,
serum concentrations occur in 30 to 60 minutes. As in leukemic pediatric patients, a
Rheumatoid Arthritis including Polyarticular-Course Juvenile Rheumatoid Arthritis
intramuscular, intravenous, or intrathecal methotrexate administration.
wide interindividual variability in the plasma concentrations of methotrexate has been
Methotrexate is indicated in the management of selected adults with severe, active,
Pulmonary function tests may be useful if methotrexate-induced lung disease is sus-
Recovery has been reported with discontinuation of therapy. (See PRECAU-
reported in pediatric patients with JRA. Following oral administration of methotrexate
rheumatoid arthritis (ACR criteria), or children with active polyarticular-course juvenile
pected, especially if baseline measurements are available. TIONS, Organ System Toxicity, Skin.)
in doses of 6.4 to 11.2 mg/m2/week in pediatric patients with JRA, mean serum con-centrations were 0.59 micromolar (range, 0.03 to 1.40) at 1 hour, 0.44 micromolar
rheumatoid arthritis, who have had an insufficient therapeutic response to, or are intol-
10. Potentially fatal opportunistic infections, especially Pneumocystis carinii pneu-
(range, 0.01 to 1.00) at 2 hours, and 0.29 micromolar (range 0.06 to 0.58) at 3 hours.
erant of, an adequate trial of first-line therapy including full dose non-steroidal anti-
Concomitant administration of some NSAIDs with high dose methotrexate therapy has
monia, may occur with methotrexate therapy.
In pediatric patients receiving methotrexate for acute lymphocytic leukemia (6.3 to
been reported to elevate and prolong serum methotrexate levels, resulting in deaths
11. Methotrexate given concomitantly with radiotherapy may increase the risk of
30 mg/m2), or for JRA (3.75 to 26.2 mg/m2), the terminal half-life has been reported to
Aspirin, NSAIDs, and/or low dose steroids may be continued, although the possibility
from severe hematologic and gastrointestinal toxicity.
soft tissue necrosis and osteonecrosis.
range from 0.7 to 5.8 hours or 0.9 to 2.3 hours, respectively.
of increased toxicity with concomitant use of NSAIDs including salicylates has not
Caution should be used when NSAIDs and salicylates are administered concomitantly
Distribution - After intravenous administration, the initial volume of distribution is
been fully explored. (See PRECAUTIONS, Drug Interactions.) Steroids may be reduced
with lower doses of methotrexate. These drugs have been reported to reduce the tubu-
approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution
gradually in patients who respond to methotrexate. Combined use of methotrexate
lar secretion of methotrexate in an animal model and may enhance its toxicity.
Methotrexate (formerly Amethopterin) is an antimetabolite used in the treatment of
is approximately 0.4 to 0.8 L/kg (40% to 80% of body weight). Methotrexate competes
with gold, penicillamine, hydroxychloroquine, sulfasalazine, or cytotoxic agents, has
Despite the potential interactions, studies of methotrexate in patients with rheumatoid
certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis.
with reduced folates for active transport across cell membranes by means of a single
not been studied and may increase the incidence of adverse effects. Rest and physio-
arthritis have usually included concurrent use of constant dosage regimens of NSAIDs,
carrier-mediated active transport process. At serum concentrations greater than
therapy as indicated should be continued.
Chemically methotrexate is N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methyl-
without apparent problems. It should be appreciated, however, that the doses used in
100 micromolar, passive diffusion becomes a major pathway by which effective intra-
L-glutamic acid. The structural formula is:
rheumatoid arthritis (7.5 to 15 mg/week) are somewhat lower than those used in
cellular concentrations can be achieved. Methotrexate in serum is approximately
Methotrexate can cause fetal death or teratogenic effects when administered to a preg-
psoriasis and that larger doses could lead to unexpected toxicity.
50% protein bound. Laboratory studies demonstrate that it may be displaced from
nant woman. Methotrexate is contraindicated in pregnant women with psoriasis or
plasma albumin by various compounds including sulfonamides, salicylates, tetracy-
rheumatoid arthritis and should be used in the treatment of neoplastic diseases only
Methotrexate is partially bound to serum albumin, and toxicity may be increased
clines, chloramphenicol, and phenytoin.
when the potential benefit outweighs the risk to the fetus. Women of childbearing
because of displacement by certain drugs, such as salicylates, phenylbutazone, pheny-
toin, and sulfonamides. Renal tubular transport is also diminished by probenecid; use
Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic
potential should not be started on methotrexate until pregnancy is excluded and
of methotrexate with this drug should be carefully monitored.
amounts when given orally or parenterally. High CSF concentrations of the drug may
should be fully counseled on the serious risk to the fetus (See PRECAUTIONS) should
Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spec-
be attained by intrathecal administration.
they become pregnant while undergoing treatment. Pregnancy should be avoided ifeither partner is receiving methotrexate; during and for a minimum of three months
trum antibiotics, may decrease intestinal absorption of methotrexate or interfere with
Rheumatrex Package Insert 10/30/03 12:36 PM Page 2
the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of
in the presence of preexisting liver damage or impaired hepatic function. Blood and Lymphatic System Disorders: suppressed hematopoiesis causing anemia,
been reported with acute, intermittent hemodialysis using a high-flux dialyzer (Wall,
to improve for another 12 weeks or more.
In psoriasis, liver function tests, including serum albumin, should be performed
aplastic anemia, pancytopenia, leukopenia, neutropenia and/or thrombocytopenia, lym-
SM et al: Am J Kidney Dis 28(6): 846-854, 1996).
The optimal duration of therapy is unknown. Limited data available from long-term
Penicillins may reduce the renal clearance of methotrexate; increased serum concen-
periodically prior to dosing but are often normal in the face of developing fibrosis or
phadenopathy and lymphoproliferative disorders (including reversible).
In postmarketing experience, overdose with methotrexate has generally occurred with
studies in adults indicate that the initial clinical improvement is maintained for at least
trations of methotrexate with concomitant hematologic and gastrointestinal toxicity
cirrhosis. These lesions may be detectable only by biopsy. The usual recommendation
Hypogammaglobulinemia has been reported rarely.
oral and intrathecal administration, although intravenous and intramuscular overdose
two years with continued therapy. When methotrexate is discontinued, the arthritis
have been observed with methotrexate. Use of methotrexate with penicillins should be
is to obtain a liver biopsy at 1) pretherapy or shortly after initiation of therapy
Cardiovascular: pericarditis, pericardial effusion, hypotension, and thromboembolic
usually worsens within 3 to 6 weeks.
(2 - 4 months), 2) a total cumulative dose of 1.5 grams, and 3) after each additional
events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis,
Reports of oral overdose often indicate accidental daily administration instead of week-
The patient should be fully informed of the risks involved and should be under con-
1.0 to 1.5 grams. Moderate fibrosis or any cirrhosis normally leads to discontinuation
retinal vein thrombosis, thrombophlebitis, and pulmonary embolus).
ly (single or divided doses). Symptoms commonly reported following oral overdose
stant supervision of the physician. (See Information for Patients under
The potential for increased hepatotoxicity when methotrexate is administered with
of the drug; mild fibrosis normally suggests a repeat biopsy in 6 months. Milder histo-
Central Nervous System: headaches, drowsiness, blurred vision, transient blindness,
include those symptoms and signs reported at pharmacologic doses, particularly
PRECAUTIONS.) Assessment of hematologic, hepatic, renal, and pulmonary function
other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been
logic findings such as fatty change and low grade portal inflammation are relatively
speech impairment including dysarthria and aphasia, hemiparesis, paresis and convul-
hematologic and gastrointestinal reaction. For example, leukopenia, thrombocytopenia,
should be made by history, physical examination, and laboratory tests before begin-
reported in such cases. Therefore, patients receiving concomitant therapy with
common pretherapy. Although these mild changes are usually not a reason to avoid or
sions have also occurred following administration of methotrexate. Following low
anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulcera-
ning, periodically during, and before reinstituting methotrexate therapy. (See PRECAU-
methotrexate and other potential hepatotoxins (eg, azathioprine, retinoids, sulfa-
discontinue methotrexate therapy, the drug should be used with caution.
doses, there have been occasional reports of transient subtle cognitive dysfunction,
tion, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding. In some
TIONS.) Appropriate steps should be taken to avoid conception during methotrexate
salazine) should be closely monitored for possible increased risk of hepatotoxicity.
In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have
mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy.
cases, no symptoms were reported. There have been reports of death following over-
therapy. (See PRECAUTIONS and CONTRAINDICATIONS.)
Methotrexate may decrease the clearance of theophylline; theophylline levels should be
been reported as risk factors for hepatotoxicity; other risk factors, similar to those
Hepatobiliary: disorders, hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis,
dose. In these cases, events such as sepsis or septic shock, renal failure, and aplastic
Weekly therapy may be instituted with the RHEUMATREX® Methotrexate Sodium
monitored when used concurrently with methotrexate.
observed in psoriasis, may be present in rheumatoid arthritis but have not been con-
decrease in serum albumin, liver enzyme elevations.
2.5 mg Tablet Dose Packs which are designed to provide doses over a range of 5 mg
Certain side effects such as mouth sores may be reduced by folate supplementation
firmed to date. Persistent abnormalities in liver function tests may precede appearance
Infection: There have been case reports of sometimes fatal opportunistic infections in
to 15 mg administered as a single weekly dose. The dose packs are not recommended
DOSAGE AND ADMINISTRATION
of fibrosis or cirrhosis in this population. There is a combined reported experience in
patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases.
for administration of methotrexate in weekly doses greater than 15 mg. All schedules
Trimethoprim/sulfa-methoxazole has been reported rarely to increase bone marrow
217 rheumatoid arthritis patients with liver biopsies both before and during treatment
Pneumocystis carinii pneumonia was the most common opportunistic infection. There
should be continually tailored to the individual patient. An initial test dose may be given
Oral administration in tablet form is often preferred when low doses are being adminis-
suppression in patients receiving methotrexate, probably by an additive antifolate
(after a cumulative dose of at least 1.5 g) and in 714 patients with a biopsy only dur-
have also been reports of infections, pneumonia, sepsis, nocardiosis, histoplasmosis,
prior to the regular dosing schedule to detect any extreme sensitivity to adverse
tered since absorption is rapid and effective serum levels are obtained.
ing treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis. Of
cryptococcosis, herpes zoster, H. simplex hepatitis, and disseminated H. simplex.
effects. (See ADVERSE REACTIONS.) Maximal myelosuppression usually occurs in
the 64 cases of fibrosis, 60 were deemed mild. The reticulin stain is more sensitive for
Choriocarcinoma and similar trophoblastic diseases: Methotrexate is administered
Carcinogenesis, Mutagenesis, and Impairment of Fertility Musculoskeletal System: stress fracture.
early fibrosis and its use may increase these figures. It is unknown whether even
orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course. Such
No controlled human data exist regarding the risk of neoplasia with methotrexate. Psoriasis: Recommended Starting Dose Schedules
longer use will increase these risks. Ophthalmic: conjunctivitis, serious visual changes of unknown etiology.
courses are usually repeated for 3 to 5 times as required, with rest periods of one or
Methotrexate has been evaluated in a number of animal studies for carcinogenic
more weeks interposed between courses, until any manifesting toxic symptoms sub-
1. Weekly single oral, IM or IV dose schedule: 10 to 25 mg per week until adequate
potential with inconclusive results. Although there is evidence that methotrexate caus-
Liver function tests should be performed at baseline and at 4-8 week intervals in
Pulmonary System: respiratory fibrosis, respiratory failure, interstitial pneumonitis;
side. The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analy-
es chromosomal damage to animal somatic cells and human bone marrow cells, the
patients receiving methotrexate for rheumatoid arthritis. Pretreatment liver biopsy
deaths have been reported, and chronic interstitial obstructive pulmonary disease has
sis of urinary chorionic gonadotropin (hCG), which should return to normal or less
2. Divided oral dose schedule: 2.5 mg at 12-hour intervals for three doses.
clinical significance remains uncertain. Non-Hodgkin’s lymphoma and other tumors
should be performed for patients with a history of excessive alcohol consumption, per-
than 50 IU/24 hr usually after the third or fourth course and usually be followed by a
have been reported in patients receiving low-dose oral methotrexate. However, there
sistently abnormal baseline liver function test values or chronic hepatitis B or C infec-
Skin: erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes,
Dosages in each schedule may be gradually adjusted to achieve optimal clinical
complete resolution of measurable lesions in 4 to 6 weeks. One to two courses of
have been instances of malignant lymphoma arising during treatment with low-dose
tion. During therapy, liver biopsy should be performed if there are persistent liver func-
alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic
response; 30 mg/week should not ordinarily be exceeded.
methotrexate after normalization of hCG is usually recommended. Before each course
oral methotrexate, which have regressed completely following withdrawal of
tion test abnormalities or there is a decrease in serum albumin below the normal range
epidermal necrolysis, Stevens-Johnson Syndrome, skin necrosis, skin ulceration, and
Once optimal clinical response has been achieved, each dosage schedule should be
of the drug careful clinical assessment is essential. Cyclic combination therapy of
methotrexate, without requiring active anti-lymphoma treatment. Benefits should be
(in the setting of well controlled rheumatoid arthritis).
reduced to the lowest possible amount of drug and to the longest possible rest period.
methotrexate with other antitumor drugs has been reported as being useful.
weighed against the potential risks before using methotrexate alone or in combination
If the results of a liver biopsy show mild changes (Roenigk grades I, II, IIIa),
Urogenital System: severe nephropathy or renal failure, azotemia, cystitis, hematuria;
The use of methotrexate may permit the return to conventional topical therapy, which
Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy
with other drugs, especially in pediatric patients or young adults. Methotrexate causes
methotrexate may be continued and the patient monitored as per recommendations
defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunc-
with methotrexate has been recommended.
embryotoxicity, abortion, and fetal defects in humans. It has also been reported to
listed above. Methotrexate should be discontinued in any patient who displays persis-
tion, vaginal discharge, and gynecomastia; infertility, abortion, fetal defects. HANDLING AND DISPOSAL
Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole.
cause impairment of fertility, oligospermia and menstrual dysfunction in humans, dur-
tently abnormal liver function tests and refuses liver biopsy or in any patient whose
Other rarer reactions related to or attributed to the use of methotrexate such as nodu-
Procedures for proper handling and disposal of anticancer drugs should be consid-
Methotrexate is administered in these disease states in doses similar to those recom-
ing and for a short period after cessation of therapy.
liver biopsy shows moderate to severe changes (Roenigk grade IIIb or IV).
losis, vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes, osteoporosis,
ered. Several guidelines on this subject have been published.1-5 There is no general
Pregnancy Infection or Immunologic States: Methotrexate should be used with extreme caution in
sudden death, reversible lymphomas, tumor lysis syndrome, soft tissue necrosis and
agreement that all of the procedures recommended in the guidelines are necessary or
Leukemia: Acute lymphoblastic leukemia in pediatric patients and young adolescents is
Psoriasis and rheumatoid arthritis: Methotrexate is in Pregnancy Category X.
the presence of active infection, and is usually contraindicated in patients with overt or
osteonecrosis. Anaphylactoid reactions have been reported.
the most responsive to present day chemotherapy. In young adults and older patients,
laboratory evidence of immunodeficiency syndromes. Immunization may be ineffective
Adverse Reactions in Double-Blind Rheumatoid Arthritis Studies HOW SUPPLIED
clinical remission is more difficult to obtain and early relapse is more common.
when given during methotrexate therapy. Immunization with live virus vaccines is gen-
The approximate incidences of methotrexate attributed (ie, placebo rate subtracted)
erally not recommended. There have been reports of disseminated vaccinia infections
Methotrexate alone or in combination with steroids was used initially for induction of
adverse reactions in 12 to 18 week double-blind studies of patients (n=128) with
after smallpox immunization in patients receiving methotrexate therapy.
remission in acute lymphoblastic leukemias. More recently corticosteroid therapy, in
rheumatoid arthritis treated with low-dose oral (7.5 to 15 mg/week) pulse methotrex-
Methotrexate Sodium Tablets contain an amount of methotrexate sodium equivalent to
Hypogammaglobulinemia has been reported rarely.
combination with other antileukemic drugs or in cyclic combinations with methotrex-
ate, are listed below. Virtually all of these patients were on concomitant nonsteroidal
Safety and effectiveness in pediatric patients have been established only in cancer
ate included, has appeared to produce rapid and effective remissions. When used for
2.5 mg of methotrexate and are round, convex, yellow tablets, scored in half on one side,
Potentially fatal opportunistic infections, especially Pneumocystis carinii pneumonia,
anti-inflammatory drugs and some were also taking low dosages of corticosteroids.
chemotherapy and in polyarticular-course juvenile rheumatoid arthritis.
induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of pred-
engraved with M above the score, and 1 below.
may occur with methotrexate therapy. When a patient presents with pulmonary symp-
Hepatic histology was not examined in these short-term studies. (See PRECAUTIONS.)
nisone, given daily, produced remissions in 50% of patients treated, usually within a
RHEUMATREX® Methotrexate Sodium Tablet 2.5 mg Dose Packs - (each tablet equivalent
Published clinical studies evaluating the use of methotrexate in children and adoles-
toms, the possibility of Pneumocystis carinii pneumonia should be considered.
Incidence greater than 10%: Elevated liver function tests 15%, nausea/vomiting 10%.
period of 4 to 6 weeks. Methotrexate in combination with other agents appears to be
cents (ie, patients 2 to 16 years of age) with JRA demonstrated safety comparable to
Pulmonary: Pulmonary symptoms (especially a dry nonproductive cough) or a non-
Incidence 3% to 10%: Stomatitis, thrombocytopenia, (platelet count less than
the drug of choice for securing maintenance of drug-induced remissions. When remis-
NDC 67253-580-42 - RHEUMATREX® Methotrexate Sodium Tablets Dose Pack –
that observed in adults with rheumatoid arthritis. (See CLINICAL PHARMACOLOGY,
specific pneumonitis occurring during methotrexate therapy may be indicative of a
sion is achieved and supportive care has produced general clinical improvement,
4 cards each containing two 2.5 mg tablets, i.e., 5 mg per week. ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION.)
potentially dangerous lesion and require interruption of treatment and careful investi-
Incidence 1% to 3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia
maintenance therapy is initiated, as follows: Methotrexate is administered 2 times
NDC 67253-580-43 - RHEUMATREX® Methotrexate Sodium Tablets Dose Pack –
gation. Although clinically variable, the typical patient with methotrexate induced lung
(WBC less than 3000/mm3), pancytopenia, dizziness.
weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2. It has
4 cards each containing three 2.5 mg tablets, i.e., 7.5 mg per week.
Clinical studies of methotrexate did not include sufficient numbers of subjects age 65
disease presents with fever, cough, dyspnea, hypoxemia, and an infiltrate on chest X-
also been given in doses of 2.5 mg/kg intravenously every 14 days. If and when
and over to determine whether they respond differently from younger subjects. In gen-
ray; infection (including pneumonia) needs to be excluded. This lesion can occur at all
Two other controlled trials of patients (n=680) with Rheumatoid Arthritis on
NDC 67253-580-44 - RHEUMATREX® Methotrexate Sodium Tablets Dose Pack –
relapse does occur, reinduction of remission can again usually be obtained by repeat-
eral, dose selection for an elderly patient should be cautious reflecting the greater fre-
7.5 mg – 15 mg/wk oral doses showed an incidence of interstitial pneumonitis of 1%.
4 cards each containing four 2.5 mg tablets, i.e., 10 mg per week.
quency of decreased hepatic and renal function, decreased folate stores, concomitant
Renal: Methotrexate may cause renal damage that may lead to acute renal failure.
NDC 67253-580-45 - RHEUMATREX® Methotrexate Sodium Tablets Dose Pack –
A variety of combination chemotherapy regimens have been used for both induction
disease or other drug therapy (ie, that interfere with renal function, methotrexate or
Nephrotoxicity is due primarily to the precipitation of methotrexate and 7-hydrox-
Other less common reactions included decreased hematocrit, headache, upper respira-
4 cards each containing five 2.5 mg tablets, i.e., 12.5 mg per week.
and maintenance therapy in acute lymphoblastic leukemia. The physician should be
folate metabolism) in this population (See PRECAUTIONS, Drug Interactions). Since
ymethotrexate in the renal tubules. Close attention to renal function including adequate
tory infection, anorexia, arthralgias, chest pain, coughing, dysuria, eye discomfort,
NDC 67253-580-46 - RHEUMATREX® Methotrexate Sodium Tablets Dose Pack –
familiar with the new advances in antileukemic therapy.
decline in renal function may be associated with increases in adverse events and
hydration, urine alkalinization and measurement of serum methotrexate and creatinine
epistaxis, fever, infection, sweating, tinnitus, and vaginal discharge.
4 cards each containing six 2.5 mg tablets, i.e., 15 mg per week. Lymphomas: In Burkitt’s tumor, Stages I-II, methotrexate has produced prolonged
serum creatinine measurements may over estimate renal function in the elderly, more
levels are essential for safe administration. Adverse Reactions in Psoriasis Store at controlled room temperature 20°-25°C (68°-77°F); excursions permitted to
remissions in some cases. Recommended dosage is 10 to 25 mg/day orally for 4 to
accurate methods (ie, creatine clearance) should be considered. Serum methotrexate
Skin: Severe, occasionally fatal, dermatologic reactions, including toxic epidermal
There are no recent placebo-controlled trials in patients with psoriasis. There are two
15°-30°C (59°-86°F). Protect from light.
8 days. In Stage III, methotrexate is commonly given concomitantly with other anti-
levels may also be helpful. Elderly patients should be closely monitored for early signs
necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and ery-
literature reports (Roenigk, 1969 and Nyfors, 1978) describing large series
tumor agents. Treatment in all stages usually consists of several courses of the drug
of hepatic, bone marrow and renal toxicity. In chronic use situations, certain toxicities
thema multiforme, have been reported in children and adults, within days of oral, intra-
(n=204, 248) of psoriasis patients treated with methotrexate. Dosages ranged up to
interposed with 7 to 10 day rest periods. Lymphosarcomas in Stage III may respond to
may be reduced by folate supplementation. Post-marketing experience suggests that
muscular, intravenous, or intrathecal methotrexate administration. Reactions were
25 mg per week and treatment was administered for up to four years. With the
combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily.
1. Controlling occupational exposure to hazardous drugs (OSHA Work-Practice
the occurence of bone marrow suppression, thrombocytopenia, and pneumonitis may
noted after single or multiple, low, intermediate or high doses of methotrexate in
exception of alopecia, photosensitivity, and “burning of skin lesions” (each 3% to 10%),
Guidelines). Am J Health Syst Pharm 1996: 53: 1669-1685.
increase with age. See Boxed WARNINGS and ADVERSE REACTIONS. Mycosis Fungoides (cutaneous T cell lymphoma): Therapy with methotrexate as a
patients with neoplastic and non-neoplastic diseases.
the adverse reaction rates in these reports were very similar to those in the rheumatoid
2. National Study Commission on Cytotoxic Exposure - Recommendations for
Organ System Toxicity
arthritis studies. Rarely, painful plaque erosions may appear.
single agent appears to produce clinical responses in up to 50% of patients treated. Other Precautions: Methotrexate should be used with extreme caution in the presence
Dosage in early stages is usuallly 5 to 50 mg once weekly. Dose reduction or cessation
Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc D, Chairman,
Gastrointestinal: If vomiting, diarrhea, or stomatitis occur, which may result in dehy-
Adverse Reactions in JRA Studies
is guided by patient response and hematologic monitoring. Methotrexate has also been
National Study Commission on Cytotoxic Exposure, Massachusetts College of
dration, methotrexate should be discontinued until recovery occurs. Methotrexate
Methotrexate exits slowly from third space compartments (eg, pleural effusions or
The approximate incidences of adverse reactions reported in pediatric patients with
administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have
Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston,
should be used with extreme caution in the presence of peptic ulcer disease or ulcera-
ascites). This results in a prolonged terminal plasma half-life and unexpected toxicity.
JRA treated with oral, weekly doses of methotrexate (5 to 20 mg/m2/wk or 0.1 to
In patients with significant third space accumulations, it is advisable to evacuate the
0.65 mg/kg/wk) were as follows (virtually all patients were receiving concomitant
Psoriasis, Rheumatoid Arthritis, and Juvenile Rheumatoid Arthritis
3. Clinical Oncological Society of Australia: Guidelines and recommendations for safe
Hematologic: Methotrexate can suppress hematopoiesis and cause anemia, aplastic ane-
fluid before treatment and to monitor plasma methotrexate levels.
nonsteroidal anti-inflammatory drugs, and some also were taking low doses of cortico-
handling of antineoplastic agents. Med J Australia 1983; 1:426-428.
mia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia. In patients with
steroids): elevated liver function tests, 14%; gastrointestinal reactions (eg, nausea,
Adult Rheumatoid Arthritis: Recommended Starting Dosage Schedules
Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radia-
4. Jones RB, et al. Safe handling of chemotherapeutic agents: A report from the Mount
malignancy and preexisting hematopoietic impairment, the drug should be used with
vomiting, diarrhea), 11%; stomatitis, 2%; leukopenia, 2%; headache, 1.2%; alopecia,
1. Single oral doses of 7.5 mg once weekly.
tion. Radiation dermatitis and sunburn may be “recalled” by the use of methotrexate.
Sinai Medical Center. CA - A Cancer Journal for Clinicians Sept/Oct 1983; 258-263.
caution, if at all. In controlled clinical trials in rheumatoid arthritis (n=128), leukopenia
0.5%; dizziness, 0.2%; and rash, 0.2%. Although there is experience with dosing up to
2. Divided oral dosages of 2.5 mg at 12 hour intervals for 3 doses given as a course
(WBC <3000/mm3) was seen in 2 patients, thrombocytopenia (platelets <100,000/mm3)
30 mg/m2/wk in JRA, the published data for doses above 20 mg/m2/wk are too limited
5. American Society of Hospital Pharmacists technical assistance bulletin on handling
in 6 patients, and pancytopenia in 2 patients. IN GENERAL, THE INCIDENCE AND SEVERITY OF ACUTE SIDE EFFECTS ARE RELAT-
to provide reliable estimates of adverse reaction rates.
cytotoxic and hazardous drugs. Am J Hosp Pharm 1990; 47:1033-1049. Polyarticular-Course Juvenile Rheumatoid Arthritis: The recommended starting dose is
ED TO DOSE AND FREQUENCY OF ADMINISTRATION. THE MOST SERIOUS REAC-
In psoriasis and rheumatoid arthritis, methotrexate should be stopped immediately if
OVERDOSAGE TIONS ARE DISCUSSED ABOVE UNDER ORGAN SYSTEM TOXICITY IN THE PRECAU-
there is a significant drop in blood counts. In the treatment of neoplastic diseases,
Leucovorin is indicated to diminish the toxicity and counteract the effect of inadver-
For either adult RA or polyarticular-course JRA dosages may be adjusted gradually to
TION SECTION. THAT SECTION SHOULD ALSO BE CONSULTED WHEN LOOKING FOR
methotrexate should be continued only if the potential benefit warrants the risk of
tently administered overdosages of methotrexate. Leucovorin administration should
achieve an optimal response. Limited experience shows a significant increase in the
INFORMATION ABOUT ADVERSE REACTIONS WITH METHOTREXATE.
severe myelosuppression. Patients with profound granulocytopenia and fever should be
begin as promptly as possible. As the time interval between methotrexate administra-
incidence and severity of serious toxic reactions, especially bone marrow suppression,
evaluated immediately and usually require parenteral broad-spectrum antibiotic therapy.
The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia,
tion and leucovorin initiation increases, the effectiveness of leucovorin in counteracting
at doses greater than 20 mg/wk in adults. Although there is experience with doses up
nausea, and abdominal distress. Other frequently reported adverse effects are malaise,
Hepatic: Methotrexate has the potential for acute (elevated transaminases) and chronic
toxicity decreases. Monitoring of the serum methotrexate concentration is essential in
to 30 mg/m2/wk in children, there are too few published data to assess how doses over
undue fatigue, chills and fever, dizziness and decreased resistance to infection.
(fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal; it generally
determining the optimal dose and duration of treatment with leucovorin.
20 mg/m2/wk might affect the risk of serious toxicity in children. Experience does sug-
has occurred after prolonged use (generally two years or more) and after a total dose
Other adverse reactions that have been reported with methotrexate are listed below
In cases of massive overdosage, hydration and urinary alkalinization may be necessary
gest, however, that children receiving 20 to 30 mg/m2/wk (0.65 to 1.0 mg/kg/wk) may
of at least 1.5 grams. In studies in psoriatic patients, hepatotoxicity appeared to be a
by organ system. In the oncology setting, concomitant treatment and the underlying
to prevent the precipitation of methotrexate and/or its metabolites in the renal tubules.
have better absorption and fewer gastrointestinal side effects if methotrexate is admin-
function of total cumulative dose and appeared to be enhanced by alcoholism, obesity,
disease make specific attribution of a reaction to methotrexate difficult.
Generally speaking, neither hemodialysis nor peritoneal dialysis have been shown to
istered either intramuscularly or subcutaneously.
diabetes and advanced age. An accurate incidence rate has not been determined; the
Alimentary System: gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diar-
improve methotrexate elimination. However, effective clearance of methotrexate has
Therapeutic response usually begins within 3 to 6 weeks and the patient may continue
rate of progression and reversibility of lesions is not known. Special caution is indicated
rhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitis.
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