See BOXED WARNINGS.
Methotrexate formulations and diluents containing
preservatives must not be used for intrathecal or high dose methotrexate
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 with increased alertness as to possible recurrence of
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.
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 (eg, 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
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.
Carcinogenesis, Mutagenesis, and 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 risks 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
Psoriasis and rheumatoid arthritis: Methotrexate is in
Pregnancy Category X. See CONTRAINDICATIONS.
Safety and effectiveness in pediatric patients have been
established only in cancer chemotherapy and in polyarticular-course juvenile
Published clinical studies evaluating the use of
methotrexate in children and adolescents (ie, 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.)
Clinical studies of methotrexate did not include
sufficient numbers of subjects age 65 and over to determine whether they
respond differently from younger subjects. In general, dose selection for an
elderly patient should be cautious reflecting the greater frequency of
decreased hepatic and renal function, decreased folate stores, concomitant disease
or other drug therapy (ie, that interfere with renal function, methotrexate or folate
metabolism) in this population (See PRECAUTIONS: DRUG INTERACTIONS).
Since decline in renal function may be associated with increases in adverse
events and serum creatinine measurements may over estimate renal function in
the elderly, more accurate methods (ie, creatine clearance) should be
considered. Serum methotrexate levels may also be helpful. Elderly patients
should be closely monitored for early signs of hepatic, bone marrow and renal
toxicity. In chronic use situations, certain toxicities may be reduced by
folate supplementation. Post-marketing experience suggests that the occurence
of bone marrow suppression, thrombocytopenia, and pneumonitis may increase with
age. See BOXED WARNINGS and ADVERSE REACTIONS.
Organ System Toxicity
If vomiting, diarrhea, or stomatitis occur, which may
result in dehydration, methotrexate should be discontinued until recovery
occurs. Methotrexate should be used with extreme caution in the presence of
peptic ulcer disease or ulcerative colitis.
Methotrexate can suppress hematopoiesis and cause anemia,
aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or
thrombocytopenia. In patients with malignancy and preexisting hematopoietic
impairment, the drug should be used with caution, if at all. In controlled
clinical trials in rheumatoid arthritis (n=128), leucopenia (WBC < 3000/mm³)
was seen in 2 patients, thrombocytopenia (platelets < 100,000/mm³) in 6
patients, and pancytopenia in 2 patients.
In psoriasis and rheumatoid arthritis, methotrexate
should be stopped immediately if there is a significant drop in blood counts.
In the treatment of neoplastic diseases, methotrexate should be continued only
if the potential benefit warrants the risk of severe myelosuppression. Patients
with profound granulocytopenia and fever should be evaluated immediately and
usually require parenteral broad-spectrum antibiotic therapy.
Methotrexate has the potential for acute (elevated
transaminases) and chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic
toxicity is potentially fatal; it generally has occurred after prolonged use
(generally two years or more) and after a total dose of at least 1.5 grams. In
studies in psoriatic patients, hepatotoxicity appeared to be a function of
total cumulative dose and appeared to be enhanced by alcoholism, obesity, diabetes
and advanced age. An accurate incidence rate has not been determined; the rate
of progression and reversibility of lesions is not known. Special caution is
indicated in the presence of preexisting liver damage or impaired hepatic
In psoriasis, liver function tests, including serum
albumin, should be performed periodically prior to dosing but are often normal
in the face of developing fibrosis or cirrhosis. These lesions may be
detectable only by biopsy. The usual recommendation is to obtain a liver biopsy
at 1) pretherapy or shortly after initiation of therapy (2 - 4 months), 2) a
total cumulative dose of 1.5 grams, and 3) after each additional 1.0 to 1.5
grams. Moderate fibrosis or any cirrhosis normally leads to discontinuation of
the drug; mild fibrosis normally suggests a repeat biopsy in 6 months. Milder
histologic findings such as fatty change and low grade portal inflammation are
relatively common pretherapy. Although these mild changes are usually not a
reason to avoid or discontinue methotrexate therapy, the drug should be used
In rheumatoid arthritis, age at first use of methotrexate
and duration of therapy have been reported as risk factors for hepatotoxicity;
other risk factors, similar to those observed in psoriasis, may be present in
rheumatoid arthritis but have not been confirmed to date. Persistent
abnormalities in liver function tests may precede appearance of fibrosis or
cirrhosis in this population. There is a combined reported experience in 217
rheumatoid arthritis patients with liver biopsies both before and during
treatment (after a cumulative dose of at least 1.5 g) and in 714 patients with
a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1
(0.1%) case of cirrhosis. Of the 64 cases of fibrosis, 60 were deemed mild. The
reticulin stain is more sensitive for early fibrosis and its use may increase
these figures. It is unknown whether even longer use will increase these risks.
Liver function tests should be performed at baseline and
at 4-8 week intervals in patients receiving methotrexate for rheumatoid
arthritis. Pretreatment liver biopsy should be performed for patients with a
history of excessive alcohol consumption, persistently abnormal baseline liver
function test values or chronic hepatitis B or C infection. During therapy,
liver biopsy should be performed if there are persistent liver function test
abnormalities or there is a decrease in serum albumin below the normal range (in
the setting of well controlled rheumatoid arthritis).
If the results of a liver biopsy show mild changes
(Roenigk grades I, II, IIIa), methotrexate may be continued and the patient
monitored as per recommendations listed above. Methotrexate should be
discontinued in any patient who displays persistently abnormal liver function
tests and refuses liver biopsy or in any patient whose liver biopsy shows
moderate to severe changes (Roenigk grade IIIb or IV).
Infection or Immunologic States
Methotrexate should be used with extreme caution in the
presence of active infection, and is usually contraindicated in patients with
overt or laboratory evidence of immunodeficiency syndromes. Immunization may be
ineffective when given during methotrexate therapy. Immunization with live
virus vaccines is generally not recommended. There have been reports of
disseminated vaccinia infections after smallpox immunization in patients
receiving methotrexate therapy.
Hypogammaglobulinemia has been reported rarely.
Potentially fatal opportunistic infections, especially Pneumocystis
carinii pneumonia, may occur with methotrexate therapy. When a patient presents
with pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia
should be considered.
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 Xray; infection (including
pneumonia) needs to be excluded. This lesion can occur at all dosages.
Methotrexate may cause renal damage that may lead to
acute renal failure. Nephrotoxicity is due primarily to the precipitation of
methotrexate and 7-hydroxymethotrexate in the renal tubules. Close attention to
renal function including adequate hydration, urine alkalinization and
measurement of serum methotrexate and creatinine levels are essential for safe
Severe, occasionally fatal, dermatologic reactions,
including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative
dermatitis, skin necrosis, and erythema multiforme, have been reported in
children and adults, within days of oral, intramuscular, intravenous, or
intrathecal methotrexate administration. Reactions were noted after single or
multiple, low, intermediate or high doses of methotrexate in patients with
neoplastic and non-neoplastic diseases.
Methotrexate should be used with extreme caution in the
presence of debility.
Methotrexate exits slowly from third space compartments
(eg, pleural effusions or ascites). This results in a prolonged terminal plasma
half-life and unexpected toxicity. In patients with significant third space
accumulations, it is advisable to evacuate the fluid before treatment and to
monitor plasma methotrexate levels.
Lesions of psoriasis may be aggravated by concomitant
exposure to ultraviolet radiation. Radiation dermatitis and sunburn may be
“recalled” by the use of methotrexate.