Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1862
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Methotrexate (Injection, Solution)
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Neoplastic Diseases Oral administration in tablet form is often
preferred when low doses are being administered since absorption is
rapid and effective serum levels are obtained. Methotrexate injection
may be given by the intramuscular, intravenous or intra-arterial route. However, the preserved formulation contains
Benzyl Alcohol and must not be used for intrathecal or high dose therapy. Parenteral drug products should be inspected visually for particulate
matter and discoloration prior to administration, whenever solutionand container permit. Choriocarcinoma and similar trophoblastic diseases: Methotrexate
is administered orally or intramuscularly in doses of 15 to 30 mg
daily for a five-day course. Such courses are usually repeated for
3 to 5 times as required, with rest periods of one or more weeks interposed
between courses, until any manifesting toxic symptoms subside. The
effectiveness of therapy is ordinarily evaluated by 24 hour quantitative
analysis of urinary chorionic gonadotropin (hCG), which should return
to normal or less than 50 IU/24 hr usually after the third or fourth
course and usually be followed by a complete resolution of measurable
lesions in 4 to 6 weeks. One to two courses of methotrexate after
normalization of hCG is usually recommended. Before each course of
the drug careful clinical assessment is essential. Cyclic combination
therapy of methotrexate with other antitumor drugs has been reported
as being useful. Since hydatidiform mole may
precede choriocarcinoma, prophylactic chemotherapy with methotrexate
has been recommended. Chorioadenoma destruens
is considered to be an invasive form of hydatidiform mole. Methotrexate is administered in these disease states in
doses similar to those recommended for choriocarcinoma. Leukemia: Acute
lymphoblastic leukemia in pediatric patients and young adolescents
is the most responsive to present day chemotherapy. In young adults
and older patients, clinical remission is more difficult to obtain
and early relapse is more common. Methotrexate
alone or in combination with steroids was used initially for induction
of remission in acute lymphoblastic leukemias. More recently corticosteroid
therapy, in combination with other antileukemic drugs or in cyclic
combinations with methotrexate included, has appeared to produce rapid
and effective remissions. When used for induction, methotrexate in
doses of 3.3 mg/min combination with 60 mg/mof prednisone, given daily, produced remissions in 50% of patients
treated, usually within a period of 4 to 6 weeks. Methotrexate in
combination with other agents appears to be the drug of choice for
securing maintenance of drug-induced remissions. When remission is
achieved and supportive care has produced general clinical improvement,
maintenance therapy is initiated, as follows: Methotrexate is administered
2 times weekly either by mouth or intramuscularly in total weekly
doses of 30 mg/m. It has also been given in doses of 2.5
mg/kg intravenously every 14 days. If and when relapse does occur,
reinduction of remission can again usually be obtained by repeating
the initial induction regimen. A variety of
combination chemotherapy regimens have been used for both induction
and maintenance therapy in acute lymphoblastic leukemia. The physician
should be familiar with the new advances in antileukemic therapy. Meningeal Leukemia: In the treatment of prophylaxis of meningeal leukemia, methotrexate
must be administered intrathecally. Preservative free methotrexate
is diluted to a concentration of 1 mg/mL in an appropriate sterile,
preservative free medium such as 0.9% Sodium Chloride Injection, USP. The cerebrospinal fluid volume is dependent on age and
not on body surface area. The CSF is at 40% of the adult volume at
birth and reaches the adult volume in several years. Intrathecal methotrexate administration at a dose of 12 mg/m(maximum 15 mg) has been reported to result in low CSF methotrexate
concentrations and reduced efficacy in pediatric patients and high
concentrations and neurotoxicity in adults. The following dosage regimen
is based on age instead of body surface area: In one study in patients under the age of 40, this
dosage regimen appeared to result in more consistent CSF methotrexate
concentrations and less neurotoxicity. Another study in pediatric
patients with acute lymphocytic leukemia compared this regimen to
a dose of 12 mg/m(maximum 15 mg), a significant reduction
in the rate of CNS relapse was observed in the group whose dose was
based on age. Because the CSF volume and turnover
may decrease with age, a dose reduction may be indicated in elderly
patients. For treatment of meningeal leukemia,
intrathecal methotrexate may be given at intervals of 2 to 5 days.
However, administration at intervals of less than 1 week may result
in increased subacute toxicity. Methotrexate is administered until
the cell count of the cerebrospinal fluid returns to normal. At this
point one additional dose is advisable. For prophylaxis against meningeal
leukemia, the dosage is the same as for treatment except for the intervals
of administration. On this subject, it is advisable for the physician
to consult the medical literature. Untoward
side effects may occur with any given intrathecal injection and are
commonly neurological in character. Large doses may cause convulsions.
Methotrexate given by the intrathecal route appears significantly
in the systemic circulation and may cause systemic methotrexate toxicity.
Therefore, systemic antileukemic therapy with the drug should be appropriately
adjusted, reduced or discontinued. Focal leukemic involvement of the
central nervous system may not respond to intrathecal chemotherapy
and is best treated with radiotherapy. Lymphomas: In Burkitt's tumor,
Stages I-II, methotrexate has produced prolonged remissions in some
cases. Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days.
In Stage III, methotrexate is commonly given concomitantly with other
antitumor agents. Treatment in all stages usually consists of several
courses of the drug interposed with 7 to 10 day rest periods. Lymphosarcomas
in Stage III may respond to combined drug therapy with methotrexate
given in doses of 0.625 to 2.5 mg/kg daily. Mycosis fungoides (cutaneous T cell
lymphoma): Therapy with methotrexate as a single agent appears
to produce clinical responses in up to 50% of patients treated. Dosage
in early stages is usually 5 to 50 mg once weekly. Dose reduction
or cessation is guided by patient response and hematologic monitoring.
Methotrexate has also been administered twice weekly in doses ranging
from 15 to 37.5 mg in patients who have responded poorly to weekly
therapy. Combination chemotherapy regimens that include intravenous
methotrexate administered at higher doses with leucovorin rescue have
been utilized in advanced stages of the disease. Osteosarcoma: An effective
adjuvant chemotherapy regimen requires the administration of several
cytotoxic chemotherapeutic agents. In addition to high-dose methotrexate
with leucovorin rescue, these agents may include doxorubicin, cisplatin,
and the combination of bleomycin, cyclophosphamide and dactinomycin
(BCD) in the doses and schedule shown in the table below. The starting
dose for high-dose methotrexate treatment is 12 grams/m. If this dose is not sufficient to produce a peak serum methotrexate
concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate
infusion, the dose may be escalated to 15 grams/min subsequent
treatments. If the patient is vomiting or is unable to tolerate oral
medication, leucovorin is given IV or IM at the same dose and schedule. When these higher doses of methotrexate are to
be administered, the following safety guidelines should be closely
observed. GUIDELINES
FOR METHOTREXATE THERAPY WITH LEUCOVORIN RESCUE 1. Administration of methotrexate should be delayed until
recovery if: ���the WBC count is less
than 1500/microliter ���the neutrophil
count is less than 200/microliter ���the platelet count is less than 75,000/microliter ���the serum bilirubin level is greater than 1.2 mg/dL ���the SGPT level is greater than 450 U ���mucositis is present, until there is evidence
of healing ���persistent pleural effusion
is present; this should be drained dry prior to infusion. 2. Adequate renal function must be documented. a. Serum creatinine must be normal, and creatinine
clearance must be greater than 60 mL/min, before initiation of therapy. b. Serum creatinine must be measured prior to each
subsequent course of therapy. If serum creatinine has increased by
50% or more compared to a prior value, the creatinine clearance must
be measured and documented to be greater than 60 mL/min (even if the
serum creatinine is still within the normal range). 3. Patients must be well hydrated, and must be treated with sodium
bicarbonate for urinary alkalinization. a.
Administer 1,000 mL/mof intravenous fluid over 6 hours
prior to initiation of the methotrexate infusion. Continue hydration
at 125 mL/m/hr (3 liters/m/day) during the
methotrexate infusion, and for 2 days after the infusion has been
completed. b. Alkalinize urine to maintain
pH above 7.0 during methotrexate infusion and leucovorin calcium therapy.
This can be accomplished by the administration of sodium bicarbonate
orally or by incorporation into a separate intravenous solution. 4. Repeat serum creatinine and serum methotrexate 24 hours
after starting methotrexate and at least once daily until the methotrexate
level is below 5 x 10mol/L (0.05 micromolar). 5. The table below provides guidelines for leucovorin
calcium dosage based upon serum methotrexate levels. (See table below.) Patients who experience delayed
early methotrexate elimination are likely to develop nonreversible
oliguric renal failure. In addition to appropriate leucovorin therapy,
these patients require continuing hydration and urinary alkalinization,
and close monitoring of fluid and electrolyte status, until the serum
methotrexate level has fallen to below 0.05 micromolar and the renal
failure has resolved. If necessary, acute, intermittent hemodialysis
with a high-flux dialyzer may also be beneficial in these patients. 6. Some patients will have abnormalities in methotrexate
elimination, or abnormalities in renal function following methotrexate
administration, which are significant but less severe than the abnormalities
described in the table below. These abnormalities may or may not be
associated with significant clinical toxicity. If significant toxicity
is observed, leucovorin rescue should be extended for an additional
24 hours (total 14 doses over 84 hours) in subsequent courses of therapy.
The possibility that the patient is taking other medications which
interact with methotrexate (e.g., medications which may interfere
with methotrexate binding to serum albumin, or elimination) should
always be reconsidered when laboratory abnormalities or clinical toxicities
are observed. CAUTION: DO NOT ADMINISTER LEUCOVORIN
INTRATHECALLY. Psoriasis,
Rheumatoid Arthritis, and Juvenile Rheumatoid Arthritis Adult Rheumatoid Arthritis: Recommended Starting Dosage Schedules Polyarticular-Course
Juvenile Rheumatoid Arthritis: The recommended starting
dose is 10 mg/mgiven once weekly. For either adult RA or polyarticular-course JRA, dosages may be adjusted
gradually to achieve an optimal response. Limited experience shows
a significant increase in the incidence and severity of serious toxic
reactions, especially bone marrow suppression, at doses greater than
20 mg/wk in adults. Although there is experience with doses up to
30 mg/m/wk in children, there are too few published data
to assess how doses over 20 mg/m/wk might affect the risk
of serious toxicity in children. Experience does suggest, however,
that children receiving 20 to 30 mg/m/wk (0.65 to 1.0
mg/kg/wk) may have better absorption and fewer gastrointestinal side
effects if methotrexate is administered either intramuscularly or
subcutaneously. Therapeutic response usually
begins within 3 to 6 weeks and the patient may continue to improve
for another 12 weeks or more. The optimal duration
of therapy is unknown. Limited data available from long-term studies
in adults indicate that the initial clinical improvement is maintained
for at least two years with continued therapy. When methotrexate is
discontinued, the arthritis usually worsens within 3 to 6 weeks. The patient should be fully
informed of the risks involved and should be under constant supervision
of the physician. (See Information
for Patients under PRECAUTIONS). Assessment of hematologic, hepatic, renal, and pulmonary function
should be made by history, physical examination, and laboratory tests
before beginning, periodically during, and before reinstituting methotrexate
therapy. (See PRECAUTIONS). Appropriate
steps should be taken to avoid conception during methotrexate therapy.
(See PRECAUTIONS and CONTRAINDICATIONS). All schedules should be continually tailored to the individual patient.
An initial test dose may be given prior to the regular dosing schedule
to detect any extreme sensitivity to adverse effects (See ADVERSE REACTIONS). Maximal myelosuppression
usually occurs in seven to ten days. Psoriasis: Recommended Starting Dose Schedule: Dosages in each schedule may be gradually adjusted
to achieve optimal clinical response; 30 mg/week should not ordinarily
be exceeded. Once optimal clinical response
has been achieved, each dosage schedule should be reduced to the lowest
possible amount of drug and to the longest possible rest period. The
use of methotrexate may permit the return to conventional topical
therapy, which should be encouraged. HANDLING AND DISPOSAL Procedures for proper handling and disposal of anticancer drugs should
be considered. Several guidelines on this subject have been published.There is no general agreement that all of the procedures
recommended in the guidelines are necessary or appropriate. DILUTION INSTRUCTIONS FOR LIQUID
METHOTREXATE INJECTION PRODUCT Methotrexate Injection, USP, Isotonic Liquid,
Contains Preservative If desired,
the solution may be further diluted with a compatible medium such
as Sodium Chloride Injection, USP. Storage for 24 hours at a temperature
of 21��C to 25��C results in a product which is within 90%
of label potency. Methotrexate Injection, USP, Isotonic Liquid, Preservative Free,
for Single Use Only If desired, the
solution may be further diluted immediately prior to use with an appropriate
sterile, preservative free medium such as 5% Dextrose Solution, USP
or Sodium Chloride Injection, USP.
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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: 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. 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 adjustthe 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.
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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 malignantgrowth 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 erosionsand
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 reductase resulting from geneamplification, 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/mprovided 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/m/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/mwas 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/mor less,
methotrexate is generally well absorbed with a mean bioavailability
of about 60%. The absorption of doses greater than 80 mg/mis 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 (C: 0.11 to 2.3 micromolar after a 20 mg/mdose) has been reported. Significant interindividual variability
has also been noted in time to peak concentration (T: 0.67 to 4 hrs after a 15 mg/mdose) and fraction of
dose absorbed. The absorption of doses greater than 40 mg/mhas 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
interindividualvariability 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/m/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/m), or for JRA (3.75 to 26.2 mg/m), 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 ofa single carrier-mediated active transport process. At
serum concentrations greater than 100 micromolar, passive diffusion
becomes a major pathway by which effective intracellular concentrations
can be achieved. Methotrexate in serum is approximately 50% protein
bound. Laboratory studies demonstrate that it may be displaced from
plasma albumin by various compounds including sulfonamides, salicylates,
tetracyclines, chloramphenicol, and phenytoin. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier
in therapeutic amounts when given orally 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/m).
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. Enterohepaticrecirculation
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 betweenmethotrexate
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. 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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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 shouldbe 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). 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.
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Parenteral: Methotrexate Injection, USP,
Isotonic Liquid, Contains Preservative. Each 25 mg/mL, 2
mL vial contains methotrexate sodium equivalent to 50 mg methotrexate. Methotrexate Injection,
USP, Isotonic Liquid, Preservative Free, for Single Use Only. Each 10 mg/mL, 2 mL vial contains methotrexate sodium equivalent
to 20 mg methotrexate. Methotrexate Injection,
USP, Isotonic Liquid, Preservative Free, for Single Use Only. 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. Store at controlled room
temperature, 25��C (77��F); excursions permitted to 15��to 30��C (59��to 86��F). PROTECT FROM LIGHT. Hospira, Inc. Lake Forest, IL 60045 Product of Australia Revision August 2007 ���LEUCOVORIN RESCUE SCHEDULES
FOLLOWING TREATMENT WITH HIGHER DOSES OF METHOTREXATE
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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.
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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.<br/>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. 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.<br/>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.<br/>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. 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.<br/>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 beforeusing 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.<br/>Pregnancy: Psoriasis and rheumatoid arthritis: Methotrexate
is in Pregnancy Category X. See CONTRAINDICATIONS.<br/>Nursing Mothers: See CONTRAINDICATIONS.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have
been established only in cancer chemotherapy and in polyarticular-course
juvenile rheumatoid arthritis. 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) following the administrations
of intravenous solutions containing the preservative benzyl alcohol.
Symptoms include a striking onset of gasping respiration, hypotension,
bradycardia, and cardiovascular collapse. Serious
neurotoxicity, frequently manifested as generalized or focal seizures,
has been reported with unexpectedly increased frequency among pediatric
patients with acute lymphoblastic leukemia who were treated with intermediate-dose
intravenous methotrexate (1 gm/m). (See PRECAUTIONS, Organ System Toxicity, Neurologic).<br/>Geriatric Use: 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 (i.e., 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 (i.e., creatinine 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 occurrence of bone marrow suppression, thrombocytopenia, and pneumonitis
may increase with age. See Boxed WARNINGS and ADVERSE REACTIONS. Organ System Toxicity Gastrointestinal: If vomiting, diarrhea, or stomatitis occur, which may result in
dehydration, methotrexate should be discontinued until recovery occurs.
Methotrexate should be used with extreme caution in the presence of
peptic ulcer disease or ulcerative colitis. Hematologic: Methotrexate
can suppress hematopoiesis and cause anemia, 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), leukopenia (WBC<3000/mm) was seen in 2 patients, thrombocytopenia (platelets<100,000/mm) 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. Hepatic: 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 function. In psoriasis, liver function tests, including serum albumin,
should be performed periodically prior to dosing but are often normal
in the face of developing fibrosis or cirrhosis. These lesions may
be detectable only by biopsy. The usual recommendation is to obtain
a liver biopsy at 1) pretherapy or shortly after initiation of therapy
(2 to 4 months), 2) a total cumulative dose of 1.5 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
with caution. In rheumatoid arthritis, age at
first use of methotrexate and duration of therapy have been reported
as risk factors for hepatotoxicity; other risk factors, similar to
those observed in psoriasis, may be present in rheumatoid arthritis
but have not been confirmed to date. Persistent abnormalities in liver
function tests may precede appearance of fibrosis or cirrhosis in
this population. There is a combined reported experience in 217 rheumatoid
arthritis patients with liver biopsies both before and during treatment
(after a cumulative dose of at lease 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 at 4 to 8 week intervals
in patients receiving methotrexate for rheumatoid arthritis. Pretreatment
liver biopsy should be performed for patients with a history of excessive
alcohol consumption, persistently abnormal baseline liver function
test values or chronic hepatitis B or C infection. During therapy,
liver biopsy should be performed if there are persistent liver function
test abnormalities or there is a decrease in serum albumin below the
normal range (in the setting of well controlled rheumatoid arthritis). If the results of a liver biopsy show mild changes (Roenigk,
grades I, II, IIIa), methotrexate may be continued and the patient
monitored as per recommendations listed above. Methotrexate should
be discontinued in any patient who displays persistently abnormal
liver function tests and refuses liver biopsy or in any patient whose
liver biopsy shows moderate to severe changes (Roenigk grade IIIb
or IV). Infection
or Immunologic States: Methotrexate should be used with
extreme caution in the presence of active infection, and is usually
contraindicated in patients with overt or laboratory evidence of immunodeficiency
syndromes. Immunization may be ineffective when given during methotrexate
therapy. Immunization with live virus vaccines is generally not recommended.
There have been reports of disseminated vaccinia infections after
smallpox immunizations 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. Neurologic: There have been
reports of leukoencephalopathy following intravenous administration
of methotrexate to patients who have had craniospinal irradiation.
Serious neurotoxicity, frequently manifested as generalized or focal
seizures, has been reported with unexpectedly increased frequency
among pediatric patients with acute lymphoblastic leukemia who were
treated with intermediate-dose intravenous methotrexate (1 gm/m). Symptomatic patients were commonly noted to have leukoencephalopathy
and/or microangiopathic calcifications on diagnostic imaging studies.
Chronic leukoencephalopathy has also been reported in patients who
received repeated doses of high-dose methotrexate with leucovorin
rescue even without cranial irradiation. Discontinuation of methotrexate
does not always result in complete recovery. A transient acute neurologic syndrome has been observed in patients
treated with high dose regimens. Manifestations of this stroke-like
encephalopathy may include confusion, hemiparesis, transient blindness,
seizures and coma. The exact cause is unknown. After the intrathecal use of methotrexate, the central nervous system
toxicity which may occur can be classified as follows: acute chemical
arachnoiditis manifested by such symptoms as headache, back pain,
nuchal rigidity, and fever; sub-acute myelopathy characterized by
paraparesis/paraplegia associated with involvement with one ormore
spinal nerve roots; chronic leukoencephalopathy manifested by confusion,
irritability, somnolence, ataxia, dementia, seizures and coma. This
condition can be progressive and even fatal. Pulmonary: Pulmonary symptoms
(especially a dry nonproductive cough) or a non-specific pneumonitis
occurring during methotrexate therapy may be indicative of a potentially
dangerous lesion and require interruption of treatment and careful
investigation. Although clinically variable, the typical patient with
methotrexate induced lung disease presents with fever, cough, dyspnea,
hypoxemia, and an infiltrate on chest X-ray; infection (including
pneumonia) needs to be excluded. This lesion can occur at all dosages. Renal: Methotrexate
may cause renal damage that may lead to acute renal failure. High
doses of methotrexate used in the treatment of osteosarcoma may cause
renal damage leading to acute renal failure. Nephrotoxicity is due
primarily to the precipitation of methotrexate and 7-hydroxymethotrexate
in the renal tubules. Close attention to renal function including
adequate hydration, urine alkalinization and measurement of serum
methotrexate and creatinine levels are essential for safe administration. Skin: Severe, occasionally
fatal, dermatologic reactions, including toxic epidermal necrolysis,
Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and
erythema multiforme, have been reported in children and adults, within
days of oral, 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. Other precautions:
Methotrexate should be used with extreme caution in the presence of
debility. Methotrexate exits slowly from third
space compartments (e.g., pleural effusions or ascites). This results
in a prolonged terminal plasma half-life and unexpected toxicity.
In patients with significant third space accumulations, it is advisable
to evacuate the fluid before treatment and to monitor plasma methotrexate
levels. Lesions of psoriasis may be aggravated
by concomitant exposure to ultraviolet radiation. Radiation dermatitis
and sunburn may be���recalled���by the use of methotrexate.
|
| dailymed-instance:overdosag... |
Leucovorin is indicated to diminish the toxicity
and counteract the effect of inadvertently administered overdosages
of methotrexate. Leucovorin administration should begin as promptly
as possible. As the time interval between methotrexate administration
and leucovorin initiation increases, the effectiveness of leucovorin
in counteracting toxicity decreases. Monitoring of the serum methotrexate
concentration is essential in determining the optimal dose and duration
of treatment with leucovorin. In cases of massive
overdosage, hydration and urinary alkalinization may be necessary
to prevent the precipitation of methotrexate and/or its metabolites
in the renal tubules. Generally speaking, neither hemodialysis nor
peritoneal dialysis has been shown to improve methotrexate elimination.
However, effective clearance of methotrexate has been reported with
acute, intermittent hemodialysis using a high-flux dialyzer (Wall,
SM et al: Am J Kidney Dis 28
(6): 846-854, 1996). Accidental intrathecal
overdosage may require intensive systemic support, high-dose systemic
leucovorin, alkaline diuresis and rapid CSF drainage and ventriculolumbar
perfusion. In postmarketing experience, overdose
with methotrexate has generally occurred with oral and intrathecal
administration, although intravenous and intramuscular overdose have
also been reported. Reports of oral overdose
often indicate accidental daily administration instead of weekly (single
or divided doses). Symptoms commonly reported following oral overdose
include those symptoms and signs reported at pharmacologic doses,
particularly hematologic and gastrointestinal reaction. For example,
leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression,
mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal
ulceration, gastrointestinal bleeding. In some cases, no symptoms
were reported. There have been reports of death following overdose.
In these cases, events such as sepsis or septic shock, renal failure,
and aplastic anemia were also reported. Symptoms
of intrathecal overdose are generally central nervous system (CNS)
symptoms, including headache, nausea and vomiting, seizure or convulsion,
and acute toxic encephalopathy. In some cases, no symptoms were reported.
There have been reports of death following intrathecal overdose. In
these cases, cerebellar herniation associated with increased intracranial
pressure, and acute toxic encephalopathy have also been reported. There are published case reports of intravenous and intrathecal
carboxypeptidase G2 treatment to hasten clearance of methotrexate
in cases of overdose.
|
| dailymed-instance:genericMe... |
methotrexate sodium
|
| dailymed-instance:fullName |
Methotrexate (Injection, Solution)
|
| dailymed-instance:adverseRe... |
IN GENERAL, THE INCIDENCE
AND SEVERITY OF ACUTE SIDE EFFECTS ARE RELATED TO DOSE AND FREQUENCY
OF ADMINISTRATION. THE MOST SERIOUS REACTIONS ARE DISCUSSED ABOVE
UNDER ORGAN SYSTEM TOXICITY IN THE PRECAUTION SECTION. THAT SECTION
SHOULD ALSO BE CONSULTED WHEN LOOKING FOR INFORMATION ABOUT ADVERSE
REACTIONS WITH METHOTREXATE. The most
frequently reported adverse reactions include ulcerative stomatitis,
leukopenia, nausea, and abdominal distress. Other frequently reported
adverse effects are malaise, undue fatigue, chills and fever, dizziness
and decreased resistance to infection. Other
adverse reactions that have been reported with methotrexate are listed
below by organ system. In the oncology setting, concomitant treatment
and the underlying disease make specific attribution of a reaction
to methotrexate difficult. Alimentary System: gingivitis, pharyngitis,
stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena,
gastrointestinal ulceration and bleeding, enteritis, pancreatitis. Blood and Lymphatic System
Disorders: suppressed hematopoiesis, anemia, aplastic anemia,
pancytopenia, leukopenia, neutropenia, thrombocytopenia, agranulocytosis,
eosinophilia, lymphadenopathy and lymphoproliferative disorders (including
reversible). Hypogammaglobulinemia has been reported rarely. Cardiovascular: pericarditis, pericardial effusion, hypotension, and thromboembolic
events (including arterial thrombosis, cerebral thrombosis, deep vein
thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary
embolus). Central
Nervous System: headaches, drowsiness, blurred vision, transient
blindness, speech impairment including dysarthria and aphasia, hemiparesis,
paresis and convulsions have also occurred following administration
of methotrexate. Following low doses, there have been occasional reports
of transient subtle cognitive dysfunction, mood alteration or unusual
cranial sensations, leukoencephalopathy, or encephalopathy. Hepatobiliary Disorders: hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis,
hepatic failure, decrease in serum albumin, liver enzyme elevations. Infection: There
have been case reports of sometimes fatal opportunistic infections
in patients receiving methotrexate therapy for neoplastic and non-neoplastic
diseases. Pneumocystis carinii pneumonia was the most common opportunistic infection. There have
also been reports of infections, pneumonia, Cytomegalovirus infection,
including cytomegaloviral pneumonia, sepsis, fatal sepsis, nocardiosis;
histoplasmosis, cryptococcosis, Herpes
zoster, H. simplex hepatitis, and disseminated H. simplex. Musculoskeletal
System: stress fracture. Ophthalmic: conjunctivitis, serious
visual changes of unknown etiology. Pulmonary System: respiratory fibrosis,
respiratory failure, alveolitis, interstitial pneumonitis deaths have
been reported, and chronic interstitial obstructive pulmonary disease
has occasionally occurred. Skin: erythematous rashes, pruritus,
urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis,
telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal
necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration
and exfoliative dermatitis. Urogenital System: severe nephropathy
or renal failure, azotemia, cystitis, hematuria, proteinuria; defective
oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction,
vaginal discharge, and gynecomastia; infertility, abortion, fetal
death, fetal defects. Other rarer reactions
related to or attributed to the use of methotrexate such as nodulosis,
vasculitis, arthralgia/myalgia, loss of libido/impotence, diabetes,
osteoporosis, sudden death, lymphoma, including reversible lymphomas,
tumor lysis syndrome, soft tissue necrosis and osteonecrosis. Anaphylactoid
reactions have been reported. Adverse Reactions in Double-Blind Rheumatoid Arthritis
Studies The approximate incidences
of methotrexate-attributed (i.e. placebo rate subtracted) adverse
reactions in 12 to 18 week double-blind studies of patients (n=128)
with rheumatoid arthritis treated with low-dose oral (7.5 to 15 mg/week)
pulse methotrexate, are listed below. Virtually all of these patients
were on concomitant nonsteroidal anti-inflammatory drugs and some
were also taking low dosages of corticosteroids. Hepatic histology
was not examined in these short-term studies. (See PRECAUTIONS). Incidence
greater than 10%: Elevated liver function tests 15%, nausea/vomiting
10%. Incidence 3% to 10%: Stomatitis, thrombocytopenia
(platelet count less than 100,000/mm). Incidence 1% to 3%: Rash/pruritis/dermatitis, diarrhea, alopecia,
leukopenia (WBC less than 3000/mm), pancytopenia, dizziness. Two other controlled trials of patients (n=680) with Rheumatoid
Arthritis on 7.5 mg to 15 mg/wk oral doses showed an incidence of
interstitial pneumonitis of 1%. (See PRECAUTIONS.) Other less common reactions included decreased
hematocrit, headache, upper respiratory infection, anorexia, arthralgias,
chest pain, coughing, dysuria, eye discomfort, epistatix, fever, infection,
sweating, tinnitus, and vaginal discharge. Adverse Reactions in Psoriasis: There are no recent placebo-controlled trials in patients
with psoriasis. There are two literature reports (Roenigk, 1969, and
Nyfors, 1978) describing large series (n=204, 248) of psoriasis patients
treated with methotrexate. Dosages ranged up to 25 mg per week and
treatment was administered for up to four years. With the exception
of alopecia, photosensitivity, and���burning of skin lesions���(each 3% to 10%), the adverse reaction rates in these reports were
very similar to those in the rheumatoid arthritis studies. Rarely,
painful plaque erosions may appear (Pearce, HP and Wilson, BB: Am Acad Dermatol 35: 835-838, 1996). Adverse Reactions in JRA Studies The approximate incidences of adverse reactions
reported in pediatric patients with JRA treated with oral, weekly
doses of methotrexate (5 to 20 mg/m/wk or 0.1 to 0.65
mg/kg/wk) were as follows (virtually all patients were receiving concomitant
nosteroidal anti-inflammatory drugs, and some also were taking low
doses of corticosteroids): elevated liver function tests, 14%; gastrointestinal
reactions (e.g., nausea, vomiting, diarrhea), 11%; stomatitis, 2%;
leukopenia, 2%; headache, 1.2%; alopecia, 0.5%; dizziness, 0.2%; and
rash, 0.2%. Although there is experience withdosing up to 30 mg/m/wk in JRA, the published data for doses above 20 mg/m/wk are too limited to provide reliable estimates of adverse
reaction rates.
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| dailymed-instance:indicatio... |
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.
|
| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
Methotrexate
|