Included as part of the PRECAUTIONS section.
Bone Marrow Suppression
XATMEP suppresses hematopoiesis and can cause severe and
life-threatening pancytopenia, anemia, leukopenia, neutropenia, and
Obtain blood counts at baseline and periodically during
treatment. Monitor patients for possible clinical complications of bone marrow
suppression. Provide supportive care and modify dose or discontinue XATMEP as
Patients treated with XATMEP are at increased risk for
developing life-threatening or fatal bacterial, fungal, or viral infections
including opportunistic infections such as Pneumocystis jiroveci pneumonia,
invasive fungal infections, hepatitis B reactivation, tuberculosis primary
infection or reactivation, and disseminated Herpes zoster and cytomegalovirus
Monitor patients for the signs and symptoms of infection
during and after treatment with XATMEP and treat promptly. Consider dose
modification or discontinuation of XATMEP in patients who develop serious
infections [see Bone Marrow Suppression].
Renal Toxicity And Increased Toxicity With Renal
XATMEP can cause renal damage including acute renal
failure. Monitor renal function to decrease the risk of renal injury and
mitigate renal toxicity.
Consider administration of glucarpidase in patients with
toxic plasma methotrexate concentrations (> 1 micromole per liter) and
delayed clearance due to impaired renal function [see glucarpidase
XATMEP can cause diarrhea, vomiting, stomatitis,
hemorrhagic enteritis, and fatal intestinal perforation. Patients with peptic
ulcer disease or ulcerative colitis are at a greater risk of developing severe
gastrointestinal adverse reactions.
Interrupt or discontinue XATMEP and institute appropriate
supportive care as needed.
Unexpectedly severe and fatal gastrointestinal toxicity
can occur with concomitant administration of XATMEP (primarily at high dosage)
and nonsteroidal anti-inflammatory drugs (NSAIDs) [see DRUG INTERACTIONS].
XATMEP can cause severe and potentially irreversible
hepatotoxicity including fibrosis, cirrhosis, and fatal liver failure. Avoid
use of XATMEP in patients with chronic liver disease.
Assess liver function prior to initiating XATMEP and
monitor liver function tests during treatment. Interrupt or discontinue XATMEP
as appropriate. Transient asymptomatic acute liver enzyme elevations are common
and are not predictive of subsequent hepatic disease. Persistent abnormalities
in liver function tests may precede appearance of fibrosis or cirrhosis.
Other risk factors for hepatotoxicity include alcoholism,
obesity, diabetes, hyperlipidemia, previous significant exposure to liver
toxins, history of liver disease, family history of inheritable liver disease,
persistent abnormal liver chemistry findings, duration of therapy, and advanced
Methotrexate-induced pulmonary toxicity including acute
or chronic interstitial pneumonitis and irreversible or fatal cases can occur
at all dose levels. Monitor patients for signs of pulmonary toxicity and
interrupt or discontinue XATMEP as appropriate.
Hypersensitivity And Dermatologic Reactions
Severe, including fatal, dermatologic reactions, such as
toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis,
skin necrosis, erythema multiforme, can occur with methotrexate. Discontinue
XATMEP if severe dermatologic reactions occur.
Anaphylaxis can occur with methotrexate. If anaphylaxis
or any other serious hypersensitivity reaction occurs, immediately discontinue
methotrexate and institute appropriate therapy. Methotrexate is contraindicated
for use in patients with a history of severe hypersensitivity.
Radiation dermatitis and sunburn may be “recalled” by the
use of methotrexate.
Secondary malignancies can occur at all dose levels of methotrexate.
There have been instances of lymphoproliferative disease
associated with low-dose oral methotrexate which have regressed completely
following withdrawal of methotrexate without institution of antineoplastic
therapy. Discontinue XATMEP first and institute appropriate treatment if the
lymphoma does not regress.
Based on published reports and methotrexate’s mechanism
of action, methotrexate can cause embryo-fetal toxicity and fetal death when
administered to a pregnant woman. In pregnant women with non-malignant
diseases, methotrexate is contraindicated. Consider the benefits and risks of
XATMEP and risks to the fetus when prescribing XATMEP to a pregnant patient
with a neoplastic disease. Advise females of reproductive potential to use
effective contraception during therapy and for 6 months after the final dose.
Advise males of reproductive potential to use effective contraception during
and for at least 3 months after the final methotrexate dose [see
CONTRAINDICATIONS, Use In Specific Populations, CLINICAL
Ineffective Immunization And Risks Associated With Live
Immunization may be ineffective when given during XATMEP
Immunization with live virus vaccines is not recommended.
There have been reports of disseminated vaccinia infections after smallpox
immunization in patients receiving methotrexate therapy.
Effects On Reproduction
Based on published reports, methotrexate can cause
impairment of fertility, oligospermia, and menstrual dysfunction. It is not
known if the infertility is reversible in affected patients. Discuss the risk
of effects on reproduction with female and male patients [see Use In Specific
Increased Toxicity Due To Third-Space Accumulation
Methotrexate can exit slowly from third-space
accumulations resulting in prolonged terminal plasma half-life and toxicity.
Evacuate significant third-space accumulations prior to methotrexate
administration [see CLINICAL PHARMACOLOGY].
Soft Tissue And Bone Toxicity With Radiation Therapy
Concomitant radiation therapy increases the risk of soft
tissue necrosis and osteonecrosis associated with methotrexate.
Closely monitor patients undergoing XATMEP therapy so
that toxic effects are detected promptly. In general, monitoring of the
following parameters is recommended: hematology at least monthly, renal function
and liver function every 1 to 2 months [see Bone Marrow Suppression, Renal Toxicity and Increased Toxicity with Renal Impairment and Hepatic Toxicity].
Increase monitoring frequency during initial dosing, dose
changes, or during periods of increased risk of elevated methotrexate blood
levels (e.g., dehydration).
Liver Function Tests
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 Hepatic Toxicity].
Pulmonary Function Tests
Pulmonary function tests may be useful if
methotrexate-induced lung disease is suspected, especially if baseline
measurements are available [see Pulmonary Toxicity].
Risk Of Improper Dosing
Both the physician and pharmacist should emphasize to the
patient that the recommended dose is taken one time weekly, as directed, and
that mistaken daily use of the recommended dose has led to fatal toxicity [see
DOSAGE AND ADMINISTRATION, OVERDOSAGE].
Advise patients to measure XATMEP with an accurate
milliliter measuring device. Inform patients that a household teaspoon is not
an accurate measuring device and could lead to overdosage, which can result in
serious adverse reactions [see OVERDOSAGE]. Advise patients to ask their
pharmacist to recommend an appropriate measuring device and for instructions
for measuring the correct dose [see DOSAGE AND ADMINISTRATION, Patient
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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.
Use In Specific Populations
Based on published reports and methotrexate’s mechanism
of action, methotrexate is a teratogen that can cause embryo-fetal toxicity and
fetal death when administered to a pregnant woman [see Data and CLINICAL
PHARMACOLOGY]. In pregnant women with non-malignant disease, XATMEP is
contraindicated. Consider the benefits and risks of XATMEP and risks to the
fetus when prescribing XATMEP to a pregnant patient with a neoplastic disease.
There are no animal data that meet current standards for nonclinical developmental
The estimated background risk of major birth defects and
miscarriage for the indicated populations are unknown. In the U.S. general
population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
Published data from cases, literature reviews, and
observational studies report that methotrexate exposure during pregnancy is
associated with an increased risk of embryo-fetal toxicity and fetal death.
Methotrexate exposure during the first trimester of pregnancy is associated
with an increased incidence of spontaneous abortions and multiple adverse
developmental outcomes, including skull anomalies, facial dysmorphism, central
nervous system abnormalities, limb abnormalities, and sometimes cardiac
anomalies and intellectual impairment. Adverse outcomes associated with
exposure during second and third trimesters of pregnancy include intrauterine
growth restriction and functional abnormalities. Because methotrexate is widely
distributed and persists in the body for a prolonged period, there is a
potential risk to the fetus from preconception methotrexate exposure.
A prospective multicenter study by U.S. and European
teratology information services evaluated pregnancy outcomes in women taking
methotrexate less than or equal to 30 mg/week after conception. The rate of
spontaneous abortion/miscarriage in pregnant women exposed to methotrexate was
42.5% (95% confidence interval [95% CI] 29.2-58.7), which was higher than in
unexposed autoimmune disease comparators (22.5%, 95% CI 16.8-29.7) and
unexposed nonautoimmune disease comparators (17.3%, 95% CI 13-22.8). Of the
live births, the rate of major birth defects in pregnant women exposed to
methotrexate after conception was higher than in autoimmune disease comparators
(adjusted odds ratio (OR) 1.8 [95% CI 0.6-5.7]) and nonautoimmune disease
comparators (adjusted OR 3.1 [95% CI 1.03-9.5]). Major birth defects associated
with pregnancies exposed to methotrexate after conception were not always
consistent with methotrexate-associated adverse developmental outcomes.
Limited published literature report the presence of
methotrexate in human milk in low amounts. The highest breast milk to plasma
concentration ratio demonstrated was 0.08:1. No information is available on the
effects of methotrexate on a breastfed infant or on milk production. Because of
the potential for serious adverse reactions, including myelosuppression, from
methotrexate in breastfed infants, advise women not to breastfeed during XATMEP
Females And Males Of Reproductive Potential
Test for pregnancy prior to initiating therapy with
XATMEP can cause fetal harm when administered to a
pregnant woman [see Use In Specific Populations].
Advise females of reproductive potential to use effective
contraception during and for 6 months after the final methotrexate dose.
Methotrexate can cause chromosomal damage to sperm cells.
Advise males with female partners of reproductive potential to use effective
contraception during and for at least 3 months after the final methotrexate
Based on published reports of female infertility after
therapy with methotrexate, advise females of reproductive potential that XATMEP
can cause impairment of fertility and menstrual dysfunction during and after
cessation of therapy. It is not known if the infertility may be reversed in all
Based on published reports of male infertility after
therapy with methotrexate, advise males of reproductive potential that XATMEP
can cause oligospermia or infertility during and after cessation of therapy. It
is not known if the infertility may be reversed in all affected males.
Safety and effectiveness of XATMEP in pediatric patients
have been established for the treatment of pediatric patients with acute
lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy
maintenance regimen and for the management of pediatric patients with active
polyarticular juvenile idiopathic arthritis (pJIA) [see Clinical Studies].
Methotrexate elimination is reduced in patients with
impaired renal function. Monitor patients with renal impairment for an extended
period of time. Consider a dose reduction or, in some cases, discontinue XATMEP
administration [see WARNINGS AND PRECAUTIONS].
The effect of hepatic impairment on methotrexate
pharmacokinetics has not been studied. Patients with hepatic impairment may be
more susceptible to hepatotoxicity [see WARNINGS AND PRECAUTIONS]. Consider
dose adjustments or alternative treatments in patients with baseline hepatic