Approved Drug Label (PDF)
Boxed Warning
(Effective March
2021, Box Warning in supplement 131 has been revised)
WARNING:
EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS, BENZYL ALCOHOL TOXICITY, and
OTHER SERIOUS ADVERSE REACTIONS
Methotrexate
Injection can cause embryo-fetal toxicity, including fetal death. For
non-neoplastic diseases, Methotrexate Injection is contraindicated in
pregnancy. Advise females and males of reproductive potential to use effective
contraception [see Contraindications (4),
Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)].
Methotrexate
Injection is contraindicated in patients with a history of severe
hypersensitivity reactions to methotrexate, including anaphylaxis [see Contraindications (4) and Warnings and
Precautions (5.2)].
Formulations with benzyl alcohol can cause severe
central nervous toxicity or metabolic acidosis. Use only preservative-free
Methotrexate Injection for treatment of neonates or low-birth weight infants
and for intrathecal use. Do not use benzyl alcohol-containing formulations for
high-dose regimens unless immediate treatment is required and preservative-free
formulations are not available [see
Dosage and Administration (2.1) and Warnings and Precautions (5.3)].
Other serious
adverse reactions, including death, have been reported with methotrexate.
Closely monitor for infections and adverse reactions of the bone marrow,
kidneys, liver, nervous system, gastrointestinal tract, lungs, and skin.
Withhold or discontinue Methotrexate Injection as appropriate [see Warnings and Precautions (5.4, 5.5,
5.6, 5.7, 5.8, 5.9, 5.10, 5.11)].
4
Contraindications
(PLR
conversion)
Methotrexate
Injection is contraindicated in:
Patients
with history of severe hypersensitivity to methotrexate [see Warnings and Precautions (5.2)].
Pregnancy
in patients with non-neoplastic diseases [see
Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].
5
Warnings and Precautions
(The following subsections created to comply with PLR;
please refer to labeling for complete information)
5.1 Embryo-Fetal
Toxicity
5.2 Hypersensitivity
Reactions
5.3 Risks of
Serious Adverse Reactions due to Benzyl Alcohol-Preservative
5.4 Myelosuppression
5.5 Serious
Infections
5.6 Renal Toxicity
5.7 Hepatotoxicity
5.8 Neurotoxicity
5.9
Gastrointestinal Toxicity
5.10 Pulmonary
Toxicity
5.11 Dermatologic
Reactions
5.12 Folic Acid
Supplementation
5.13 Secondary Malignancies
5.14 Tumor Lysis
Syndrome
5.15 Immunization
and Risks Associated with Live Vaccine
5.16 Infertility
5.17 Increased
Risk of Adverse Reactions Due to Third Space Accumulation
5.18 Increased
Risk of Soft Tissue and Bone Toxicity with Concomitant Radiotherapy
5.19 Risk of
Serious Adverse Reactions with Medication Errors
6
Adverse Reactions
(PLR
conversion)
The
following adverse reactions are described, or described in greater detail, in
other sections:
Hypersensitivity
Reactions [see Warnings and Precautions (5.2)]
Myelosuppression
[see Warnings and Precautions (5.4)]
Serious
Infections [see Warnings and Precautions (5.5)]
Renal
Toxicity [see Warnings and Precautions (5.6)]
Hepatotoxicity
[see Warnings and Precautions (5.7)]
Neurotoxicity
[see Warnings and Precautions (5.8)]
Gastrointestinal
Toxicity [see Warnings and Precautions (5.9)]
Pulmonary
Toxicity [see Warnings and Precautions (5.10)]
Dermatologic
Reactions [see Warnings and Precautions (5.11)]
Secondary
Malignancies [see Warnings and
Precautions (5.13)]
Tumor
Lysis Syndrome [see Warnings and
Precautions (5.14)]
Increased
Risk of Adverse Reactions due to Third Space Accumulation [see Warnings and Precautions
(5.17)]
6.1 Clinical Trials Experience
(PLR conversion; please refer to labeling for
complete information)
6.2 Postmarketing Experience
(PLR conversion; please refer to labeling for
complete information)
7
Drug Interactions
(The following subsections created to comply with PLR;
please refer to labeling for complete information)
7.1
Effects of Other Drugs on Methotrexate
7.2
Effects of Methotrexate on Other Drugs
8
Use in Specific Populations
8.1 Pregnancy
(PLLR
conversion)
Risk
Summary
Methotrexate
Injection is contraindicated in pregnant women with non-neoplastic diseases.
Based on published reports and its mechanism of action, methotrexate can cause
embryo-fetal toxicity and fetal death when administered to a pregnant woman [see Data and Clinical Pharmacology (12.1)].
There are no animal data that meet current standards for nonclinical
developmental toxicity studies. Advise pregnant women with neoplastic diseases
of the potential risk to a fetus. The preservative benzyl alcohol can cross the
placenta; when possible, use the preservative-free formulation when
Methotrexate Injection is needed during pregnancy to treat a neoplastic disease
[see Warnings and Precautions (5.3) and
Use in Specific Populations (8.4)].
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%, respectively.
Data
Human Data
Published
data from case reports, 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, CNS 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 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 patients with autoimmune disease (22.5%, 95% CI 16.8–29.7) and
unexposed patients with non-autoimmune disease (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 unexposed patients with
autoimmune disease (adjusted odds ratio (OR) 1.8 [95% CI 0.6–5.7]) and
unexposed patients with non-autoimmune disease (adjusted OR 3.1 [95% CI
1.03–9.5]) (2.9%). Major birth defects associated with pregnancies exposed to
methotrexate after conception were not always consistent with
methotrexate-associated adverse developmental outcomes.
8.2 Lactation
(PLLR
conversion)
Risk
Summary
Limited
published literature reports the presence of methotrexate in human milk in low
amounts, with the highest breast milk to plasma concentration ration reported
to be 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 from methotrexate in breastfed infants, advise women not to
breastfeed during treatment with Methotrexate Injection and for 1 week after
the final dose.
8.3 Females and Males of Reproductive Potential
(PLLR
conversion)
Methotrexate
can cause malformations and fetal death at doses less than or equal to the
recommended clinical doses [see Use in
Specific Populations (8.1)].
Pregnancy Testing
Verify
the pregnancy status of females of reproductive potential prior to initiating
Methotrexate Injection [see
Contraindications (4) and Use in Specific Populations (8.1)].
Contraception
Females
Advise
females of reproductive potential to use effective contraception during and for
6 months after the final dose of Methotrexate Injection therapy.
Males
Methotrexate
can cause chromosomal damage to sperm cells. Advise males with female partners of
reproductive potential to use effective contraception during and for 3 months
after the final dose of Methotrexate Injection therapy.
Infertility
Females
Based
on published reports of female infertility after therapy with methotrexate,
advise females of reproductive potential that Methotrexate Injection 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 affected
females.
Males
Based
on published reports of male infertility after therapy with methotrexate,
advise males that Methotrexate Injection 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.
8.4 Pediatric Use
(PLR
conversion)
The
safety and effectiveness of Methotrexate Injection in pediatric patients have
been established for ALL, meningeal leukemia prophylaxis and treatment,
non-Hodgkin lymphoma, osteosarcoma and in pJIA. Clinical studies evaluating the
use of methotrexate in pediatric patients with pJIA demonstrated safety
comparable to that observed in adults with RA [see Adverse Reactions (6.1)]. The safety and effectiveness of
Methotrexate Injection have not been established in pediatric patients for the
treatment of breast cancer, squamous cell carcinoma of the head and neck,
gestational trophoblastic neoplasia, rheumatoid arthritis, and psoriasis.
Additional
risk information is described below.
Risks
of Serious Adverse Reactions due to Benzyl Alcohol-Preservative
Due
to the risk of serious adverse reactions and fatal gasping syndrome following
administration of intravenous solutions containing the preservative benzyl
alcohol in neonates, use only preservative-free Methotrexate Injection in
neonates and low-birth weight infants. The “gasping syndrome” is characterized
by CNS depression, metabolic acidosis, and gasping respirations.
Serious
adverse reactions including fatal reactions and the “gasping syndrome” occurred
in premature neonates and low-birth weight infants in the neonatal intensive
care unit who received drugs containing benzyl alcohol as a preservative. In
these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels
of benzyl alcohol and its metabolites in the blood and urine (blood levels of
benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions include
gradual neurological deterioration, seizures, intracranial hemorrhage,
hematological abnormalities, skin breakdown, hepatic and renal failure,
hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth
weight infants may be more likely to develop these reactions because they may
be less able to metabolize benzyl alcohol.
When
prescribing in infants (non-neonate, non-low-birth weight), if a
preservative-free formulation of Methotrexate Injection is not available and
use of a benzyl alcohol-containing formulation is necessary, consider the
combined daily metabolic load of benzyl alcohol from all sources including
Methotrexate Injection (Methotrexate Injection contains 9.4 mg of benzyl
alcohol/per mL) and other drugs containing benzyl alcohol. The minimum amount
of benzyl alcohol at which serious adverse reactions may occur is not known.
Do
not administer methotrexate formulations containing benzyl alcohol
intrathecally due to the risk of severe neurotoxicity [see Warnings and Precautions (5.3)].
Leukemia/Lymphoma
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 g/m2) [see
Warnings and Precautions (5.8)].
8.5 Geriatric Use
(PLR
conversion)
Clinical
studies of methotrexate did not include sufficient numbers of subjects aged 65
and over to determine whether they respond differently from younger subjects.
8.6 Renal Impairment
(PLR
conversion)
Methotrexate
elimination is reduced in patients with renal impairment [creatinine clearance
(CLcr) less than 90 mL/min, calculated using Cockcroft-Gault] [see Clinical Pharmacology (12.3)].
Patients with renal impairment are at increased risk for methotrexate adverse
reactions.
Follow
recommendations to promote methotrexate elimination and decrease risk of acute
kidney injury and other methotrexate toxicities in patients who are receiving
intermediate- or high-dose regimens [see
Dosage and Administration (2.2) and Warnings and Precautions (5.6)]. Consider
reducing the dose or discontinuing
Methotrexate Injection in patients with renal impairment as appropriate.
8.7 Hepatic Impairment
(PLR
conversion)
The
pharmacokinetics and safety of methotrexate in patients with hepatic impairment
is unknown Patients with hepatic impairment may be at increased risk for
methotrexate adverse reaction based on elimination characteristics of
methotrexate [see Clinical Pharmacology
(12.3)]. Consider reducing the dose or discontinuing Methotrexate Injection
in patients with hepatic impairment as appropriate [see Warnings and Precautions (5.7)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(Newly
added section)
Advise
the patient to read the FDA-approved patient labeling (Patient Information). Embryo-Fetal Toxicity
Advise
females of reproductive potential of the potential risk to a fetus and to
inform their healthcare provider of a known or suspected pregnancy [see Contraindications (4), Warnings and
Precautions (5.1), and Use in Specific Populations (8.1)].
Advise
females of reproductive potential to use effective contraception during
methotrexate therapy and for 6 months after the final dose [see Use in Specific Populations (8.3)].
Advise
males of reproductive potential to use effective contraception during methotrexate
therapy and for 3 months after the final dose [see Use in Specific Populations (8.3)].
Hypersensitivity
Reactions
Advise patients of
the potential risk of hypersensitivity and that Methotrexate Injection is
contraindicated in patients with a history of severe hypersensitivity to
methotrexate. Advise patients to seek immediate medical attention if signs or
symptoms of a hypersensitivity reaction occur [see Warnings and Precautions (5.2)].
Myelosuppression
and Serious Infections
Advise
patient to contact their healthcare provider immediately for new onset fever,
symptoms of infection, easy bruising or persistent bleeding [see Warnings and Precautions (5.4, 5.5)].
Renal Toxicity
Advise
patients that methotrexate can cause renal toxicity. Advise patients to
immediately contact their healthcare provider for signs or symptoms of renal
toxicity, such as marked increases or decreases in urinary output [see Warnings and Precautions (5.6)].
Hepatotoxicity
Advise
patients to report signs or symptoms of hepatic toxicity and avoidance of
alcohol during methotrexate treatment [see
Warnings and Precautions (5.7)].
Neurotoxicity
Advise
patient to contact their healthcare provider immediately if they develop new
neurological symptoms [see Warnings and
Precautions (5.8)].
Gastrointestinal
Toxicity
Advise
patients to contact their healthcare provider if they develop diarrhea,
vomiting, or stomatitis. Advise patients to immediately contact their
healthcare provider for high fever, rigors, persistent or severe abdominal
pain, severe constipation, hematemesis, or melena [see Warnings and Precautions (5.9)].
Pulmonary Toxicity
Advise
patients to contact their healthcare provider for symptoms of cough, fever, and
dyspnea [see Warnings and Precautions
(5.10)].
Dermatologic
Toxicity
Advise
patients that Methotrexate Injection can cause serious skin rash and to
immediately contact their healthcare provider for new or worsening skin rash.
Advise patients to avoid excessive sun exposure and to use sun protection
measures [see Warnings and Precautions
(5.11)].
Secondary
Malignancies
Advise
patients on the risk of second primary malignancies during treatment with
Methotrexate Injection [see Warnings and Precautions (5.13)].
Lactation
Advise
women not to breastfeed during treatment with methotrexate and for 1 week after
the final dose [see Use in Specific
Populations (8.2)].
Infertility
Advise
females and males of reproductive potential that methotrexate may cause
impairment of fertility [see Use in
Specific Populations (8.3)].
Drug
Interactions
Advise
patients and caregivers to inform their healthcare provider of all concomitant
medications, including prescription medicines, over-the-counter drugs,
vitamins, and herbal products [see Drug
Interactions (7)].
Instruct
patients being treated for neoplastic indication to not take products
containing folic acid or folinic acid unless directed to do so by their
healthcare provider [see Warnings and
Precautions (5.12)].
Other
(Labeling revised to comply with PLR)
Get Email Alerts |
Guide
