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)] 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.
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.
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
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.
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)].
Clinical studies of methotrexate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
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.
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)].
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)] 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.
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.
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
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.
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)].
Clinical studies of methotrexate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
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.
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)].
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