Dosage & Administration
Recommended Dosage:
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Xatmep Prescribing Information
Methotrexate can cause the following severe or fatal adverse reactions. Monitor closely and modify dose or discontinue methotrexate as appropriate.
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- Bone marrow suppression [see Warnings and Precautions ]
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- Serious infections [see Warnings and Precautions ]
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- Renal toxicity and increased toxicity with renal impairment [see Warnings and Precautions ]
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- Gastrointestinal toxicity [see Warnings and Precautions ]
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- Hepatic toxicity [see Warnings and Precautions ]
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- Pulmonary toxicity [see Warnings and Precautions ]
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- Hypersensitivity and dermatologic reactions [see Warnings and Precautions ]
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- Methotrexate can cause embryo-fetal toxicity, including fetal death. Use in pJIA is contraindicated in pregnancy. 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 and males of reproductive potential to use effective contraception during and after treatment with XATMEP [see Contraindications , Warnings and Precautions , Use in Specific Populations ].
Acute Lymphoblastic Leukemia
XATMEP is indicated for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen.
Polyarticular Juvenile Idiopathic Arthritis
XATMEP is indicated in the management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) 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).
Important Administration Information
XATMEP is intended for oral use only. Use another formulation of methotrexate for alternative dosing in patients who require dosing via other routes of administration. Instruct patients and caregivers that the recommended dose should be taken weekly, as directed, and that mistaken daily use of the recommended dose has led to fatal toxicity [see Warnings and Precautions ( 5.15), Overdosage ].
It is important that XATMEP be measured with an accurate measuring device [see Warnings and Precautions ( 5.15), Patient Counseling Information ]. A household teaspoon is not an accurate measuring device. A pharmacist can provide an appropriate device and can provide instructions for measuring the correct dose.
Acute Lymphoblastic Leukemia
The recommended starting dose of XATMEP, in multi-agent combination chemotherapy maintenance regimens, is 20 mg/m2 given one time weekly. After initiating XATMEP, continuation of appropriate dosing requires periodic monitoring of absolute neutrophil count (ANC) and platelet count to assure sufficient drug exposure (that is to maintain ANC at a desirable level) and to adjust for excessive hematological toxicity.
Polyarticular Juvenile Idiopathic Arthritis
The recommended starting dose of XATMEP is 10 mg/m2 given one time weekly.
Dosages should be tailored to the individual patient and adjusted gradually to achieve an optimal response. Although there is experience with doses up to 30 mg/m2/week in pediatric patients, doses greater than 20 mg/m2/week may result in a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression. Doses between 20 and 30 mg/m2/week (0.65 to 1 mg/kg/week) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered by an alternative route using another formulation.
Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.
Certain side effects such as mouth sores may be reduced by folate supplementation with methotrexate in pJIA.
Evaluations Prior to Starting Methotrexate
Assess hematologic, hepatic, and renal function before beginning, as well as periodically during and before reinstituting, therapy with XATMEP [see Warnings and Precautions , Warnings and Precautions ( 5.9), Use in Specific Populations ].
Handling Information
XATMEP is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
XATMEP is a clear yellow to orange oral solution that contains 2.5 mg of methotrexate per milliliter.
Pregnancy
Risk Summary
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 toxicity studies.
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%, respectively.
Data
Human Data
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.
Lactation
Risk Summary
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 therapy.
Females and Males of Reproductive Potential
Pregnancy Testing
Test for pregnancy prior to initiating therapy with XATMEP.
Contraception
Females
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.
Males
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 dose.
Infertility
Females
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 affected females.
Males
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.
Pediatric Use
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 ].
Renal Impairment
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 ].
Hepatic Impairment
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 impairment.
XATMEP is contraindicated in the following:
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- Pregnancy in patients with non-malignant diseases. XATMEP can cause embryo-fetal toxicity and fetal death when administered during pregnancy [see Warnings and Precautions , Use in Specific Populations ].
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- Patients with severe hypersensitivity to methotrexate [see Warnings and Precautions , Adverse Reactions ].