Dosage & Administration
Recommended Dosage:
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Xatmep Prescribing Information
• Bone marrow suppression[see Warnings and Precautions ()]5.1 Bone Marrow SuppressionXATMEP suppresses hematopoiesis and can cause severe and life-threatening pancytopenia, anemia, leukopenia, neutropenia, and thrombocytopenia.
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 needed.
• Serious infections[see Warnings and Precautions ()]5.2 Serious InfectionsPatients treated with XATMEP are at increased risk for developing life-threatening or fatal bacterial, fungal, or viral infections including opportunistic infections such as
Pneumocystis jirovecipneumonia, invasive fungal infections, hepatitis B reactivation, tuberculosis primary infection or reactivation, and disseminatedHerpes zosterand cytomegalovirus infections.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 Warnings and Precautions ].• Renal toxicity and increased toxicity with renal impairment[see Warnings and Precautions ()]5.3 Renal Toxicity and Increased Toxicity with Renal ImpairmentXATMEP 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 Prescribing Information].• Gastrointestinal toxicity[see Warnings and Precautions ()]5.4 Gastrointestinal ToxicityXATMEP 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 (7.1)].• Hepatic toxicity[see Warnings and Precautions ()]5.5 Hepatic ToxicityXATMEP 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 age.
• Pulmonary toxicity[see Warnings and Precautions ()]5.6 Pulmonary ToxicityMethotrexate-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[see Warnings and Precautions ()]5.7 Hypersensitivity and Dermatologic ReactionsSevere, 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.
• 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 (4 CONTRAINDICATIONSXATMEP is contraindicated in the following:
• 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 ].• Patients with severe hypersensitivity to methotrexate[see Warnings and Precautions , Adverse Reactions ].
• Pregnancy (patients with pJIA) .• Severe hypersensitivity to methotrexate .
), Use in Specific Populations (5.9 Embryo-Fetal ToxicityBased 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 Pharmacology ].,8.1 PregnancyRisk SummaryBased 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 Dataand 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.
DataHuman DataPublished 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.
)].8.3 Females and Males of Reproductive PotentialPregnancy TestingTest for pregnancy prior to initiating therapy with XATMEP.
ContraceptionFemalesXATMEP 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.
MalesMethotrexate 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.
InfertilityFemalesBased 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.
MalesBased 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.
XATMEP is a folate analog metabolic inhibitor indicated for the:
• Treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as a component of a combination chemotherapy maintenance regimen ().1.1 Acute Lymphoblastic LeukemiaXATMEP is indicated for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a multi-phase, combination chemotherapy maintenance regimen.
• Management of pediatric patients with active polyarticular juvenile idiopathic arthritis (pJIA) who are intolerant of or had an inadequate response to first-line therapy ().1.2 Polyarticular Juvenile Idiopathic ArthritisXATMEP 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).
• Use another formulation of methotrexate for patients requiring dosing via routes of administration other than oral ().2.1 Important Administration InformationXATMEP 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.• Measure with an accurate measuring device ().2.1 Important Administration InformationXATMEP 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.
Recommended Dosage:
• ALL: 20 mg/m2 one time weekly ().2.2 Acute Lymphoblastic LeukemiaThe recommended starting dose of XATMEP, in multi-agent combination chemotherapy maintenance regimens, is 20 mg/m2given 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.
• pJIA: Starting dose of 10 mg/m2 one time weekly ().2.3 Polyarticular Juvenile Idiopathic ArthritisThe recommended starting dose of XATMEP is 10 mg/m2given 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.
XATMEP is a clear yellow to orange oral solution that contains 2.5 mg of methotrexate per milliliter.
Lactation: Advise women not to breastfeed (
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.
XATMEP is contraindicated in the following:
• 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 (5.9 Embryo-Fetal ToxicityBased 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 Pharmacology ].)]8.1 PregnancyRisk SummaryBased 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 Dataand 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.
DataHuman DataPublished 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.
• Patients with severe hypersensitivity to methotrexate[see Warnings and Precautions (.), Adverse Reactions (5.7 Hypersensitivity and Dermatologic ReactionsSevere, 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.
,6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in practice.
The most frequently reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other frequently reported adverse reactions are malaise, fatigue, chills, fever, dizziness, and decreased resistance to infection. Folate deficiency states may increase methotrexate toxicity.
Polyarticular Juvenile Idiopathic ArthritisThe approximate incidences of adverse reactions reported in pediatric patients with JIA treated with oral, weekly doses of methotrexate (5 to 20 mg/m2/week or 0.1 to 0.65 mg/kg/week) were as follows (virtually all patients were receiving concomitant nonsteroidal 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 with dosing up to 30 mg/m2/week in JIA, the published data for doses above 20 mg/m2/week are too limited to provide reliable estimates of adverse reaction rates.
)]6.2 Postmarketing ExperienceAdditional adverse reactions which have been identified during postmarketing use of methotrexate are listed below by organ system.
Blood and Lymphatic System Disorders:Suppressed hematopoiesis causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, lymphadenopathy, lymphoproliferative disorders (including reversible), hypogammaglobulinemiaCardiovascular:Thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, and pulmonary embolus), pericarditis, pericardial effusion, hypotensionEye Disorders:Optic neuropathy, transient blindness, blurred vision, ocular irritation, conjunctivitis, xerophthalmiaGastrointestinal Disorders:Gingivitis, pharyngitis, stomatitis, anorexia, nausea, vomiting, diarrhea, hematemesis, melena, gastrointestinal ulceration and bleeding, enteritis, pancreatitisHepatobiliary Disorders:Hepatotoxicity, acute hepatitis, chronic fibrosis and cirrhosis, decreased serum albumin, liver enzyme elevationsImmune System Disorders:Vasculitis, lymphomas, and anaphylactoid reactionsInfections:Fatal opportunistic infections (most commonlyPneumocystis jirovecipneumonia). There have also been reports of other infections, pneumonia, sepsis, nocardiosis, histoplasmosis, cryptococcosis,Herpes zoster,Herpes simplexhepatitis, and disseminatedHerpes simplexMetabolism:Hyperglycemia and tumor lysis syndromeMusculoskeletal System:Stress fracture, soft tissue necrosis, osteonecrosis, arthralgia, myalgia, osteoporosisNervous System Disorders: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 reports of transient subtle cognitive dysfunction, mood alteration, unusual cranial sensations, leukoencephalopathy, or encephalopathy.
Renal Disorders:Azotemia, hematuria, proteinuria, cystitisReproductive Disorders:Defective oogenesis or spermatogenesis, menstrual dysfunction, loss of libido, impotence, vaginal discharge, gynecomastiaRespiratory Disorders:Pulmonary fibrosis, respiratory failure, chronic interstitial obstructive pulmonary disease, pleuritic pain and thickening alveolitisSkin Disorders:Erythematous rashes, pruritus, urticaria, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, skin necrosis, skin ulceration, accelerated nodulosis, and exfoliative dermatitis.