Introduction
Xatmep is an oral methotrexate solution approved by the FDA for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL) as part of a maintenance therapy regimen, and for management of active polyarticular juvenile idiopathic arthritis (pJIA) in children who have had an insufficient response to or are intolerant of first-line therapy. This ready-to-use formulation provides precise dosing for pediatric patients who may have difficulty swallowing tablets.
Mechanism of Action
Methotrexate, the active ingredient in Xatmep, is an antimetabolite that inhibits dihydrofolate reductase, the enzyme that converts dihydrofolic acid to tetrahydrofolic acid. This inhibition disrupts DNA synthesis, repair, and cellular replication. Methotrexate has cytotoxic effects on rapidly dividing cells, particularly malignant cells in leukemia, and immunomodulatory effects in autoimmune conditions like juvenile idiopathic arthritis.
Indications
- Maintenance therapy in pediatric acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy regimen
- Management of active polyarticular juvenile idiopathic arthritis (pJIA) in children who have had an inadequate response to or are intolerant of first-line therapy
Dosage and Administration
ALL Maintenance Therapy:- Usual dosage: 20 mg/m² orally once weekly
- May be adjusted based on patient response and toxicity
- Initial dose: 10 mg/m² orally once weekly
- May be gradually increased to a maximum of 30 mg/m² weekly based on clinical response
- Oral administration only
- Use provided calibrated oral syringe for accurate dosing
- May be taken with or without food
- Shake bottle well before each use
- Renal impairment: Dose reduction required based on creatinine clearance
- Hepatic impairment: Use with caution and consider dose reduction
Pharmacokinetics
Absorption: Oral bioavailability is approximately 60% at lower doses, with peak plasma concentrations occurring 1-2 hours after administration. Distribution: Widely distributed in body tissues, with volume of distribution approximately 0.4-0.8 L/kg. Protein binding is approximately 50%. Metabolism: Undergoes minimal hepatic metabolism via oxidation to 7-hydroxymethotrexate. Elimination: Primarily excreted renally via glomerular filtration and active tubular secretion. Elimination half-life is approximately 3-10 hours at conventional doses.Contraindications
- Hypersensitivity to methotrexate or any component of the formulation
- Pregnancy and breastfeeding
- Significant renal impairment
- Preexisting blood dyscrasias
- Active infectious disease
- Immunodeficiency syndromes
Warnings and Precautions
Black Box Warning:- Methotrexate has been associated with fatal toxic reactions including myelosuppression, opportunistic infections, and gastrointestinal toxicity
- Can cause severe hepatotoxicity, including fibrosis and cirrhosis
- May cause fetal death and congenital abnormalities
- Requires close monitoring of hematologic, hepatic, renal, and pulmonary function
- Risk of opportunistic infections, including Pneumocystis jirovecii pneumonia
- Potential for pulmonary toxicity (fibrosis, pneumonitis)
- Dermatologic reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis
- Risk of tumor lysis syndrome in leukemia patients
- Neurotoxicity, especially with intrathecal administration or high doses
Drug Interactions
- NSAIDs: May decrease methotrexate clearance and increase toxicity
- Probenecid: Reduces renal clearance of methotrexate
- Penicillins: May increase methotrexate concentrations
- Trimethoprim/sulfamethoxazole: Increases risk of bone marrow suppression
- Live vaccines: Contraindicated due to immunosuppression
- Folic acid antagonists: Enhanced toxicity
Adverse Effects
Common (≥10%):- Nausea/vomiting
- Stomatitis
- Diarrhea
- Alopecia
- Elevated liver enzymes
- Myelosuppression (anemia, leukopenia, thrombocytopenia)
- Severe hepatotoxicity
- Pulmonary fibrosis/pneumonitis
- Severe mucositis
- Opportunistic infections
- Renal failure
- Neurotoxicity
- Dermatologic reactions
Monitoring Parameters
Baseline:- Complete blood count with differential
- Comprehensive metabolic panel (including renal and hepatic function)
- Chest X-ray
- Pregnancy test in females of reproductive potential
- Weekly CBC during initial treatment, then monthly
- Liver function tests monthly
- Renal function tests monthly
- Pulmonary function monitoring as clinically indicated
- Regular assessment for signs of infection
- Monitoring for gastrointestinal toxicity
- Periodic liver biopsy consideration with prolonged use
- Bone density monitoring
- Ophthalmologic examinations
Patient Education
- Take exactly as prescribed, typically once weekly (not daily)
- Use provided oral syringe for accurate dosing
- Report any signs of infection (fever, chills, sore throat)
- Monitor for mouth sores, diarrhea, or unusual bleeding/bruising
- Avoid alcohol consumption due to increased hepatotoxicity risk
- Use effective contraception during treatment and for at least 6 months after discontinuation
- Inform all healthcare providers about methotrexate therapy
- Keep out of reach of children and pets
- Store at room temperature, protect from light
References
1. FDA prescribing information: Xatmep (methotrexate) oral solution 2. National Comprehensive Cancer Network (NCCN) Guidelines: Pediatric Acute Lymphoblastic Leukemia 3. American College of Rheumatology Guidelines for Juvenile Idiopathic Arthritis 4. Bleyer WA. The clinical pharmacology of methotrexate: new applications of an old drug. Cancer. 1978;41(1):36-51. 5. Cronstein BN. The mechanism of action of methotrexate. Rheum Dis Clin North Am. 1997;23(4):739-755. 6. American Academy of Pediatrics. Red Book: 2021 Report of the Committee on Infectious Diseases. 7. Weinblatt ME. Methotrexate in juvenile rheumatoid arthritis. Arthritis Rheum. 1992;35(4):410-415.
Note: This monograph provides general information and should not replace clinical judgment. Always consult current prescribing information and clinical guidelines.