FDA Approves Oral Methotrexate; Plus Restrictions for 2 Analgesics in Children

The U.S. Food and Drug Administration (FDA) has approved a new formulation of methotrexate designed as an oral solution for pediatric patients. Also, the agency recently introduced age restrictions for codeine and tramadol for children under age 12, citing their risks for slowed or difficult breathing and death.

FDA Approves Oral Methotrexate
Methotrexate (Xatmep), a folate analog metabolic inhibitor, is now available as an oral solution at a concentration of 2.5 mg/mL. This solution is a ready-to-use product designed to improve the accuracy of dosing and dispensing by eliminating the need for tablet crushing or extemporaneous compounding for pediatric dosing. This new formulation limits the risk of inadvertent methotrexate exposure and saves time. The medication requires refrigeration, but may be stored at room temperature for up to 60 days after dispensing.

The formulation was approved for managing pediatric patients with active polyarticular juvenile idiopathic arthritis who have had an insufficient therapeutic response to or are intolerant of an adequate trial of first-line therapy, such as full-dose non-steroidal anti-inflammatory drugs. It can also be used to treat pediatric patients with acute lymphoblastic leukemia as part of a multi-phase, combination chemotherapy maintenance regimen.

Analgesic Contraindications for Children & Nursing Mothers
The FDA has restricted the use of codeine and tramadol in children.² Both codeine, which is approved for pain and cough, and tramadol, which is approved for pain, carry serious risks, including slowed or difficult breathing and death, which appear to be greater in children under 12 years of age. These drugs should not be used in patients of this age group. Additionally, the use of codeine and tramadol should be limited in some older children. All tramadol-containing products and single-ingredient codeine products are FDA approved for use only in adults.

New labeling: The FDA will add a warning that recommends breastfeeding mothers refrain from using tramadol and codeine due to potential harm to their infants. Nursing infants whose mothers are taking these medications are at risk for excessive sleepiness, difficulty breastfeeding and serious breathing problems that may result in death. Tramadol is now contraindicated for use in children younger than 12 years old. A new contraindication was added to the tramadol label, warning against using it in children younger than 18 years old for post-operative pain from tonsillectomy and/or adenoid removal. Also, new label warnings for both codeine and tramadol advise against their use in children 12–18 years old who are obese, have severe lung disease or have obstructive sleep apnea, due to the increased risks for serious breathing trouble.

The FDA literature review spans multiple decades (1969–2015) and identified 64 cases of serious breathing problems, including 24 deaths, with the use of codeine-containing products in patients younger than 18 years old. Additional cases may exist that were not reported to the FDA. With tramadol, FDA identified nine cases of serious breathing problems, which included three deaths, in patients younger than 18 years old. Most of the serious side effects with both medications occurred in children younger than 12 years old, some of which occurred after a single dose.

Numerous infants of breastfeeding mothers experienced excessive sleepiness and serious breathing problems, and one death was reported. Tramadol use during breastfeeding did not result in any adverse events, but risk does exist because tramadol and its active ingredient are excreted into breast milk.

Michele B. Kaufman, PharmD, BCGP, is a freelance medical writer based in New York City and a pharmacist at New York Presbyterian Lower Manhattan Hospital.

References

1. Silvergate Pharmaceuticals Inc. News release: FDA approves Xatmep, the first and only ready-to-use methotrexate oral solution. 2017 Apr 26.
2. U.S. Food and Drug Administration. FDA drug safety communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. 2017 Apr 20.