- February 16, 2021: Phenytoin (Dilantin-125®) – FDA updated the Prescribing Information related to serious dermatologic reactions (severe cutaneous adverse reactions, or SCARs), drug interactions, and use in patients with decreased CYP2c9 function. Updates include the following additions to specific PI sections. Please refer to the full PI for context.
Section 5.3, Serious Dermatologic Reactions (additions bolded below)
…In addition, retrospective, case-control, genome-wide association studies in patients of southeast Asian ancestry have also identified an increased risk of SCARs in carriers of the decreased function CYP2C9*3 variant, which has also been associated with decreased clearance of phenytoin. Consider avoiding DILANTIN as an alternative to carbamazepine in patients who are positive for HLA-B*1502 or in CYP2C9*3 carriers [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.5)].
The use of HLA-B*1502 or CYP2C9 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.
Section 7, Drug Interactions (additions underlined)
Phenytoin is extensively bound to plasma proteins and is prone to competitive displacement. Phenytoin is primarily metabolized by the hepatic cytochrome P450 enzyme CYP2C9 and to a lesser extent by CYP2C19 and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. ...
Section 8, Use in Specific Populations, Subsection 8.7 Use in Patients with Decreased CYP2C9 Function (new subsection added)
Patients who are intermediate or poor metabolizers of CYP2C9 substrates (e.g., *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (e.g.,*1/*1). Thus, patients who are known to be intermediate or poor metabolizers may ultimately require lower doses of phenytoin to maintain similar steady-state concentrations compared to normal metabolizers. If early signs of dose-related central nervous system (CNS) toxicity develop, serum concentrations should be checked immediately [see Clinical Pharmacology (12.5)].
- February 5, 2021: Benzodiazepines – clonazepam, diazepam, midazolam, lorazepam, and clobazam (various manufacturers and formulations); FDA announced updates to PI for benzodiazepines, including these used as antiseizure medications. Among the black-box safety warnings now included are:
As just one example, clobazam changes are detailed, with prominent black box warnings, in its PI and summarized in the corresponding label revision approval letter. Each drug can be searched in the Drugs@FDA database, with links to the PI and letter found for each specific manufacturer and formulation under the header, Approval Date(s) and History, Letters, Labels, Reviews.
- Concomitant use with opioids may result in profound sedation, respiratory depression, coma, and death
- Risk of abuse, misuse, and addiction, which can lead to overdose and death
- Abrupt discontinuation or rapid dosage reduction after continued use may precipitate acute withdrawal reactions, which can be life-threatening
- January 29, 2021: FDA Safety Warning on the Cardiac Effects of Lamotrigine: An Advisory from the Ad Hoc ILAE/AES Task Force – A preprint version of this joint ILAE/AES statement is provided here in advance of copublication in Epilepsia Open and Epilepsy Currents to assist AES members in managing clinical care and communications with patients about the October 9, 2020, new safety warning and prescribing information updates related to lamotrigine.