- December 22, 2021: Paxlovid™ – Interactions and adverse effects with various antiseizure medications (ASMs) - The FDA issued an Emergency Use Authorization for Paxlovid™ for the oral treatment of mild to moderate COVID-19 in adults and children (>12 years and weighing >40 kg). Paxlovid is likely to be widely prescribed, and related important considerations for patients on antiseizure medications are detailed in the February 2, 2022 AES email to members, Paxlovid™ Information from FDA and Guidance for AES Members. Key concerns include: (1) Concomitant use of Paxlovid with the ASMs carbamazepine, phenobarbital, phenytoin, and primidone is contraindicated, and alternate oral or intravenous COVID-19 treatments should be considered and; (2) Potential for increases in plasma concentrations of a number of ASMs that are metabolized, at least in part, by CYP3A4 means that patients on these ASMs warrant closer monitoring for potential toxicity or dose adjustments while being treated with Paxlovid™. Details, pharmacologic basis, and links to additional information from FDA are included in the AES email to members.
- November 30, 2021: Divalproex sodium (Depakote®) - the FDA updated prescribing information to add tubulointerstitial nephritis to section 6.4, Adverse Reactions, Postmarketing Experience. Updates apply to oral delayed and extended release tablets and oral delayed release pellet/sprinkle capsule formulations. See the prescribing information and letter for more information.
- October 29, 2021: Zimmer Biomet ROSA One 3.1 Brain Application–
Class I Recall due to Software Error - Zimmer Biomet is
recalling the ROSA One 3.1 Brain Application due to a software error that could
lead to incorrect placement of instruments during stereotactic neurosurgical
procedures (for example, techniques to direct the tip of a tool using
coordinates provided by medical imaging to reach a specific part of the brain).
If such an error occurs, it could cause adverse events such as stroke, serious
injury, severe disability, and death. There have been three complaints and no
deaths or injuries reported about this device issue. The FDA has identified
this as a Class I recall, the most serious type of recall. Use of these devices
may cause serious injuries or death. For further details, see the FDA recall notice. An FDA recall database entry provides guidance on avoiding steps that
may trigger the software error and actions to be taken without delay by all
users of the ROSA One 3.1 Brain application device. On September 22, 2021,
Zimmer Biomet alerted affected consignees of the software via “Urgent Medical
Device Correction” letters. The company expects to visit each customer site,
estimated between February and May 2022, to implement software updates. Both
the recall database entry and the recall notice provide contact information.
- October 28, 2021: Ethosuximide (Zarontin®) – FDA approved an update to the Warnings and Adverse Reactions sections of the prescribing information to add thrombocytopenia, as described in the approval letter.
- October 14, 2021: Lacosamide (Vimpat®) - FDA expanded age indications for oral and intravenous monotherapy and adjunctive therapy in the treatment of partial onset seizure patients, to include ages >1 month to <4 years (previously >4 years). Age indications remain at >4 years for use as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures. Details and updated dosage and oral solution shelf-life information are found in the prescribing information and associated FDA approval letter.
- September 30, 2021: Cannabidiol (Epidiolex®) - As summarized in this FDA Drug Safety-related labeling alert, with full details in the prescribing information, FDA announced label changes related to:
- Drug Interactions (Section 7.2, Effect of Epidiolex on Other Drugs) – New information about coadministration of Epidiolex with sensitive P-gp substrates given orally:
- Everolimus: When initiating Epidiolex in patients taking everolimus, monitor therapeutic drug levels of everolimus and adjust the dosage accordingly. When initiating everolimus in patients taking a stable dosage of Epidiolex, a lower starting dose of everolimus is recommended, with therapeutic drug monitoring.
- Other orally administered sensitive P-gp substrates (e.g., sirolimus, tacrolimus, digoxin): Increases in exposure may be observed on coadministration with Epidiolex, so therapeutic drug monitoring and dose reduction of other P-gp substrates should be considered when given orally and concurrently with Epidiolex.
- Adverse Reactions(Section 6.1, Clinical Trials Experience) –Increases in pneumonia with concomitant clobazam: This added subsection reports clinical trial observations of increases in pneumonia in patients with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC) who were receiving Epildiolex with concomitant clobazam.
- September 15, 2021: Lacosamide (Vimpat®) - Dyskinesia is added to neurologic disorders in Subsection 6.2 (Adverse Reactions; Postmarketing Experience) of the prescribing information, to read "Neurologic disorders: dyskinesia, new or worsening seizures."
- August 27, 2021: Brivaracetam (Briviact®) – FDA approved expanded age indications for Briviact for the treatment of partial-onset seizures to include patients one month of age and older, applicable to brivaracetam tablets for oral use, oral solution, and injection for intravenous use. The PI and approval letter provide details.
- August 18, 2021: Methsuximide (Celontin®) - An anticipated temporary shortage in August-September 2021 is reported by Parke-Davis, division of Pfizer Inc. As described in the 2010 Celontin Prescribing Information (PI), this drug was approved for the treatment of absence seizures refractory to other drugs. Currently, there is no generic form of methsuximide available. Methsuximide is in the succinimide class of antiseizure medications (ASMs) along with ethosuximide (2016 PI) and phensuximide. (Chen et al. 1963. PMID 14020499) Adverse effects of the succinimide ASMs are broadly similar. In some circumstances, if a patient’s methsuximide dosing could be interrupted during a shortage, providers may wish to consider switching to ethosuximide (Zarontin®). For more information about ethosuximide, see the AES 2020 summary of ASMs available in the United States. As of August 18, 2021, a methsuximide shortage is not reported in the FDA Drug Shortages database. AES will continue to monitor and alert members to status updates.
- June 30, 2021: Topiramate (Topamax®) label change. The FDA approved a label change to add the following ophthalmologic findings to subsection 5.1 (Warnings and Precautions; Acute Myopia and Secondary Angle Closure Glaucoma Syndrome): choroidal detachments, retinal pigment and epithelial detachments, and macular striae. Details are available in the prescribing information and approval letter.
- April 16, 2021: Everolimus (Afinitor® and Afinitor/Disperz®) tablets for oral suspension – The FDA updated Prescribing Information to include a new Warning and Precaution: Radiation sensitization and recall, in some cases severe, involving cutaneous and visceral organs (including radiation esophagitis and pneumonitis) have been reported in patients treated with radiation prior to, during, or subsequent to Afinitor/Afinitor Disperz treatment. Updates include advice to monitor patients closely when the drug is administered during or sequentially with radiation treatment. Corresponding updates were made to PI sections on Adverse Reactions, Postmarketing Experience, Patient Counseling information, and Patient Information/Patient Package Insert.
- March 31, 2021: Lamotrigine (Lamictal®) – FDA updated Prescribing Information Warnings and Precautions summary related to cardiac rhythm and conduction abnormalities: “Based on in vitro findings, Lamictal could cause serious arrhythmias and/or death in patients with certain underlying cardiac disorders or arrhythmias. Any expected or observed benefit of Lamictal in an individual patient with clinically important structural or functional heart disease must be carefully weighed against the risk for serious arrythmias and/or death for that patient.” This replaces the summary from an October 2020 PI update that read, “Avoid Lamictal in patients with underlying cardiac disorders or arrhythmias.”
Along with the March 31, 2021 PI update, FDA issued and broadly distributed a Drug Safety Communication about lamotrigine. The communication summarized related concerns and announced that FDA will require postmarket safety studies to evaluate whether other sodium channel blockers in the same drug class, as listed in the communication, have similar effects on the heart. The communication advises, “...sodium channel blockers approved for epilepsy, bipolar disorder, and other indications should not be considered safer alternatives to lamotrigine in the absence of additional information.” Specific guidance for health care professionals is provided as well patient messaging that states in part, “Patients should not stop taking your medicine without first talking to your prescriber, because stopping lamotrigine can lead to uncontrolled seizures, or new or worsening mental health problems...”
AES provided practical guidance for clinicians through a recorded March 11 webinar, Lamotrigine and the Heart, Cause for Concern? and a joint ILAE/AES advisory statement on cardiac effects of lamotrigine in Epilepsy Currents. AES will continue to keep members apprised of related news.
- 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.