Drug News and FDA Alerts

• CERLIPONASE ALFA (Brineura) – July 24, 2024 – The FDA has updated the Prescribing Information (PI) to expand the indication and usage to patients of all ages, including those less than 3 years of age, with neuronal ceroid lipofuscinosis type 2 (CLN2 disease), also known as tripeptidyl peptidase 1 (TPP1) deficiency, including those who are symptomatic or asymptomatic. Additionally, the FDA has added a Boxed Warning to indicate that patients treated with enzyme replacement therapies have experienced life-threatening hypersensitivity reactions, including anaphylaxis and that the anaphylaxis has occurred during the early course of enzyme replacement therapy as well as after extended duration of therapy. Patients less than 3 years of age may be at increased risk for developing hypersensitivity reactions with BRINEURA use compared to patients 3 years of age and older. BRINEURA is not recommended for use in patients less than 37 weeks post-menstrual age (gestational age at birth plus post-natal age) or those weighing less than 2.5 kg due to physiologic immaturity which may increase risk of serious and clinically significant adverse reactions. New data were also added to Sections 5, Warnings and Precautions; 6, Adverse Reactions; 8, Using in Specific Populations; and 17, Patient Counseling Information.
• Vigabatrin (Vigafyde) – June 17, 2024 – The FDA approved a new vigabatrin preparation for the treatment of infantile spasms as monotherapy in infants 1 month to 2 years of age. The new product is a prepared solution rather than a powder for solution. Note that Vigafyde is a concentrated formulation (100 mg/mL) as compared to the recommended final concentrations of other vigabatrin solutions (e.g., 50 mg/mL). The strength and the dose should be verified prior to prescribing, dispensing, and administering. Vigafyde is not indicated for the treatment of refractory focal seizures.  
• Lacosamide (Motpoly XR) – June 6, 2024 – The FDA approved a new indication for this preparation as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and in pediatric patients weighing at least 50 kg.  As specified in the Prescribing Information, the recommended initial dosage as adjunctive therapy is 100 mg once daily, and the respective dosage range is 200 to 400 mg once daily. The changes to the indication and summary of safety and effectiveness pertains only to the Motpoly XR formulation. The FDA specifically noted the following in the label "Additional pediatric use information is approved for UCB Inc.'s Vimpat (lacosamide) tablets, oral solution, and intravenous solution. However, due to UCB Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information."  The additional indication is described in Section 1, Indications and Uses: 1.2 Primary Generalized Tonic-Clonic Seizures. New data were also added to Sections 2.1, Dosage Information; 6.1, Clinical Trials Experience; 8.4, Pediatric Use; 12.3, Pharmacokinetics (subsection, Pediatric Patients); 14 (14.3, Adjunctive Therapy in Patients with Primary Generalized Tonic-Clonic Seizures); and the Medication Guide. 
• Cenobamate (Xcopri) – April 30, 2024 – The FDA has updated the Prescribing Information (PI) to add data on hepatic impairment and tablet crushing. The updates are to Section 8, Use in Specific Populations: Subsection 8.7, Hepatic Impairment. The addition to the label defines severe hepatic impairment (10-15 points on Child-Pugh assessment; Class C). In addition, details related to the use of crushed Xcopri tablets were added to Section 17, Patient Counseling Information, under subsections Patient Information (Dosing Instructions) and to the Medication Guide (How should I take XCOPRI?). 
• Diazepam (Libervant) – April 26, 2024 – The FDA approved a new drug application for the use of Libervant (diazepam) buccal film 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg for the acute treatment of intermittent, stereotypical episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 2 to 5 years of age. This added to the current diazepam preparations that include oral tablets, solutions, and concentrates, injections, rectal gels, and an intranasal spray. 
• Lidocaine – March 29, 2024 – The FDA has issued a warning advising consumers to avoid certain topical pain relief products with concentrations of lidocaine over 4%, due to potential health hazards, including the risk of seizures. For more information, please see the FDA release.
• Valproate – February 28, 2024 – Recently, the Medicines and Healthcare Products Regulatory Agency (MHRA) changed their valproate prescribing regulations in the UK. Starting in January 2024, valproate prescriptions to females younger than 55 years, including children, require approval from two physician specialists. The aim is to reduce valproate prescriptions that do not meet the current UK guidelines by reducing unnecessary exposure during fetal development. The teratogenic risks of valproate are well established, and this regulatory change is not based on new evidence. AES is not recommending any changes to current valproate prescribing regulations in the United States. A review of valproate during pregnancy may be found on the AES website.
• Felbatol (Felbamate) – February 9, 2024 – Felbatol oral suspension has been discontinued by Mylan Specialty, a Viatris Company. Felbatol tablets remain available. Felbamate oral suspension and tablets continue to be available from other manufacturers. More information is available on the FDA Drug Shortage website.
  

• Clobazam (e.g. Onfi, Sympazan) - November 28, 2023 - The FDA released a drug safety communication warning that in rare cases clobazam can cause Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). DRESS is a rare but serious reaction that can be life-threatening if not diagnosed and treated quickly. The current FDA labeling for clobazam does not include mention of DRESS, although it does include risk of similar symptoms in subsection 5.6 Serious Dermatological Reactions. The FDA is now requiring manufacturers to add information about DRESS to both the Prescribing Information and the Medication Guide (details of the exact content are not currently available).
• Levetiracetam (e.g. Keppra, Spritam) - November 28, 2023 - The FDA released a drug safety communication warning that in rare cases levetiracetam can cause Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). DRESS is a rare but serious reaction that can be life-threatening if not diagnosed and treated quickly. Subsection 5.5, of the Warnings and Precautions from the current FDA Prescribing Information includes information about the risk of symptoms similar to those of DRESS and subsection 6.2, Post Marketing Experience, does include mention of DRESS among a list of other adverse reactions identified post-approval. The FDA is now requiring manufacturers to add new warnings about DRESS to both the Prescribing Information and the Medication Guide (details of the exact content are not currently available).
• Levetiracetam (Keppra®) - August 17, 2023 - The FDA approved updates to the Prescribing Information (PI). The updates are to Section 6, Adverse Reactions: Section 6.2 Post marketing Experience: The following were added to the list of adverse reactions reported in patients receiving Keppra worldwide: “obsessive-compulsive disorders (OCD)” and “worsening of seizures including in patients with SCN8A mutations.”
• July 26, 2023 - The World Health Organization Committee on Essential Medicines has updated the core list of essential medicines to include levetiracetam and remove phenytoin. Essential medicines are those that satisfy the priority healthcare needs of a population. They are selected with due regard to disease prevalence and public health relevance, evidence of efficacy and safety, and comparative cost-effectiveness. Full details of the Expert Committee’s recommendations, describing the additions, changes and removal of medicines, and decisions not to recommend medicines are available in the executive summary. 
• Ganaxolone (Ztalmy®)- June 23, 2023 - The FDA updated the Prescribing Information (PI) with information on the use of Ztalmy® in patients with hepatic impairment. The PI was updated with new sections: Section 2.3: Dosage for Patients with Severe Hepatic Impairment and Section 8.6: Hepatic Impairment, which provide information on dosage adjustments during titration and maintenance for patients with severe hepatic impairment. Section 12.3 Pharmacokinetics, Specific Populations, Patients with hepatic impairment was also updated. 
• Brivaracetam (Briviact) - May 17, 2023 - The FDA approved updates to the Prescribing Information (PI). The updates are to Section 8, Use in Specific Populations: Section 8.1 Pregnancy: The risk summary was updated from "no data available" to "insufficient to identify a risk of major birth defects, miscarriage, or other maternal or fetal outcomes associated with Brivaracetam use during pregnancy." Section 8.2 Lactation: The risk summary was updated from "no data available" to "brivaracetam is present in human milk. There is insufficient information on effects in breastfed infant or on milk production."
• Lacosamide (Motpoly XR) – May 4, 2023 - The FDA approved a new drug application for Lacosamide (Motpoly XR) extended-release capsules, 100 mg, 150 mg, and 200 mg for the treatment of partial-onset seizures in adults and in pediatric patients weighing at least 50 kg. As specified in the Prescribing Information (PI), the recommended dose range is 200 to 400 mg given once daily. AES Treatments Committee Note: In 2017, the International League Against Epilepsy (ILAE) revised the operational classification of seizure types. The current terminology for ‘partial-onset seizure’ is ‘focal seizure’. 
• Topiramate – May 3, 2023 – The FDA approved Prescribing Information (PI) updates to add progestin-only contraceptives to Subsection 7.4, Contraceptives under Section 7, Drug Interactions. The updated subsection reads: “The possibility of decreased contraceptive efficacy and increased breakthrough bleeding may occur in patients taking contraceptive products with Topiramate. Patients taking estrogen-containing or progestin-only contraceptives should be asked to report any change in their bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough bleeding [see Clinical Pharmacology (12.3)].”
  
• Lacosamide (Vimpat®) – April 28, 2023 – The FDA approved Prescribing Information (PI) updates, described in the approval letter as related to the “use of alternate initial dosing (loading dose) for initiation of lacosamide treatment in partial onset seizure patients ≥1month to <17 years of age and in primary generalized tonic-clonic seizure patients ≥4 to <17 years, across all formulations.” Details are found in the updated PI, Dosage and Administration [Section 2], in Subsection 2.1, Table 1, and in particular in the newly added Subsection 2.2, Alternate Initial Dosage Information to Achieve the Maintenance Dosage in a Shorter Timeframe, and in the related Table 2. In addition, updates related to loading dose and pediatric indications were made to Warnings and Precautions [Section 5], Adverse Reactions [Section 6], Use in Specific Populations, [Section 8, Subsections 8.6 and 8.7] related to renal impairment and hepatic impairment, and the Medication Guide [Section 17].
  
• Fenfluramine hydrochloride (Fintepla®) oral solution – April 17, 2023 – The Prescribing Information (PI) has been updated to remove Section 9 Drug Abuse and Dependence. Fintepla oral solution is no longer subject to the Controlled Substance Act (CSA) based on a December 2022 DEA Final Rule that removes fenfluramine from the schedules of the controlled substance act. The manufacturer is beginning the process of updating the compendia in states where they hold licensure. Once this process is completed, in most cases prescribers will be able to write a prescription for a full year's supply, versus the current limitation of six months, although the Fintepla Risk Evaluation and Mitigation Strategies (REMS) Program still requires cardiac monitoring via echocardiogram and cardiovascular status assessments every six months. 
  
• Carbamazepine (Carbatrol®) – April 11, 2023 – The FDA updated the Prescribing Information (PI) to add hyperammonemia to Adverse Reactions, under the Metabolism subsection which now reads, “Metabolism: Fever and chills, decreased levels of plasma calcium leading to osteoporosis, and hyperammonemia have been reported.” Additional PI updates to the Warnings and Precautions, Adverse Reactions, Drug Interactions, and Use in Specific Populations sections, as well as the addition of a Medication Guide, were based on approved labeling of the listed drug, Tegretol®, the PI for which was last updated March 20, 2018.
  
• Divalproex sodium (Depakote) - February 24, 2023 – The FDA approved revisions to Drug Interactions [Section 7] in the Prescribing information (PI) to include interactions with methotrexate and cannabidiol. Revisions include:

Methotrexate was added in Effects of Co-Administered Drugs on Valproate Clearance [Subsection 7.1] under the heading, Drugs for which a potentially important interaction has been observed: Methotrexate may decrease serum valproate levels and potentially result in increased frequency of seizures or bipolar symptoms. Prescribers should monitor serum valproate concentrations and clinical response when adding or discontinuing methotrexate and adjust valproate dosage, if necessary.

Cannabidiol was added in a new subsection [7.4]: Concomitant administration of valproate and cannabidiol has been associated with an increased risk of ALT and/or AST elevation. This has been manageable by dose reduction or, in more severe cases, by discontinuation of one or both drugs. Liver function, including serum transaminase and total bilirubin levels, should be monitored during concomitant treatment [see Warnings and Precautions (5.1)].

The Drug Interactions PI updates were made for extended-release oral tablets, delayed-release oral tablets, and delayed-release capsule formulations of divalproex sodium. The referenced extensive updates to the Medication Guide are included only in the PI for the extended-release oral tablet formulation, where all three formulations are listed.

• Benzodiazepine class – January 13, 2023 – The FDA approved Prescribing Information (PI) updates related to use of all benzodiazepines in the class during late pregnancy and breastfeeding. See the updated PI for clobazam as one example of the changes made to Warnings and Precautions [Section 5] and Use in Specific Populations [Section 8], as well as corresponding updates to Patient Counseling Information [Section 17] and the Medication Guide. New risk summaries and clinical considerations information include:

Use of benzodiazepines late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns.

Pregnant females should be advised of the risks, be asked to inform their healthcare provider if they become pregnant and be encouraged to enroll voluntarily in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant while on a benzodiazepine.

Breastfeeding patients should be advised to inform their healthcare providers of the use of benzodiazepines and should be instructed to monitor their infants for excessive sedation, poor feeding, and poor weight gain, and to seek medical attention if they notice these signs.

• Lacosamide (Vimpat®) - September 30, 2022 – The FDA approved Prescribing Information (PI) updates to Section 8, Use in Specific Populations. Changes include types of available data pertaining to the use of lacosamide during pregnancy (Risk Considerations for Pregnancy, Section 8.1 and Lactation, Section 8.2). Additions to Lactation, Risk Considerations include: “Data from published literature indicate that lacosamide is present in human milk. There are reports of increased sleepiness in breastfed infants exposed to lacosamide (see Clinical Considerations). There is no information on the effects of lacosamide on milk production.” The following was added to Lactation, Clinical Considerations: “Monitor infants exposed to VIMPAT through breastmilk for excess sedation.” Corresponding updates were made to Patient Counseling Information (Section 17) and the Medication Guide (last 3 pages of the PI).
• Midazolam Injection (autoinjector) - Monday, August 8, 2022 - The FDA approved a new drug application from Rafa Laboratories, Ltd. for use of a midazolan autoinjector for the treatment of status epilepticus in adults. As specified in the Prescribing Information (PI), the recommended dose is a single 10mg dose, administered by intramuscular injection in the mid-outer thigh (vastus lateralis muscle) using the 10mg/0.7mL single-dose pre-filled autoinjector.
  
  The PI states that "continuous monitoring of respiratory and cardiac function is recommended" and that the injection "should be administered by trained personnel who have had adequate training in the recognition and treatment of status epilepticus and first aid/basic airway management." A stated Contraindication [Section 4] is for patients with a known hypersensitivity to midazolam.
  
  The PI also details Dosage and Administration instructions [Section 2], Warnings and Precautions [Section 5], Adverse Reactions [Section 6], Use in Specific Populations [Section 8]; among other important information. Details specified in the FDA approval letter include an expiry dating period of 24 months from the date of manufacture, when stored at controlled room temperature (68-77° F), based on stability data submitted to date; and requirements for a postmarketing risk identification and analysis to identify unexpected serious risk related to device reliability that could potentially lead to adverse events including death due to status epilepticus.
• Stiripentol (Diacomit) - Thursday, July 14, 2022 – The FDA approved expanded age indications for use of Diacomit capsule and oral suspension formulations for the treatment of seizures associated with Dravet Syndrome in patients taking clobazam, to include pediatric patients who are six months to less than two years of age and weighing 7 kg or more. The updated Prescribing Information (PI) adds related Dosing Information (Section 2.2). Additional changes include a change in verbiage from “powder for oral suspension” to “for oral suspension” throughout the content of PI, and updates to the Medication Guide and Instructions for Use in the PI, as summarized in the accompanying approval letter.
• Cenobamate (Xcopri ®) - Monday, June 27, 2022 – The FDA approved two additions to the Prescribing Information (PI) and Medication Guide, as summarized in the approval letter: 1) Psychiatric disorders (psychosis [hallucinations, delusions/paranois], hostility, aggression) is added to a newly created PI section, Adverse Reactions; Postmarketing Experience (Section 6.2); and 2) addition of information pertaining to the presence of cenobamate in rat milk based on a nonclinical study to PI section, Use in Specific Populations; Lactation (Section 8.2). FDA notes that because the Adverse Reactions addition is based on post-marketing use data reported voluntarily from populations of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
• Fosphenytoin sodium (Cerebyx®) injection – Thursday, April 28, 2022 – The FDA updated the last paragraph of the Prescribing Information, Warnings and Precautions section 5.9, Hematopoietic Complications. With the new addition of the last two sentences, the last paragraph now reads, “In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs. Macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Pure red cell aplasia has also been reported with phenytoin.”
• Topiramate (Eprontia™) – April 2022 | A recent manufacturer Prescribing Information update amends Administration Information (section 2.4) and Storage and Handling (section 16.2) to advise discarding the unused portion 60 days after first opening; this update extends shelf life from the prior 30 days, pending FDA approval and PI posting.
  
  This update follows the November 5, 2021 FDA Prescribing Information and approval of a new drug application to provide for the use of Eprontia (topiramate) 25 mg/mL oral solution for the following indications:
  • Monotherapy epilepsy: initial monotherapy for the treatment of partial-onset or primary generalized tonic-clonic seizures in patients two years of age and older.
  • Adjunctive therapy epilepsy: adjunctive therapy for the treatment of partial-onset seizures, primary generalized tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome in patients two years of age and older.
  • Migraine: preventive treatment of migraine in patients 12 years of age and older.
  The AES Treatments Committee offers the following related guidance: Eprontia is a 25 mg/mL concentration, which is different from concentrations of topiramate suspensions that have previously been compounded for patients by pharmacies (6 mg/mL or 20 mg/mL concentrations are most common). When switching from compounded topiramate suspension to Eprontia, prescribers, patients, and caregivers should be aware of this difference. Per Institute for Safe Medication Practices (ISMP) Safe Practice Recommendations and the American Society of Hospital Pharmacists (ASHP) Standardize 4 Safety initiative, prescriptions for oral solutions and suspensions should be written to specify doses in metric weight (e.g., mg of topiramate), rather than mL volume of solution. 

• Fenfluramine (Fintepla®) – Monday, March 28, 2022 | The FDA approved new Indications and Usage to include treatment of seizures associated with Lennox-Gastaut Syndrome in patients two years of age and older. Previously, fenfluramine was approved only for treatment of seizures associated with Dravet syndrome in patients two years of age and older. Corresponding details for Lennox-Gastaut Syndrome are found in the updated Prescribing Information under Dosage and Administration (PI Section 2), Warnings and Precautions (PI Section 5), and Adverse Reactions (PI Section 6).
• Ganaxolone (Ztalmy®) – Friday, March 18, 2022 | The FDA approved a new drug application that provides for the use of Ztalmy oral suspension for the treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients two years of age and older. See dosage and administration and other important details in the Prescribing Information and approval letter.
• Diazepam nasal spray (Valtoco) – Friday, February 4, 2022 | The FDA approved an update to the Prescribing Information Section 6.1, Adverse Reactions, Clinical Trials Experience, to update the local adverse reactions occurring in Valtoco-treated patients based on greater numbers of clinical studies subjects (220; previously 190) over at least one year (previously at least six months). The most common local adverse reactions occurring in Valtoco-treated patients are nasal discomfort (6%), dysgeusia (3%), and epistaxis (2%); this update removes nasal congestion (3%) from the list.
• Topiramate (Trokendi XR®) – Thursday, February 3, 2022 | The FDA approved a supplemental new drug application that provides for inclusion of additional ophthalmologic findings (choroidal detachments, retinal pigment epithelial detachments, and macular striae) in the Prescribing Information, Warnings and Precautions, Acute Myopia and Secondary Angle Closure Glaucoma Syndrome (subsection 5.1).
• Everolimus (Afinitor® and Afinitor Disperz®) - Monday, February 1, 2022 | The FDA approved a supplemental new drug application to add lymphedema to the Adverse Reactions, Postmarketing Experience section of the Prescribing Information for everolimus tablets and everolimus tablets for oral suspension, and to make minor editorial revisions to the PI and Patient Labeling.
• Topiramate (Topamax®) – Tuesday, January 13, 2022 | The FDA approved revisions to the Prescribing Information. This statement was added to Pediatric Use (section 8.4):  “Safety and effectiveness in patients below the age of 2 years have not been established for the monotherapy treatment in partial-onset epilepsy." Additions to Warnings and Precautions included: metabolic acidosis (section 5.4), decreases in bone mineral density (Section 5.9), negative effects on growth (height and weight) (section 5.10), and kidney stones (section 5.13). Revisions reflect safety outcomes from a Postmarketing study entitled, A Randomized, Active-controlled, Open-label, Flexible-dose Study to Assess the Safety and Tolerability of Topiramate as Monotherapy Compared with Levetiracetam as Monotherapy in Pediatric Subjects with New or Recent-onset Epilepsy. 

• 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:
  • 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
  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.

• 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.

• 01/29/21 – 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.
• 10/09/20 - Lamotrigine (Lamictal®) – The FDA approved new Warnings and Precautions for the Prescribing Information (PI) regarding cardiac arrhythmias. In vitro testing showed that Lamictal exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations, so it could slow ventricular conduction (widen QRS) and induce proarrhythmia, including sudden death, in patients with structural heart disease or myocardial ischemia. Avoid the use of Lamictal in patients who have cardiac conduction disorders (i.e., second- or third-degree heart block), ventricular arrhythmias, or cardiac disease or abnormality (i.e., myocardial ischemia, heart failure, structural heart disease, Brugada syndrome, or other sodium channelopathies). Concomitant use of other sodium channel blockers may increase the risk of proarrhythmia. Related updates were made in other sections of the PI, including Pharmacodynamics and Patient Counseling, as well as the Medication Guide.
• 10/05/20 - Midazolam (Nayzilam®) nasal spray – The manufacturer today notified health care professionals and AES of an anticipated temporary shortage of Nayzilam® (midazolam) nasal spray, C-IV, through the end of October 2020, due to a manufacturing delay unrelated to COVID-19. The company states, “UCB, Inc. is committed to restoring the supply of Nayzilam® as soon as possible. Patients or caregivers experiencing difficulty accessing Nayzilam® are encouraged to call ucbCARES® at +1-844-599-2273 for assistance.” As of this post, midazolam nasal spray does not yet appear among reported shortages on the FDA Drug Shortages website, although injectable midazolam is listed as “currently in shortage.”
• 09/23/20 – Benzodiazepines – The FDA issued a Drug Safety Communication requiring Boxed Warning updates for all benzodiazepine medications to improve the safe use of this drug class and address the serious risks of abuse, addiction, physical dependence, and withdrawal reactions. In addition to the Boxed Warning updates, FDA is requiring the addition of information to the Prescribing Information and Medication Guides for these medications (links are to general FDA lookup sites). The Drug Safety Communication provides details, rationale for the new requirements, and information for health professionals. FDA encourages patients and health care professionals to report side effects of benzodiazepines and other medications to the FDA MedWatch program.
• 8/31/20 – Cenobamate (Xcopri®) tablets – FDA approved updated Prescribing Information that incorporates a March 10, 2020, Drug Enforcement Administration (DEA) scheduling determination. In an interim final rule, DEA placed cenobamate in schedule V of the Controlled Substances Act. SK Life Science, Inc. filed a supplemental new drug application with FDA on March 11, 2020, to add the final scheduling information to the PI. Additional details are in the FDA approval letter. The drug was initially approved November 21, 2019, with highlights of PI, pending the DEA scheduling determination (See related entry on this page)
• 8/31/20 – Lamotrigine (Lamictal®) - FDA approved a GlaxoSmithKline supplemental new drug application to provide for addition of the following to the Adverse Reactions; Postmarketing Experience section of the Prescribing Information for several formulations of Lamictal (lamotrigine) tablets: “Renal and Urinary Disorders: Tubulointerstitial nephritis (has been reported alone and in association with uveitis).” Please see the approval letter and the PI for details.
• 7/31/20 – Cannabidiol [CBD] (Epidiolex®) – The U.S. Food and Drug Administration (FDA) approved Epidiolex (cannabidiol) [CBD] oral solution for the treatment of seizures associated with tuberous sclerosis complex in patients one year of age and older. Epidiolex was previously approved for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome. See details in the updated prescribing information, the FDA approval letter, and an FDA press release. 
• 6/26/20 – Fenfluramine (Fintepla®) – FDA announced approval of a new drug application from Zogenix, Inc. that provides for the use of Fintepla (fenfluramine), oral solution 2.5 mg per mL for the treatment of seizures associated with Dravet syndrome in patients 2 years of age and older, as specified in the Prescribing Information. The Medication Guide provides information for patients. The FDA approval letter notes that this drug has an orphan drug designation for this indication and is currently controlled in Schedule IV of the Controlled Substances Act. FDA will transmit a scheduling recommendation to the Drug Enforcement Administration (DEA), but the drug remains a controlled substance while DEA is making its final scheduling decision, at which time revisions to the PI, Medication Guide, and Instructions for Use will be required. In addition, physicians who prescribe, pharmacies that dispense, and patients who receive, fenfluramine (Fintepla) must be certified in the fenfluramine (Fintepla) Risk Evaluation and Mitigation Strategy (REMS) program, as detailed in the FDA approval letter.
• 6/8/2020 – Topiramate (Topamax®) tablets and sprinkle capsules – FDA approved a supplemental new drug application from Janssen Pharmaceuticals that provides for the addition of serious skin reaction, Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), to the Warnings and Precautions and Patient Counseling Information sections of the Prescribing Information (PI) and to the Medication Guide. See details in the FDA approval letter and updated PI.
• 05/19/2020 – Valproate – FDA-approved AbbVie supplement applications for revisions to labeling information to reflect new data pertaining to an increased risk of attention-deficit/hyperactivity disorder (ADHD) in children who were exposed to valproate in utero. In addition, Prescribing Information (PI) warning updates include additional descriptive information on birth defects, decreased IQ, and neurodevelopmental disorders following in utero exposure. FDA approval letters and the updated labeling information (PI) are linked from FDA pages for each form of the medication: Depakote (divalproex sodium) delayed-release tablets, Depakote sprinkle capsules (divalproex sodium delayed-release capsules), Depakote ER (divalproex sodium) extended-release tablets, Depakene (valproic acid) capsules, Depakene (valproic acid) oral solution, and Depacon (valproate sodium) injection. The PIs provide supporting data and specific information related to the updates (In each PI, see especially Section 5, Warnings and Precautions, and Section 8.1, Use in Specific Populations – Pregnancy).
• 04/03/2020 – Levetiracetam Immediate-Release Oral Tablets, USP – FDA re-verified shortage status for various manufacturers. FDA first reported this drug as “Currently in Shortage” on 04/01/2019.
• 04/02/2020 – Midazolam Injection, USP – FDA first reported status as “Currently in Shortage” with various manufacturers reporting “Demand Increase for the Drug,” one manufacturer reporting “On allocation,” and one manufacturer reporting “Limited supply. On allocation for 2020. Cannot supply market demand.” 
• 4/1/2020 - Levetiracetam Extended-Release Oral Tablets, USP – FDA re-verified shortage status for various manufacturers. Recent manufacturer reports of potential shortages began December 3, 2019, and FDA first reported this drug as “Currently in Shortage” on 05/28/2019. 
• 1/24/2020 - Vigabatrin (Sabril®) – The U.S. Food and Drug Administration (FDA) approved a supplemental new drug application to provide for expanded use of Sabril to patients 2 years of age and older with refractory complex partial seizures (rCPS) and proposed modifications to the related risk evaluation and mitigation strategy (REMS). Previously indicated for Infantile Spasms, the added Sabril indication is for: “Refractory Complex Partial Seizures as adjunctive therapy in patients 2 years of age and older who have responded inadequately to several alternative treatments; SABRIL is not indicated as a first-line agent.” Details are in the updated Prescribing Information for Sabril, with additional information in the FDA approval letter.
• 1/10/2020 – Diazepam (Valtoco®) nasal spray; FDA approved an application from Neuralis Inc. for a new dosage form (nasal spray) of diazepam, as noted on this page in the FDA-Approved Drugs database. Approved dosage levels are 5 mg, 7.5 mg, and 10 mg. The Prescribing Information provides additional details.
• 1/10/20 - Recall of Lamotrigine Tablets USP, 100 mg, 100 Count Bottles – Taro Pharmaceuticals U.S.A., Inc. is voluntarily recalling one (1) lot of Lamotrigine 100 mg Tablets, Lot # 331771 (expiration date June 2021) in 100 count bottles, NDC 51672-4131-1 to the consumer level. This single lot of Lamotrigine 100 mg Tablets Lot #331771 (expiration date June 2021) was found to have been cross-contaminated with a small amount of another drug substance (Enalapril Maleate) used to manufacture another product at the same facility. Details and a product label photo are on the US Food and Drug Administration (FDA) page on the recall announcement, and the company press release on the recall provides additional information.

• 12/20/19 - The U.S. Food and Drug Administration (FDA) announced a recall of the LivaNova VNS Therapy SenTiva Generator due to an unintended reset error that causes the system to stop delivering VNS therapy. If device replacement is needed, there is a risk associated with additional surgery to replace the generator. LivaNova has received 14 reports of unexpected reset errors. 4 patients have required early revision surgery for failed devices. No deaths related to this issue have been reported. On July 31, 2019, LivaNova implemented additional mitigations and at this time, no reset errors have been observed since the implementation of these mitigations. These additional mitigations are currently under review by the FDA. The full FDA announcement provides details and recommended actions for providers and patients.
• 12/19/19 - The U.S. Food & Drug Administration (FDA) issued a Drug Safety Communication warning that serious breathing difficulties may occur in patients using gabapentin (Neurontin, Gralise, Horizant) or pregabalin (Lyrica, Lyrica CR) who have respiratory risk factors. These include use of opioid pain medicines and other drugs that depress the central nervous system and conditions such as chronic obstructive pulmonary disease (COPD) that reduce lung function. The elderly are also at higher risk. An FDA portal on the safety communication links to additional details, including data on which the safety concern is based, advice for health care professionals and patients and caregivers, and where to report side effects. In addition to the safety communication, FDA is requiring that 1) new warnings about the risk of respiratory depression be added to the prescribing information of the gabapentinoids, and 2) drug manufacturers conduct clinical trials to further evaluate abuse potential of the gabapentinoids, particularly in combination with opioids, because misuse and abuse of these products together is increasing, and co-use may increase the risk of respiratory depression. Gabapentin and pregabalin are FDA-approved for a variety of conditions, including seizures, nerve pain, and restless legs syndrome. FDA announced in July 2019 the approval of the first pregabalin generics of Lyrica. 
• 11/21/19 – The U.S. Food and Drug Administration (FDA) approved cenobamate tablets (Xcopri, SK Life Science Inc.) as a new treatment option for partial onset seizures in adults, based on two randomized controlled trials that established safety and efficacy. The FDA announcement was released November 21, and highlights of prescribing Information (PI) are dated 11/2019, pending DEA controlled substance scheduling. It is hoped that cenobamate (Xcopri) will be available in pharmacies shortly after scheduling has been completed.
• 10/23/19 – The FDA approved a prescribing information (PI) change for Keppra® (levetiracetam). Previously approved only for adjunctive therapy, Keppra indications now include monotherapy for partial-onset seizures in patients 1 month of age and older. The updated PI includes related updates to information on dosing and discontinuation. Recommended dosing is the same for monotherapy and adjunctive therapy. The updated PI includes no change to Keppra indications for use only as adjunctive therapy in the treatment of myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy (JME) and in the treatment of primary generalized tonic-clonic seizures (GTCS) in patients 6 years of age and older with idiopathic generalized epilepsy. See highlights of the updated PI.
• 7/31/19 – The FDA approved addition of the following statement to section 5.4 (Warnings and Precautions; Neurotoxicity) of the Prescribing Information (PI) for Sabril (vigabatrin): "Intramyelinic edema (IME) has been reported in postmortem examination of infants being treated for IS with vigabatrin.” See details in the FDA letter of approval and the updated PI.
• 7/22/19 - A July 22, 2019 announcement from the U.S. Food and Drug Administration, Center for Drug Evaluation and Research (FDA CDER) highlighted the July 19, 2019 approval of multiple applications of first generics of Lyrica (pregabalin) for indications that include “adjunctive therapy for the treatment of partial onset seizures in patients 17 years of age and older.” CDER Director, Janet Woodcock, MD, cited “FDA’s longstanding commitment to advance patient access to lower cost, high-quality generic medicines.” The announcement also summarizes patient Medication Guide warnings required to be dispensed with pregabalin. Details (dosage levels, manufacturers, and indications) about first-time generic drugs approved in 2019, including pregabalin, can be found at this FDA First Generic Drug Approvals 2019 page.
• 5/17/19 - On May 17, 2019, the Food & Drug Administration approved Nayzilam (midazolam) intranasal spray for the treatment of seizure clusters and acute repetitive seizures that are distinct from the patient’s usual seizure pattern in patients with epilepsy 12 years of age and older. The prescribing information may be found here.
• 2/26/19 Intravenous Levetiracetam distributed by Dr. Reddy’s Laboratories Inc. A labeling error incorrectly stating the product strength resulted in a Class I recall of 2770 i.v. bags of levetiracetam in 0.54% sodium chloride injection, 1500 mg/100 mL (15 mg/mL), distributed in the US by Dr. Reddy's Laboratories Inc. The February 20, 2019, FDA Enforcement Report states, "the preprinted text on the primary infusion bag and the NDC incorrectly identifies the product as levetiracetam in 0.75% sodium chloride (1000 mg/100 mL). However, the external foil pouch correctly identifies the product as levetiracetam in 0.54% sodium chloride injection (1500 mg/100 mL).” The recall affects bags manufactured by Gland Pharma Limited from lot ABD807 (Exp. 5/20). More here.
• 2/26/19 - Lamictal (lamotrigine): Health Canada and the European Medicine Agency have recently issued 2 warnings regarding lamotrigine. First, Brugada-type ECG arrhythmogenic ST-T abnormalities and typical Brugada ECG pattern have been reported in patients treated with lamotrigine. The use of lamotrigine should be carefully considered in patients with Brugada syndrome. Second, lamotrigine also has been reported to pass into breast milk, resulting in lamotrigine plasma total levels in neonates and older infants of up to approximately 50% of the mother’s level. Therefore, in some breastfed infants, plasma concentrations of lamotrigine may reach levels at which pharmacological effects occur. The potential benefits of breastfeeding should be weighed against the potential risk of adverse effects occurring in the infant. Should a woman decide to breastfeed while on therapy with lamotrigine, the infant should be monitored for adverse effects, such as sedation, rash, and poor weight gain. More here. 
• 1/17/19 - The FDA has cleared the Embrace watch for use in epilepsy patients ages 6 years and older. It was first approved in January 2018 for adults aged ≥ 21 years. The watch detects convulsive seizures by combing information from both electrodermal and accelerometry biosensors. When a seizure is detected, an automated alert can be sent to a caregiver, when the watch detects unusual patterns that may be associated with a convulsive seizure. Clinical trials have demonstrated accuracy rates greater than 95% for detecting generalized convulsive seizures. More here.

• 11/11/18 - The FDA approved new prescribing information for Vimpat (lacosamide). In addition to the previously known 0.4% risk of first-degree AV block (PR interval >200 msec) observed in preclinical trials, additional cardiac risks have been identified. "In the post-marketing setting, there have been reports of cardiac arrhythmias in patients treated with VIMPAT, including bradycardia, AV block, and ventricular tachyarrhythmia, which have rarely resulted in asystole, cardiac arrest, and death. Most, although not all, cases have occurred in patients with underlying proarrhythmic conditions, or in those taking concomitant medications that affect cardiac conduction or prolong the PR interval. These events have occurred with both oral and intravenous routes of administration and at prescribed doses as well as in the setting of overdose. Vimpat should be used with caution in patients with underlying proarrhythmic conditions such as known cardiac conduction problems (e.g., marked first-degree AV block, second-degree or higher AV block, and sick sinus syndrome without pacemaker), severe cardiac disease (such as myocardial ischemia or heart failure, or structural heart disease), and cardiac sodium channelopathies (e.g., Brugada Syndrome). VIMPAT should also be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium channel blockers, beta-blockers, calcium channel blockers, potassium channel blockers, and medications that prolong the PR interval. The PI PDF is attached here.
• 11/12/18 - The FDA approved new prescribing information (PI) for VIMPAT, which now contains additional serious warnings about cardiac arrhythmias including ventricular arrhythmias. VIMPAT is indicated for the treatment of partial-onset seizures in patients 4 years of age and older. Additional information regarding the updated PI is located here.
• 10/18/18 - The FDA approved new labeling for oral Dilantin (phenytoin) suspension. Section 5.6 of the Prescribing information indicates, "Cases of bradycardia and cardiac arrest have been reported in Dilantin-treated patients, both at recommended phenytoin doses and levels and in association with phenytoin toxicity. Most of the reports of cardiac arrest occurred in patients with underlying cardiac disease." It is important not to confuse this warning with the existing concerns for intravenous phenytoin or fosphenytoin. The updated labeling information is located here.
• 9/1/2018 - The FDA has extended the labeling for Fycompa (perampanel). It is now indicated for the treatment of focal onset seizures with or without progression to bilateral tonic-clonic seizures in children as young as age 4 years. This indication includes both monotherapy and adjunctive therapy. The revised PI can be located here.
• 8/20/18 - The FDA approved Diacomit (stiripentol) for the treatment of seizures associated with Dravet syndrome in persons 2 years of age and older. Diacomit is approved for use as an adjunct to clobazam, with which it has a drug-drug interaction. It is available as capsules or oral powder for suspension and is not scheduled. Prescribing information is located on the FDA CDER website here. 
• 8/8/18 - The FDA has launched a new medication guide database to replace the current medication guide webpage. Features of the new database include active ingredient and brand name search for medication guides, download capabilities to CSV and Excel spreadsheets, streamlined data entry for faster database updates, and improved mobile device usability. Click here to view the new medication guide database.
• 7/18/18 - The FDA updated the prescribing information (PI) for Lamictal (lamotrigine) to include the extremely rare occurrence of hemophagocytic lymphohistiocytosis in 8 cases worldwide since 1994. The revised PI states, "Hemophagocytic lymphohistiocytosis (HLH) has occurred in pediatric and adult patients taking Lamictal for various indications. HLH is a life-threatening syndrome of pathologic immune activation characterized by clinical signs and symptoms of extreme systemic inflammation. It is associated with high mortality rates if not recognized early and treated. Common findings include fever, hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms, cytopenias, high serum ferritin, and liver function and coagulation abnormalities. In cases of HLH reported with Lamictal, patients have presented with signs of systemic inflammation (fever, rash, hepatosplenomegaly, and organ system dysfunction) and blood dyscrasias. Symptoms have been reported to occur within 8 to 24 days following the initiation of treatment." Providers should review the new PI which provides further guidance on differential diagnosis and treatment. HLH has signs which may overlap with other diagnoses including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson syndrome, and toxic epidermal necrolysis. The July 2018 revised PI can be located here.
• 6/25/2018 - The FDA approved Epidiolex (cannabidiol) for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients two years of age and older. This new antiepileptic drug will be available shortly after the Drug Enforcement Agency issues a scheduling determination 90 days after the FDA-approval date. Additional information is located here and the PI is here.
• 5/10/2018 - The FDA approved an extension to the indication for Briviact (brivaracetam). Briviact is now indicated for the treatment of partial onset seizures in children four years of age and older, and in adults. The i.v. formulation is not approved for children ages four to 15 years. Additional information for download is located here.
• 4/27/2018 - The FDA approved the Deep Brain Stimulation (DBS) System for Epilepsy. The device delivers electrical pulses to a location inside the brain which is involved in seizures. The system consists of a pulse generator (IPG) implanted under the skin of the upper chest, and two leads implanted in the brain. The Medtronic DBS System for Epilepsy helps reduce the frequency of seizures in epilepsy patients who have frequent, disabling, partial-onset seizures and have not responded well to antiepileptic medications. Additional information is located here.
• 4/25/2018 The FDA is providing health care providers with preliminary information concerning magnetic resonance (MR) thermometry reliability with magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) devices.
  
  The FDA is currently evaluating data, which suggests that potentially inaccurate MR thermometry information can be displayed during treatment. For example, MR parameters such as voxel size (measurement of the image resolution or detail) and MR image acquisition time (e.g., up to 8 seconds) may contribute to inaccurate MR thermometry readings and potential errors in the ablation assessment. In addition, MRgLITT devices may not account for the continued thermal spread of energy to the surrounding tissue (as the target ablation area returns to its baseline temperature), which may result in an underestimation of thermal damage.
  
  The FDA reviewed Medical Device Reports (MDRs) and literature reports which describe adverse events, such as neurological deficits (e.g., focal motor deficits, aphasia, cognitive changes), increased intracerebral edema or pressure, intracranial bleeding, and/or visual changes (e.g., visual field deficits, blurry vision) when these devices were used to treat intra-cranial lesions. Several of these reports note which events required urgent medical and/or surgical intervention, and may have been associated with patient deaths. However, it is unclear at this time, whether an inaccuracy of MR thermometry directly caused or contributed to these events. Additional information is located here. 
• 4/25/2018 - The FDA has issued a new warning that the medication Lamictal (lamotrigine) for seizures and bipolar disorder can cause a rare, but very serious reaction that excessively activates the body’s infection-fighting immune system. This can cause severe inflammation throughout the body and lead to hospitalization and death, especially if the reaction is not diagnosed and treated quickly. As a result, the FDA is requiring a new warning about this risk be added to the prescribing information in the lamotrigine drug labels. Additional information is located here. 
• 4/10/2018 - The FDA approved the use of Afinitor (everolimus) for the adjunctive treatment of adult and pediatric patients aged two years and older with tuberous sclerosis complex (TSC)-associated focal-onset seizures. Additional information is located here.

• 11/02/2017 - The FDA expanded the approval for Vimpat oral tablets and solution to include children. The approval is now for the treatment of partial-onset seizures in patients age 4 and older as monotherapy or adjunctive therapy. Vimpat injection remains approved for this indication only for patients 17 years and older. More information is available here.
• 08/2017 - Health Canada updated the Keppra monograph to add warnings for pancytopenia and rhabdomyolysis and is available here. The risk of pancytopenia has been included in the warnings and precautions sections of the Canadian product monograph for Keppra (levetiracetam). The risk of rhabdomyolysis/blood creatine phosphokinase increase has been included in the post-market adverse drug reactions section.
• 08/17/2017 - The FDA approved an extension of the indication for eslicarbazebine (Aptiom). Aptiom is now indicated down to age 4 years for both monotherapy and adjunctive therapy for the treatment of partial (focal) onset seizures. The updated prescribing information can be found here.
• 08/15/2017 - The FDA approved an extension on the indication for brivaracetam (Briviact) Briviact is now indicated for both monotherapy and adjunctive therapy for persons age 16 years and above for the treatment of partial (focal) onset seizures. The updated prescribing information can be found here.
• 07/26/2017 - The FDA approved an important change to the Fycompa (perampanel) prescribing information. Perampanel is now approved as monotherapy for patients 12 years of age and older who have partial (focal)-onset seizures both with and without progression to generalized tonic-clonic seizures. This new, expanded FDA indication does not include monotherapy for primary generalized tonic-clonic seizures, where perampanel is still approved as adjunctive treatment. This is the first antiepileptic drug (AED) to receive approval for monotherapy use under the FDA's new rule granting a monotherapy indication based solely on the results of randomized controlled trials of adjunctive therapy for partial (focal)-onset seizures. Additional information regarding the prescribing information is located here.
• 03/28/2017 - The FDA announced an update to the Vimpat (lacosamide) prescribing information to include a warning about rare cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS; formerly known as multiorgan hypersensitivity). Additionally, cardiogenic shock has been added as an effect of Vimpat overdose. More information is available here.
• 03/07/2017 - The FDA sent a letter to Sunovion asking that Prescribing Information be updated to include the occurrence of toxic epidermal necrolysis (TEN) with the use of Aptiom. This is in addition to the warnings of Stevens-Johnson Syndrome (SJS) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRWSS) listed in the current Prescribing Information. More here.
• 02/20/2017 - VistaPharm, Inc is recalling more than 12,000 units of Phenytoin Oral Suspension, USP 100 mg/ 4 mL, 50 unit dose cups of 4 mL per case, Rx only, according to the US Food and Drug Administration’s (FDA) latest Drug Enforcement Report (February 15, 2017).  The recall was initiated on January 18, 2017, due to, 'CGMP Deviations: Purified water used to manufacture the drug products may have been contaminated with Burkholderia cepacia,' according to the FDA.  The affected products were distributed throughout the United States. Known lot numbers include 428700 (Exp. 11/17) and 409500 (Exp. 06/17). On February 2, 2017, the FDA designated the recall a class II, meaning that exposure might cause temporary health problems, but is unlikely to cause injuries of a serious nature.
• 02/07/2017 - Health Canada has published a review that concluded that there may be a link between the use of levetiracetam (Keppra) and the risk of acute kidney injury. The current product information for Keppra informs that cases of acute kidney injury have been reported in patients treated with levetiracetam. Health Canada has requested that the other manufacturers of levetiracetam-containing products also update their product information with the same wording. More information is available here.
• 01/05/2017 - The FDA has issued a new class warning for the use of benzodiazepines concomitantly with opiates.
  This would include AEDs such as Onfi (clobazam), Klonopin (clonazepam), Ativan (lorazepam), Diastat (rectal diazepam) and others. The warning states, "concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.' Please see the attached prescribing information regarding Onfi (clobazam)." More information here and here. Find Onfi prescribing information here.

• 12/12/2016 - Health Canada carried out a safety review after learning that the European Medicines Agency was looking into a potential interaction between levetiracetam and methotrexate. The interaction between the two drugs may lead to higher amount of methotrexate in the blood, which may cause serious side effects. The side effects, which can be fatal, include sudden (acute) kidney failure.
• 11/18/2016 - FDA recalls of Clonazepam Tablets, USP, 0.5 mg, a drug used to treat certain seizure and panic disorders. The recall affects certain packages. More information here.
• 11/7/2016 - Health Canada has indicated a potential link to respiratory depression—including sedation, somnolence, and loss of consciousness—in patients treated with gabapentin, particularly in patients having lung, kidney, or nervous system diseases that impact breathing, as well as in those that are elderly, or using other drugs that can affect breathing such as opioids, or in those are at higher risk of serious breathing problems. Additional information concerning the risk of respiratory depression has been added to the Warnings and Precautions section of the Canadian product monograph (CPM) for Neurontin (gabapentin). Concomitant use of CNS depressants with gabapentin is also a contributing factor. More information here.
• 10/18/2016 - EMA recommends measures to ensure safe use of Keppra oral solution. More information here.
• 10/17/2016 - FDA approves Carnexiv - i.v. carbamazepine, marketed by Lundbeck. More information here.
• 10/6/2016 - FDA recalls lamotrigine tablets, USP, 150 mg, due to misprinted tablets. The medication (NDC 29300-113-05) was packaged in 500-count bottles. More information here.
• 9/26/2016 - Zarontin (ethosuximide) - Defective Capsules Associated with Reduced Efficacy (Increased Frequency of Seizures). More information here.
• 8/31/2016 - Levetiracetam may rarely be associated with acute renal failure. Recently, the Ministry of Health, Labour, and Welfare in Japan reported that a patient treated with levetiracetam developed acute renal failure within 90 days of the initiation of the treatment. The condition resolved after discontinuation of levetiracetam. In Japan, the prescribing information for levetiracetam now lists acute renal failure as one of the serious adverse reactions. Currently, no specific monitoring is recommended with levetiracetam, but obtaining baseline renal tests before initiation of levetiracetam and periodically thereafter could be done to assess renal function.
• 8/30/2016 - Lamotrigine Orally Disintegrating Tablet 200 mg by Impax: Recall - Incorrect Labeling of Blister Cards. More information here.
• 8/16/2016 - The manufacturer is advising healthcare providers that POTIGA (ezogabine) Tablets, CV, 50mg, 200mg, 300mg, and 400mg will no longer be commercially available after June 30, 2017. GSK intends to permanently discontinue the product due to the very limited usage of the medicine and the continued decline in new patient initiation. Discontinuation is not due to efficacy or safety reasons. Read more. [PDF]
• 8/15/2016 - In an enforcement letter the week of August 1st, the FDA ordered a recall of Divalproex 100 mg delayed-release tablets manufactured by Teva, Inc. due to failed specifications. The recall number is D-1449-2016 and code information is Lot #: 02D163, Exp. 9/2017.
• 5/29/2016 - A new boxed warning has been added to the prescribing information for ezogabine: "Potiga (ezogabine) can cause retinal abnormalities with funduscopic features similar to those seen in retinal pigment dystrophies, which are known to result in damage to the photoreceptors and vision loss. Macular abnormalities characterized as vitelliform lesions have also been observed. All patients taking Potiga should have baseline and periodic (every 6 months) systematic visual monitoring by an ophthalmic professional. Testing should include visual acuity, dilated fundus photography, and optical coherence tomography." Click here to download. [PDF]
• 4/18/2016 - Study in Neurology finds pregabalin may be linked to major birth defects. View the Pubmed citation. 
• 4/12/2016 - The FDA issues overview, "FDA Regulation of Marijuana: Past Actions, Future Plans." Click here to download. [PDF]
• 4/6/2016 - The FDA and the manufacturer updated the prescribing information for Zonegran (zonisamide) to include a warning about Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) also known as multiorgan hypersensitivity. Download the revised prescribing information here. [PDF]
• 2/19/2016 - FDA approves Briviact (brivaracetam) as an add-on treatment to other medications to treat partial-onset seizures in patients age 16 years and older with epilepsy. Click here for more information.