Hand holding Valtoco Nasal Spray

Neurelis Announces Rapid and Broad Payer Coverage of Valtoco (diazepam nasal spray)

Neurelis Press Release

  • More than 176 million lives in the U.S. now covered by payers/managed care/insurance plans within months of FDA approval of VALTOCO, the first and only nasal spray treatment of seizure clusters in patients 6 years of age and older
  • Neurelis’ patient assistance program supports eligible patients who have no health insurance
  • Co-pay program for VALTOCO helps commercial patients lower their out-of-pocket costs to as low as $20

Neurelis, Inc., announced today that insurers and managed care plans now provide coverage for more than 176 million lives for the company’s lead product, VALTOCO® (diazepam nasal spray). VALTOCO was approved by the U.S. Food and Drug Administration (FDA) on January 10, 2020, for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in adult and pediatric patients 6 years of age and older.

“It is a very positive signal that insurers are quickly providing coverage for VALTOCO,” said Chuck DeWildt, the company’s Chief Commercial Officer. “We’ve accomplished in just over four months what takes many companies up to a year to do. I’d like to commend our market access team and the payers for understanding that this is a large unmet need for people with epilepsy and we look forward to even more lives being covered in the coming months to provide this important product to the people who need it.”

In the United States, there are over 3.4 million people with epilepsy, with approximately 200,000 new patients diagnosed each year. Despite the availability of chronic, daily oral medications to control epilepsy, a significant number of these patients continue to experience seizures. Of these uncontrolled patients, as many as 170,000 are at risk for episodes of frequent seizure activity, also known as cluster or acute repetitive seizures, representing a significant unmet need in the epilepsy community.

DeWildt added that Neurelis has initiated a patient assistance program to support eligible patients who do not have access to insurance. In addition, he said, the company’s co-pay plan has been able to help eligible commercial insurance patients to pay as little as $20 for VALTOCO. “These plans take on even more importance at a time when the COVID-19 pandemic has economically hurt so many people, including those in the epilepsy community,” DeWildt said.

One other important program initiated by the company is myNEURELIS™. myNEURELIS provides individualized support for VALTOCO patients, including access to nurse educators, insurance coverage checks, financial assistance for those who need it, and more. For more information, please visit www.myNEURELIS.com.

“We understand that the epilepsy community has been waiting more than two decades for a version of diazepam that is delivered in an effective combination of reliability, safety, and tolerability in a ready-to-use nasal spray,” DeWildt said. “We are so grateful to be able to bring VALTOCO to the community and remain dedicated to providing access to this vital medication for everyone who needs it.”


VALTOCO is a proprietary formulation of diazepam incorporating the science of Intravail®. Intravail transmucosal absorption enhancement technology enables the noninvasive delivery of a broad range of protein, peptide, and small-molecule drugs. In its approval of VALTOCO, the FDA recognized VALTOCO’s intranasal route of administration as clinically superior to the previously approved standard of care treatment (a rectal gel formulation of diazepam). In a long-termopen-labelrepeat-dose clinical trial, the safety of VALTOCO was evaluated and more than 4,000 seizures were treated. The clinical trial included adult and pediatric patients aged 6 and older. VALTOCO was generally safe and well tolerated during clinical studies. The most common adverse reactions for diazepam (at least 4%) were somnolence, headache, and nasal discomfort. For more information on VALTOCO, please visit www.valtoco.com.

About Neurelis

Neurelis, Inc. is an innovation-driven neuroscience company providing a highly differentiated approach to target unmet medical needs. Neurelis is focused on the development and commercialization of product candidates for epilepsy and the broader central nervous system (CNS) market. On January 10, 2020, the U.S. Food and Drug Administration (FDA) approved Neurelis’ VALTOCO® (diazepam nasal spray) as an acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from an individual’s usual seizure pattern in adult and pediatric patients 6 years of age and older. In addition to VALTOCO, the company is developing NRL-2 for intermittent use to control acute panic attacks, NRL-3 as a noninvasive acute therapy to stop seizures that have progressed to status epilepticus, and NRL-4 as a noninvasive rescue therapy to address the escalation of psychomotor agitation (PMA) symptoms outside of the medical setting. The Neurelis technology platform includes Intravail®, ProTek® and Hydrogel™, three proprietary, noninvasive drug-delivery and stabilization technologies applicable to a wide range of molecules, including therapeutic proteins, peptides, non-peptide macromolecules, and small molecules. For more information on Neurelis, please visit www.neurelis.com.

Important Safety Information about VALTOCO:


VALTOCO® (diazepam nasal spray) is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 6 years of age and older.



Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.

  • Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate
  • Limit dosages and durations to the minimum required
  • Follow patients for signs and symptoms of respiratory depression and sedation

Contraindications: VALTOCO is contraindicated in patients with:

  • Known hypersensitivity to diazepam
  • Acute narrow-angle glaucoma

Central Nervous System (CNS) Depression

Benzodiazepines, including VALTOCO, may produce CNS depression. Caution patients against engaging in hazardous activities requiring mental alertness, such as operating machinery, driving a motor vehicle, or riding a bicycle, until the effects of the drug, such as drowsiness, have subsided, and as their medical condition permits.

The potential for a synergistic CNS-depressant effect when VALTOCO is used with alcohol or other CNS depressants must be considered, and appropriate recommendations made to the patient and/or care partner.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including VALTOCO, increase the risk of suicidal ideation and behavior. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or unusual changes in mood or behavior. Advise patients and caregivers to be alert for these behavioral changes and to immediately report them to a healthcare provider.


Benzodiazepines, including VALTOCO, can increase intraocular pressure in patients with glaucoma. VALTOCO may only be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. VALTOCO is contraindicated in patients with narrow-angle glaucoma.

Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative

VALTOCO is not approved for use in neonates or infants. Serious and fatal adverse reactions, including “gasping syndrome,” can occur in neonates and low-birth-weight infants treated with benzyl alcohol-preserved drugs, including VALTOCO. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known.

Adverse Reactions

The most common adverse reactions (at least 4%) were somnolence, headache, and nasal discomfort.

Diazepam, the active ingredient in VALTOCO, is a Schedule IV controlled substance.

To report SUSPECTED ADVERSE REACTIONS, contact Neurelis, Inc. at 1-866-696-3873 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).

Please see full Prescribing Information, including Boxed Warning, for additional important safety information.

Healthcare Utilization and Associated Costs Following Initiation of Perampanel (Fycompa®) in Patients with Epilepsy

Abstract, published in Epilepsy & Behavior

Purpose: This study compared health service utilization and costs for patients with epilepsy before and after initiation of perampanel and compared with matched controls.

Results: Three hundred and forty-three patients treated with perampanel were identified. One hundred and eighty-three (53.4%) were male, with an average age of 39 and an average epilepsy duration of 21 years. Two hundred and eighty-seven (83.7%) were matched to controls. Inpatient admissions with a primary diagnosis of epilepsy and neurology specific outpatient appointments were significantly reduced following initiation with perampanel. Total costs attributable to epilepsy and overall secondary costs were also significantly reduced. There was no significant difference in primary care, outpatient, or general inpatient admissions. Compared with controls, there was a significant reduction in primary epilepsy admissions but a significant increase in outpatient appointments and accident and emergency contacts for patients treated with perampanel.

Conclusion: Treatment with perampanel is associated with reduced epilepsy-related inpatient admissions and accident and emergency contacts.

Study Shows that Birth Defects Attributed to Valproate (Depakote®) Do Not Involve a Genetic Component

Abstract, published in Epilepsia

Objective: Sodium valproate (VPA), the most effective antiepileptic drug for patients with genetic generalized epilepsy (GGE), that is, generalized epilepsy cause by a mutation,  dramatically increases the risk of a range of birth defects. Although the mechanisms underlying these birth defects are not known, they may involve genetic risk factors. This study aimed to develop an animal model of VPA-induced birth defects.

Results: The team used three different rat models of epilepsy, each of which had a different genetic mutation. VPA-exposed pups showed significant reductions in weight, length, and whole-body development compared with controls. Specifically, VPA treatment altered the distances between individual vertebrae in the backbone in all three rat models, more frequently than in controls.

Significance: Exposure of embryos to VPA during pregnancy results in similar developmental and morphological abnormalities in three different rat models, indicating that the genetic underpinnings of epilepsy do not contribute markedly to VPA-induced birth defects. These models may be used in future studies to investigate mechanisms involved in the pathogenesis of antiepileptic drug–induced birth defects.

Influence of Stiripentol (Diacomit®) on Perampanel (Fyncompa®) Serum Levels

Abstract, published in Epilepsy Research

Stiripentol is an orphan drug successfully used in combination with valproate (Depakote®) and clobazam (Onfi®) in the treatment of Dravet syndrome. Perampanel has also been added by experts. In this study, we investigated the influence of stiripentol on perampanel serum levels by using the doses and corresponding perampanel serum levels of 10 patients. The impact of stiripentol on the perampanel serum levels was significant, with perampanel serum levels increasing linearly with the stiripentol doses.

Researchers conclude that dose adjustments of stiripentol and perampanel when administered together, should be done carefully to avoid side effects or even severe intoxication. Hence, perampanel serum level monitoring seems advisable.

A Review of Drug-Drug Interactions of the Antiepileptic Drug Brivaracetam (Briviact®)

Abstract, published in Epilepsy Research

Brivaracetam is an antiepileptic drug (AED) indicated for the treatment of focal seizures, with improved safety and tolerability vs first-generation AEDs. Brivaracetam binds with high affinity to synaptic vesicle protein 2A, a protein located on the surface of nerve cells in the brain, which confers its antiseizure activity. Brivaracetam is rapidly absorbed, extensively metabolized, and exhibits linear and dose-proportional pharmacokinetics at therapeutic doses. Brivaracetam does not interact with most metabolizing enzymes and drug transporters, and therefore does not interfere with drugs that use these metabolic routes.

The favorable pharmacokinetic profile of brivaracetam and lack of clinically relevant drug – drug interactions with commonly prescribed AEDs or oral contraceptives allows administration without dose adjustment and avoids potential untoward events from decreased efficacy of an AED or oral contraceptive due to a drug – drug interaction. Few agents have been reported to affect the pharmacokinetics of brivaracetam.

The strong enzyme-inducing AEDs carbamazepine (Tegretol®), phenytoin (Dilantin®) and primidone (Mysoline®), along with its metabolite phenobarbital, have been shown to moderately lower brivaracetam plasma concentrations, with no adjustment of brivaracetam dose needed. Dose adjustment should be considered when brivaracetam is coadministered with the more potent enzyme-inducer, rifampin (Rifadin). Additionally, caution should be used when adding or ending treatment with the strong enzyme inducer, St. John’s wort. In summary, brivaracetam (50–200 mg/day) has a favorable pharmacokinetic profile and is associated with few clinically relevant drug–drug interactions.

Epilepsy Research Findings: May 2020

In this month’s epilepsy research news, we highlight an unexpected health benefit of epilepsy neurostimulators and report on a potential explanation for the effectiveness of fenfluramine in Dravet syndrome. We also present a study suggesting that people who have achieved long-term seizure freedom should speak with their doctors more often about the possibility of weaning off medications to reduce unnecessary drug burdens.

In addition, given the impact that the COVID-19 pandemic is having on all our lives, we feature two COVID-19 related articles: one examines the psychological well-being of people with epilepsy and the other highlights recommendations for patients, caregivers, and clinicians from a group of well-known neurologists.

Finally, we encourage you to participate in ongoing research about COVID-19’s impact on the rare disease community. Patients and caregivers who take this survey will help the rare disease research community shed light on their needs during the COVID-19 pandemic and future health crises.

Summaries of these articles are presented below:

Research News

  • Neurostimulators and Psychiatric Disorders: Brain wave recordings from responsive neurostimulator systems allow physicians to differentiate seizure-induced neurobehavioral symptoms from those caused by comorbid psychiatric disorders such as anxiety, depression, and psychosis. This additional information can help guide medication or therapy changes to target the psychiatric illness itself instead of similar symptoms brought on by the seizures themselves. Learn More
  • Fenfluramine and Dravet Syndrome: Researchers may have discovered how fenfluramine, which is currently being investigated as an add-on therapy to reduce seizures in people with Dravet syndrome, also seems to promote long-term improvements in cognition, behavior and emotional control. The beneficial effects of seizure reduction and cognitive enhancement may result from the drug’s synergistic effect on two different proteins found on the surface of nerve cells. Learn More
  • Antiseizure Drug (ASD) Withdrawal: A Norwegian survey found that people who have achieved long-term seizure-freedom are not talking to their doctors often enough about a plan for discontinuing drug treatment. This suggests that many patients may be living with an unnecessary drug burden. Learn More
  • COVID-19 and Psychological Distress: A study conducted at the epilepsy center of West China Hospital showed that people with epilepsy suffered from significantly more psychological distress compared to controls. The research found that independent predictors of this distress are time spent paying attention to COVID-19 and a diagnosis of drug-resistant epilepsy. Learn More
  • COVID-19, Epilepsy Management, and Safety: Leading neurologists published two key suggestions on caring for people with epilepsy during the COVID-19 pandemic. First, as much care as possible should be administered at home, including the strategic use of rescue therapies, to keep people out of health care facilities, where they are more likely to encounter COVID-19. Second, to minimize the risk of increased seizure severity or frequency, physicians should ensure that their patients adhere to treatment plans and have a regular supply of medication. Learn More
  • Rare Disease Community and COVID-19, a Survey: A new online survey created by the National Institute of Health aims to find out how the COVID-19 pandemic is impacting individuals with rare diseases, their families, and their caregivers. We encourage you to check it out! Learn More

In case you missed it! Our COVID-19 and Epilepsy Resource Hub is now live with resources to help families understand the potential impacts of COVID-19 on epilepsy care. This resource hub includes a guide to preparing for telehealth visits, recorded Q&A sessions, frequently asked questions, and more. Visit Now

Pregnancy After Valproate (Depakote®) Withdrawal – Fetal Malformations and Seizure Control

Objective: To assess the outcomes in women with epilepsy in relation to fetal malformation and epileptic seizure control during pregnancy when valproate (VPA) intake was ceased, or the drug’s dose was reduced before pregnancy.

Methods: Statistical analysis of data collected in the Australian Pregnancy Register between 1999 and 2018 concerning 580 pregnancies previously treated with VPA, with the VPA dose reduced or the drug withdrawn prior to pregnancy in 158 cases.

Results: Although the available data have limitations, fetal malformation rates in the pregnancies studied were lower in the VPA changed pregnancies (4.5%) than in the VPA unchanged comparator pregnancies (10.9%), and were only 2.7% where VPA intake was ceased before pregnancy. Seizure-affected pregnancies were more frequent in the VPA changed pregnancies than in the VPA unchanged ones (46.2% vs 30.8%). Convulsive seizure-affected pregnancies also were increased, but the difference was not statistically significant.

Significance: Prepregnancy reduction in valproate dosage reduced the hazard of fetal malformations, whereas ceasing intake of the drug decreased the hazard to one similar to that which applies in the general population, but at a cost of decreased control of epileptic seizures during the pregnancies studied. Further investigations are needed to see whether such findings apply more widely in women with epilepsy.

Study Shows that Add-On Lacosamide (Vimpat®) is Effective for Epilepsy in Patients with Brain Tumors


To evaluate the effectiveness and tolerability of lacosamide added to one or two antiepileptic drugs (AEDs) in the treatment of patients with brain tumor–related epilepsy (BTRE), and to evaluate patients’ global impression of change and quality of life (QoL).


Patients were recruited from 24 sites in Europe. Ninety-three patients received lacosamide, of whom 79 (84.9%) completed the study. At 6 months, 66 of 86 (76.7%) patients were 50% responders and 30 of 86 (34.9%) were seizure?free. Improvements were reported by 49 of 76 (64.5%) patients, according to a validated patient self-assessment. Improvements were observed in 52 of 81 (64.2%) patients, according to a clinician’s evaluation. Quality of Life and symptom outcome measures remained stable. The 6-month retention rate was 86.0% (N = 93). Fifteen (16.1%) patients reported adverse drug reactions, which were severe enough for four patients (4.3%) that they had to drop out of the study.


Results of this prospective, noninterventional study suggest that add-on lacosamide is effective and generally well tolerated in patients with brain-tumor related epilepsy.

Influence of Dose and Antiepileptic Comedication on Brivaracetam (Briviact®) Serum Concentrations in Patients with Epilepsy

The aim of this study was to investigate the influence of concomitant antiepileptic drugs (AEDs) on brivaracetam (BRV) trough serum concentrations, the lowest serum concentration reached by BRV before the next dose is taken.

A total number of 368 routinely collected blood samples from 148 inpatients from Mara Hospital (Bethel Epilepsy Center) and von Bodelschwingh Foundation Bethel, both in Germany, were retrospectively evaluated. Analyses showed that BRV trough serum concentrations were significantly lower in patients with strong enzyme-inducing AEDs (carbamazepine (Tegretol®), phenytoin (Dilantin®), and/or phenobarbital/primidone (Solfoton®/Mysoline®, -49%), but were not affected by concomitant intake of oxcarbazepine (Trileptal®) or eslicarbazepine (Aptiom®). Age and gender did not have a significant effect. An alternative model analyzing the BRV level-to-dose ratios yielded comparable results.

According to the research team, the results from routine therapeutic drug monitoring data indicate that the effect of enzyme-inducing AEDs on BRV serum concentrations is stronger than the 20%-30% reduction in BRV exposure previously reported in pharmacokinetics studies. Further research is necessary to evaluate these differences and to elucidate possible clinical consequences.

Study suggests that the dual mechanism of a new antiepileptic drug may explain its effectiveness in Dravet Syndrome

In addition to promoting the release of serotonin, a brain chemical typically associated with feelings of well-being and happiness, fenfluramine also seems to control the activity of sigma-1 receptors found on the surface of nerve cells, a study has found.

This dual mechanism of action is likely responsible for the deep and sustained effectiveness of the medication at reducing the frequency of seizures in children and young adults with Dravet syndrome, researchers noted.

Results of the study, “Fenfluramine acts as a positive modulator of sigma-1 receptors,” were published in the journal Epilepsy & Behavior.