Nayzilam

Description

NAYZILAM contains midazolam, a compound belonging to the benzodiazepine class. Midazolam is chemically designated as 8-Chloro-6-(ο-fluorophenyl)-1-methyl-4H-imidazo1,5-abenzodiazepine, with an empirical formula of C18H13ClFN3 and a molecular weight of 325.8. The substance appears as a white or yellowish crystalline powder that is practically insoluble in water, but soluble in methanol, and freely soluble in acetone and alcohol.

NAYZILAM is formulated as a nasal spray, presenting as a clear, colorless to yellowish liquid. Each single-dose unit is designed for nasal administration, delivering 5 mg of midazolam in 0.1 mL of solution. The formulation includes ethanol, PEG-6 methyl ether, polyethylene glycol 400, propylene glycol, and purified water. The pH of the solution ranges from approximately 5.0 to 9.0.

Uses and Indications

NAYZILAM is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity, specifically seizure clusters or acute repetitive seizures, that are distinct from a patient's usual seizure pattern. This indication applies to patients with epilepsy who are 12 years of age and older.

There are no teratogenic or nonteratogenic effects associated with NAYZILAM.

Dosage and Administration

NAYZILAM is to be administered exclusively via the nasal route. The initial dose consists of one spray, delivering a 5 mg dose into one nostril. If the patient does not respond to the initial dose, a second dose of one additional spray (5 mg) may be administered into the opposite nostril after a minimum interval of 10 minutes.

The maximum dosage and treatment frequency should be strictly adhered to; no more than two doses of NAYZILAM should be used to treat a seizure cluster. Furthermore, it is recommended that NAYZILAM be utilized to manage no more than one episode every three days, with a cap of five episodes treated per month.

Contraindications

Patients with hypersensitivity to midazolam should not use NAYZILAM due to the risk of severe allergic reactions. Additionally, the use of NAYZILAM is contraindicated in patients with acute narrow-angle glaucoma, as it may exacerbate this condition.

NAYZILAM contains midazolam, a Schedule IV controlled substance, which carries a potential for abuse and addiction. The intentional non-therapeutic use of this medication, even once, poses risks of misuse and addiction, characterized by a strong desire to take the drug, difficulties in controlling use, and potential tolerance or physical dependence.

Patients may experience physical dependence if NAYZILAM is used more frequently than recommended. Abrupt discontinuation or rapid dosage reduction can lead to acute withdrawal reactions, including seizures, which may be life-threatening. Those at increased risk for withdrawal reactions include individuals on higher dosages or those with prolonged use. A gradual tapering of the medication is advised to mitigate withdrawal risks.

Warnings and Precautions

Concomitant use of NAYZILAM with other central nervous system (CNS) depressants, including alcohol, may lead to an increased CNS-depressant effect. Additionally, the use of moderate or strong CYP3A4 inhibitors alongside NAYZILAM can result in prolonged sedation due to decreased plasma clearance of midazolam. Healthcare professionals should closely monitor patients for signs of excessive sedation and adjust dosages accordingly.

The use of antiepileptic drugs, including NAYZILAM, has been associated with an increased risk of suicidal ideation and behavior. It is imperative that healthcare providers assess patients for any history of mood disorders and monitor for any emerging signs of suicidal thoughts or actions throughout the treatment period.

Patients receiving NAYZILAM may experience impaired cognitive function, with a notable incidence of partial or complete impairment of recall for several hours post-administration. This cognitive impairment should be considered when advising patients about activities that require full alertness, such as driving or operating machinery.

NAYZILAM can elevate intraocular pressure in individuals with glaucoma. Therefore, it is recommended that patients with open-angle glaucoma undergo an ophthalmologic evaluation following treatment to assess any changes in their condition.

The administration of NAYZILAM during pregnancy poses risks of neonatal sedation and/or withdrawal syndrome. Healthcare providers should counsel pregnant patients regarding these potential risks and consider alternative therapies when appropriate.

There are significant risks associated with the concomitant use of NAYZILAM and opioids. This combination may lead to profound sedation, respiratory depression, coma, and even death. Furthermore, the use of benzodiazepines, including NAYZILAM, carries the potential for abuse, misuse, and addiction, which can result in overdose or fatal outcomes. Prior to prescribing NAYZILAM, and throughout the course of treatment, it is essential to evaluate each patient's risk for these issues.

Although NAYZILAM is indicated for intermittent use, exceeding the recommended frequency may lead to acute withdrawal reactions upon abrupt discontinuation or rapid dosage reduction. Such withdrawal reactions can be life-threatening. For patients who have used NAYZILAM more frequently than advised, a gradual tapering of the medication is recommended to mitigate the risk of withdrawal symptoms. Regular monitoring and supportive care should be provided during this process.

Side Effects

Patients receiving NAYZILAM may experience a range of adverse reactions. Common adverse reactions, occurring in 5% or more of participants in clinical trials, include somnolence (10%), headache (7%), nasal discomfort (5%), throat irritation (2%), and rhinorrhea (3%). Other reactions noted include dysarthria (2%) and product taste abnormality (4%).

Serious warnings associated with NAYZILAM include risks from concomitant use with opioids, which may lead to profound sedation, respiratory depression, coma, and death. The potential for abuse, misuse, and addiction is significant, necessitating careful assessment of each patient's risk prior to prescribing. Abrupt discontinuation or rapid dosage reduction can precipitate acute withdrawal reactions, which may be life-threatening.

In addition to the common adverse reactions, patients may experience central nervous system (CNS) depression when NAYZILAM is used with other CNS depressants or moderate to strong CYP3A4 inhibitors. The use of antiepileptic drugs, including NAYZILAM, has been associated with an increased risk of suicidal behavior and ideation. Impaired cognitive function is also a concern, as midazolam can lead to partial or complete impairment of recall for several hours post-administration.

Patients with glaucoma should be aware that NAYZILAM may increase intraocular pressure. Furthermore, use during pregnancy can result in neonatal sedation and/or withdrawal syndrome.

Adverse reactions related to benzodiazepine abuse or misuse may include abdominal pain, amnesia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, dizziness, euphoria, impaired concentration and memory, irritability, muscle pain, slurred speech, and vertigo. Severe reactions can manifest as delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulties, and death.

Signs and symptoms of acute withdrawal may include abnormal involuntary movements, anxiety, blurred vision, depression, dizziness, fatigue, gastrointestinal disturbances, headache, irritability, insomnia, memory impairment, muscle pain, panic attacks, restlessness, tachycardia, and tremor. More severe reactions can include catatonia, convulsions, delirium tremens, hallucinations, mania, psychosis, seizures, and suicidality.

Protracted withdrawal syndrome may occur, characterized by persistent anxiety, cognitive impairment, depression, insomnia, and various motor symptoms that can last beyond 4 to 6 weeks following initial withdrawal. Tolerance to NAYZILAM may develop with use that exceeds recommended frequencies.

Drug Interactions

Co-administration of NAYZILAM with moderate or strong CYP3A4 inhibitors is contraindicated due to the potential for significant drug interactions. Caution is advised when using NAYZILAM alongside mild CYP3A4 inhibitors, as this may alter the pharmacokinetics of NAYZILAM.

When NAYZILAM is used in conjunction with opioids, there is an increased risk of respiratory depression. Healthcare providers should closely monitor patients for signs of respiratory compromise and consider dosage adjustments as necessary.

The concomitant use of NAYZILAM with other central nervous system (CNS) depressants may heighten the risks of hypoventilation, airway obstruction, desaturation, or apnea. This combination can also lead to profound and/or prolonged effects of NAYZILAM. It is recommended that patients receiving these combinations be monitored closely for respiratory function and sedation levels.

Packaging & NDC

The table below lists all NDC Code configurations of Nayzilam (midazolam), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of NAYZILAM have been evaluated in pediatric patients aged 12 to 17 years. The use of NAYZILAM in this age group is supported by evidence from an adequate and well-controlled study conducted in adults and adolescents experiencing seizure clusters. However, safety and effectiveness in pediatric patients below the age of 12 years have not been established.

Geriatric Use

Elderly patients, particularly those aged 65 and older, may exhibit different pharmacokinetic responses to NAYZILAM compared to younger individuals, as safety and efficacy studies did not include a sufficient number of subjects in this age group to draw definitive conclusions. Notably, geriatric patients tend to have longer elimination half-lives for midazolam and its metabolites, which can lead to prolonged drug exposure and increased risk of adverse effects.

Additionally, alterations in drug distribution and diminished hepatic and/or renal function are common in this population. Patients over 70 years of age may be particularly sensitive to the effects of the medication. It is important to note that the administration of intramuscular midazolam in elderly patients has been associated with rare reports of death, particularly under circumstances that suggest cardiorespiratory depression. In many of these cases, patients were also receiving other central nervous system (CNS) depressants, such as narcotics, which can further compromise respiratory function.

Given these considerations, close monitoring of geriatric patients is strongly recommended to ensure safety and efficacy when administering NAYZILAM. Dose adjustments may be necessary based on individual patient factors, including age, overall health status, and concurrent medications.

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including NAYZILAM, during pregnancy. Healthcare providers are encouraged to recommend that pregnant patients taking NAYZILAM enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/http://www.aedpregnancyregistry.org/.

Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal. Benzodiazepines, including NAYZILAM, cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Therefore, it is essential to monitor neonates exposed to NAYZILAM during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems, as well as for signs of withdrawal, and to manage these neonates accordingly.

Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with major birth defects. Although early studies indicated an increased risk of congenital malformations with diazepam and chlordiazepoxide, no consistent pattern has been noted. Most recent case-control and cohort studies, which adjusted for confounding exposures to alcohol, tobacco, and other medications, have not confirmed these findings. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Animal studies have shown that administration of midazolam to rats and rabbits during the period of organogenesis did not result in any apparent adverse effects on development. Additionally, when midazolam was administered intravenously to pregnant rats during late gestation and throughout lactation, no clear adverse effects were noted in the offspring. However, published data suggest the possibility of neuronal cell death and long-term effects on neurobehavioral and immunological function in animals following prenatal or early postnatal exposure at clinically relevant doses. Notably, administration of benzodiazepines, including midazolam, to neonatal rats has been associated with widespread apoptotic neurodegeneration in the developing brain at plasma concentrations relevant for seizure control in humans, particularly during a critical period of brain development that corresponds to the third trimester of pregnancy in humans.

Lactation

Midazolam is excreted in human milk. Reports indicate that infants exposed to benzodiazepines through breast milk may experience sedation, poor feeding, and poor weight gain. Currently, there are no data available regarding the effects of midazolam on milk production.

When considering the use of NAYZILAM in lactating mothers, it is essential to weigh the developmental and health benefits of breastfeeding against the mother's clinical need for the medication and any potential adverse effects on the breastfed infant. Infants who are exposed to NAYZILAM through breast milk should be closely monitored for signs of sedation, poor feeding, and poor weight gain.

Renal Impairment

In patients with renal impairment, particularly those with moderate and severe conditions, there may be a slower elimination of midazolam and its metabolites, potentially leading to prolonged drug exposure. A population pharmacokinetic analysis indicates that the pharmacokinetics of midazolam and 1-OH midazolam are expected to be similar in subjects with mild renal impairment compared to those with normal renal function. However, safety and efficacy studies of NAYZILAM did not include patients with severe renal impairment, and there were insufficient subjects with moderate renal impairment for a comprehensive population pharmacokinetic analysis. Therefore, caution is advised when administering NAYZILAM to patients with moderate to severe renal impairment, and appropriate monitoring should be considered to mitigate the risk of prolonged drug effects.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Overdosage of benzodiazepines is primarily characterized by central nervous system depression, which can manifest in a spectrum ranging from drowsiness to coma.

Symptoms of Overdosage

In cases of mild to moderate overdosage, patients may exhibit a variety of symptoms, including drowsiness, confusion, dysarthria, lethargy, a hypnotic state, diminished reflexes, ataxia, and hypotonia. It is important to note that paradoxical or disinhibitory reactions, although rare, can occur. These reactions may present as agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and increased talkativeness. In severe instances of overdosage, patients may experience respiratory depression and coma.

Risk Factors

The combination of benzodiazepines with other central nervous system depressants, such as alcohol and opioids, significantly increases the risk of fatal outcomes. Clinicians should be vigilant for markedly abnormal vital signs, including lowered or elevated blood pressure, heart rate, or respiratory rate, as these may indicate the involvement of additional substances in the overdosage.

Management of Overdosage

Management of benzodiazepine overdosage should focus on general supportive measures. This includes the administration of intravenous fluids and ensuring airway maintenance. Flumazenil, a specific benzodiazepine receptor antagonist, may be utilized for the complete or partial reversal of the sedative effects of benzodiazepines. However, caution is warranted, as flumazenil can precipitate withdrawal and adverse reactions, including seizures, particularly in cases of mixed overdosage with drugs that increase seizure risk, such as tricyclic and tetracyclic antidepressants. The risk of withdrawal seizures is further heightened in patients with a history of epilepsy.

Flumazenil is contraindicated in patients who have received benzodiazepines for the management of potentially life-threatening conditions, such as status epilepticus. If flumazenil is deemed necessary, it should be administered as an adjunct to supportive management rather than as a replacement.

For additional guidance on the management of benzodiazepine overdosage, healthcare professionals are encouraged to contact the Poison Help line at 1-800-222-1222 or consult a medical toxicologist.

Nonclinical Toxicology

Midazolam maleate was evaluated for its carcinogenic potential in a two-year dietary study involving mice and rats at doses of 0, 1, 9, or 80 mg/kg/day. In female mice receiving the highest dose, there was a significant increase in the incidence of hepatic tumors. Additionally, high-dose male rats exhibited a small but statistically significant increase in benign thyroid follicular cell tumors. The highest dose that did not result in increased tumor incidences in both species (9 mg/kg/day) is approximately 4 and 9 times the recommended human dose (RHD) of 10 mg based on body surface area (mg/m²). The mechanism underlying the induction of these tumors remains unclear. It is noteworthy that these tumors were observed following chronic administration, while human use typically involves single or multiple doses.

In terms of mutagenicity, midazolam demonstrated a negative profile for genotoxicity in both in vitro assays (Ames test and mammalian cell clastogenicity) and in vivo assessments (mouse bone marrow micronucleus assay).

Regarding fertility, a study involving the oral administration of midazolam at doses of 0, 1, 4, or 16 mg/kg to male and female rats prior to and during mating, as well as throughout gestation and lactation, revealed no adverse effects on fertility in either sex.

Postmarketing Experience

Postmarketing experience has identified reports of respiratory depression, cardiac arrest, and respiratory arrest associated with the use of NAYZILAM. Additionally, there have been cases of abuse, misuse, and addiction, particularly when NAYZILAM is used in combination with other medications, alcohol, and/or illicit substances. Reports of withdrawal reactions have been noted, including clinically significant physical dependence and acute withdrawal reactions that can be life-threatening upon abrupt discontinuation or rapid dosage reduction. Instances of protracted withdrawal syndrome have also been reported, with withdrawal symptoms lasting weeks to more than 12 months. Furthermore, postmarketing experience has indicated an increased risk of suicidal thoughts and behavior in patients taking NAYZILAM, necessitating monitoring for signs of depression and unusual changes in mood or behavior.

Patient Counseling

Advise patients and caregivers to read the FDA-approved patient labeling, including the Medication Guide and Instructions for Use, to ensure they understand the proper use of NAYZILAM. Inform them that potentially fatal additive effects may occur if NAYZILAM is used with opioids, and emphasize that NAYZILAM should not be used concomitantly with opioids unless under the supervision of a healthcare provider.

If a decision is made to prescribe NAYZILAM alongside opioids, instruct caregivers to closely monitor patients for signs and symptoms of respiratory depression and sedation. It is important to inform patients that using NAYZILAM more frequently than recommended, even at the recommended dosages, increases the risk of abuse, misuse, and addiction, which can lead to overdose and death, particularly when combined with other medications, alcohol, or illicit substances.

Patients should be made aware of the signs and symptoms of benzodiazepine abuse, misuse, and addiction, and they should seek medical help if they experience these issues. Additionally, counsel patients on the proper disposal of any unused medication. Inform them that using NAYZILAM more frequently than recommended may lead to clinically significant physical dependence, and that abrupt discontinuation or rapid dosage reduction can precipitate acute withdrawal reactions, which may be life-threatening.

Patients should also be informed that some individuals taking benzodiazepines have experienced a protracted withdrawal syndrome, with symptoms lasting from weeks to over 12 months. Warn patients and caregivers about the risks of respiratory depression, cardiac arrest, and respiratory arrest associated with NAYZILAM use.

Advise caregivers on the signs and symptoms of respiratory depression to monitor for, the duration for which patients should be observed after administering NAYZILAM, and the circumstances under which a second dose should not be given. They should also be informed about when to seek emergency medical care.

Caution patients and caregivers that using NAYZILAM in combination with alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea, and may contribute to profound and/or prolonged drug effects. Advise patients against engaging in hazardous activities requiring mental alertness, such as operating machinery or driving, until they have fully returned to their baseline level of functioning.

Counsel patients, their caregivers, and families that antiepileptic drugs (AEDs), including NAYZILAM, may increase the risk of suicidal thoughts and behavior. They should be vigilant for any emergence or worsening of signs and symptoms of depression, unusual changes in mood or behavior, or thoughts of self-harm. Any concerning behaviors should be reported immediately to healthcare providers.

Finally, warn patients that midazolam, including NAYZILAM, is associated with a high incidence of partial or complete impairment of recall for several hours. Counsel patients on when it is safe for them to engage in activities requiring complete mental alertness, operate hazardous machinery, or drive a motor vehicle after taking NAYZILAM.

Storage and Handling

The product is supplied in blister packaging, which should remain unopened until the time of use. It is essential to avoid testing or priming the unit prior to administration. The nasal spray unit must not be utilized if it appears damaged.

For optimal storage, the product should be maintained at a controlled room temperature between 20°C to 25°C (68°F to 77°F). Temporary excursions are permissible within the range of 15°C to 30°C (59°F to 86°F).

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Nayzilam as submitted by UCB, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)