Included as part of the "PRECAUTIONS" Section
Risks From Concomitant Use With Opioids
Concomitant use of benzodiazepines, including NAYZILAM, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe NAYZILAM concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when NAYZILAM is used with opioids [see DRUG INTERACTIONS].
Risks Of Cardiorespiratory Adverse Reactions
Serious cardiorespiratory adverse reactions have occurred after administration of midazolam. These have included respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury. There have also been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical manipulations, particularly in patients with hemodynamic instability. Hypotension occurs more frequently in patients premedicated with a narcotic. The danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve [see Use In Specific Populations]; patients with chronic obstructive pulmonary disease are highly sensitive to the respiratory depressant effect of midazolam.
Respiratory depression was observed with the administration of NAYZILAM during clinical trials [see ADVERSE REACTIONS]. Cardiac or respiratory arrest caused by NAYZILAM was not reported during clinical trials.
Central Nervous System Depression From Concomitant Use With Other Central Nervous System Depressants, Or Moderate Or Strong CYP3A4 Inhibitors
Drug products containing midazolam, including NAYZILAM, have a central nervous system (CNS) depressant effect.
Risks From Concomitant Use With Other CNS Depressants
The potential for an increased CNS-depressant effect from concomitant use with alcohol or other CNS depressants (e.g., opioids) must be considered by the prescribing physician, and appropriate recommendations made to the patient and/or caregiver [see Risks From Concomitant Use With Opioids and Drug Abuse And Dependence].
Concomitant use of barbiturates, alcohol, or other CNS depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect [see DRUG INTERACTIONS].
Risks From Concomitant Use With Moderate Or Strong CYP3A4 Inhibitors
There is a potential for prolonged sedation from concomitant use with moderate or strong CYP3A4 enzyme inhibitors because of much higher midazolam exposures [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
Suicidal Behavior And Ideation
Antiepileptic drugs (AEDs), including NAYZILAM, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono-and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
||Placebo Patients with Events/1000 Patients
||Drug Patients with Events per 1000 Patients
||Relative Risk: Incidence of Drug Events in Drug Patients /Incidence in Placebo Patients
||Risk Difference: Additional Drug Patients with Events per 1000 Patients
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing midazolam or any other AED must balance the risk of suicidal thoughts or behaviors with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Impaired Cognitive Function
Midazolam, including NAYZILAM, is associated with a high incidence of partial or complete impairment of recall for several hours following an administered dose. Gross tests of recovery from the effects of midazolam cannot be relied upon to predict reaction time under stress. It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided, and as their medical condition permits. For pediatric patients, particular care should be taken to ensure safe ambulation.
Benzodiazepines, including NAYZILAM, can increase intraocular pressure in patients with glaucoma. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam. NAYZILAM may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. Patients with open-angle glaucoma may need to have their ophthalmologic status evaluated following treatment with NAYZILAM. NAYZILAM is contraindicated in patients with narrow-angle glaucoma.
Other Adverse Reactions
When midazolam was used for sedation, reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity, and combativeness have been reported . These reactions may be caused by inadequate or excessive dosing or improper administration of midazolam; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions.
Patient Counseling Information
Advise patients and caregivers to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Risks From Concomitant Use With Opioids
Inform patients and caregivers that potentially fatal additive effects may occur if NAYZILAM is used with opioids and not to use NAYZILAM concomitantly with opioids unless supervised by a healthcare provider. If a decision is made to prescribe NAYZILAM concomitantly with opioids, instruct caregivers to follow patients closely for signs and symptoms of respiratory depression and sedation [see WARNINGS AND PRECAUTIONS].
Risks Of Cardiorespiratory Adverse Reactions
Warn patients and caregivers about the risks of respiratory depression, cardiac and respiratory arrest [see WARNINGS AND PRECAUTIONS].
Advise caregivers on the signs and symptoms of respiratory depression to look for, how long to observe patients after administering NAYZILAM, the circumstances under which a second dose should not be given, and the circumstances under which emergency medical care should be summoned [see DOSAGE AND ADMINISTRATION].
CNS Depression From Concomitant Use With Other CNS Depressants
Warn patients and caregivers that the use of NAYZILAM in combination with alcohol or other CNS depressant drugs may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect [see WARNINGS AND PRECAUTIONS].
Caution patients against engaging in hazardous occupations requiring mental alertness, such as operating machinery, driving a motor vehicle or riding a bicycle until they have completely returned to their level of baseline functioning.
Suicidal Behavior And Ideation
Counsel patients, their caregivers, and families that AEDs, including NAYZILAM, may increase the risk of suicidal thoughts and behavior and that they should be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior or the emergence of suicidal thoughts, behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers [see WARNINGS AND PRECAUTIONS].
Impaired Cognitive Function
Warn patients that midazolam, including NAYZILAM, is associated with a high incidence of partial or complete impairment of recall for the next several hours. Counsel patients on when they can engage in activities requiring complete mental alertness, operate hazardous machinery, or drive a motor vehicle after taking NAYZILAM [see WARNINGS AND PRECAUTIONS].
Instruct patients to inform their physician if they are pregnant or are planning to become pregnant. Several studies have suggested an increased risk of congenital malformations associated with the use of benzodiazepine drugs. Animal studies have demonstrated an effect on early brain development and long-term cognitive effects with exposure to anesthetic and sedation drugs in the third trimester of gestation. Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. The registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use In Specific Populations].
Instruct patients to inform their physicians if they are nursing [see Use In Specific Populations].
Important Treatment Instructions
Instruct patients and caregivers on what is and is not an intermittent and stereotypic episode of increased seizure activity (i.e., seizure cluster) that is appropriate for treatment, and the timing of administration in relation to the onset of the episode.
Instruct patients and caregivers on what to observe following administration, and what would constitute an outcome requiring immediate medical attention.
Instruct patients and caregivers not to administer a second dose of NAYZILAM if they are concerned by the patient’s breathing, the patient requires emergency rescue treatment with assisted breathing or intubation, or there is excessive sedation [see DOSAGE AND ADMINISTRATION].
Advise patients and caregivers on how frequently they can treat successive seizure cluster episodes over time.
Advise patients and caregivers to not open the blister packaging until ready to use. Instruct
them to not test or prime before use and to not use if the nasal spray unit appears damaged.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Midazolam maleate was administered in the diet to mice and rats for 2 years at doses of 0, 1, 9, or 80 mg/kg/day. In female mice in the highest dose group there was a marked increase in the incidence of hepatic tumors. In high-dose male rats there was a small but statistically significant increase in benign thyroid follicular cell tumors. The highest dose not associated with increased tumor incidences in mice and rats (9 mg/kg/day) is approximately 4 and 9 times, respectively, the recommended human dose (RHD) of 10 mg based on body surface area (mg/m2). The pathogenesis of induction of these tumors is not known. These tumors were found after chronic administration, whereas human use will ordinarily be of single or several doses.
Midazolam was negative for genotoxicity in in vitro (Ames, mammalian cell clastogenicity) and in vivo (mouse bone marrow micronucleus) assays.
Impairment Of Fertility
When midazolam (0, 1, 4, or 16 mg/kg) was orally administered to male and female rats prior to and during mating and continuing in females throughout gestation and lactation, no adverse effects on male or female fertility were noted.
Use In Specific Populations
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as NAYZILAM, during pregnancy. Encourage women who are taking NAYZILAM during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.
There are no adequate and well-controlled studies of NAYZILAM in pregnant women.
Available data suggest that the class of benzodiazepines is not associated with marked increases in risk for congenital anomalies. Although some early epidemiological studies suggested a relationship between benzodiazepine drug use in pregnancy and congenital anomalies such as cleft lip and or palate, these studies had considerable limitations. More recently completed studies of benzodiazepine use in pregnancy have not consistently documented elevated risks for specific congenital anomalies. There is insufficient evidence to assess the effect of exposure to benzodiazepines during pregnancy on neurodevelopment.
There are clinical considerations regarding exposure to benzodiazepines during the second and third trimesters of pregnancy or immediately prior to or during childbirth. These risks include decreased fetal movement and/or fetal heart rate variability, “floppy infant syndrome,” dependence, and withdrawal (see Clinical Considerations and Human Data).
Administration of midazolam to rats and rabbits during the period of organogenesis or to rats during late pregnancy and throughout lactation at doses greater than those used clinically did not result in any apparent adverse effects on development (see Animal Data). However, published data for midazolam and other benzodiazepines 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. NAYZILAM should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Advise a pregnant woman and women of childbearing age of the potential risk to a fetus.
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. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Fetal/Neonatal Adverse Reactions
Infants born to mothers who have taken benzodiazepines during the later stages of pregnancy can develop dependence, and subsequently withdrawal, during the postnatal period. Clinical manifestations of withdrawal or neonatal abstinence syndrome may include hypertonia, hyperreflexia, hypoventilation, irritability, tremors, diarrhea, and vomiting. These complications can appear shortly after delivery to 3 weeks after birth and persist from hours to several months depending on the degree of dependence and the pharmacokinetic profile of the benzodiazepine. Symptoms may be mild and transient or severe. Standard management for neonatal withdrawal syndrome has not yet been defined. Observe newborns who are exposed to NAYZILAM in utero during the later stages of pregnancy for symptoms of withdrawal and manage accordingly.
Labor and Delivery
Administration of benzodiazepines immediately prior to or during childbirth can result in a floppy infant syndrome, which is characterized by lethargy, hypothermia, hypotonia, respiratory depression, and difficulty feeding. Floppy infant syndrome occurs mainly within the first hours after birth and may last up to 14 days. Observe exposed newborns for these symptoms and manage accordingly.
Although there are no adequate and well-controlled studies of NAYZILAM in pregnant women, there is information about benzodiazepines as a class. Dolovich et al. published a meta-analysis of 23 studies that examined the effects of benzodiazepine exposure during the first trimester of pregnancy. Eleven of the 23 studies included in the meta-analysis considered the use of chlordiazepoxide and diazepam and not other benzodiazepines. The authors considered case-control and cohort studies separately. The data from the cohort studies did not suggest an increased risk for major malformations (OR 0.90; 95% CI 0.61—1.35) or for oral cleft (OR 1.19; 95% CI 0.34—4.15). The data from the case-control studies suggested an association between benzodiazepines and major malformations (OR 3.01, 95% CI 1.32— 6.84) and oral cleft (OR 1.79; 95% CI 1.13—2.82). The limitations of this meta-analysis included the small number of reports included in the analysis, and that most cases for analyses of both oral cleft and major malformations came from only three studies. A follow up to that meta-analysis included 3 new cohort studies that examined risk for major malformations and one study that considered cardiac malformations. The authors found no new studies with an outcome of oral clefts. After the addition of the new studies, the odds ratio for major malformations with first trimester exposure to benzodiazepines was 1.07 (95% CI 0.91—1.25).
Neonatal Withdrawal and Floppy Infant Syndrome
Neonatal withdrawal syndrome and symptoms suggestive of floppy infant syndrome associated with administration of benzodiazepines during the later stages of pregnancy and peripartum period have been reported. Findings in published scientific literature suggest that the major neonatal side effects of benzodiazepines include sedation and dependence with withdrawal signs. Data from observational studies suggest that fetal exposure to benzodiazepines is associated with the neonatal adverse events of hypotonia, respiratory problems, hypoventilation, low Apgar score, and neonatal withdrawal syndrome.
When midazolam (0, 0.2, 1, or 4 mg/kg/day) was administered intravenously to pregnant rats during the period of organogenesis, no adverse effects on embryofetal development were observed. The highest dose tested, which was associated with minimal evidence of maternal toxicity, is approximately 4 times the maximum recommended human dose (MRHD) of 10 mg based on body surface area (mg/m2).
When midazolam (0, 0.2, 0.6, and 2 mg/kg/day) was administered intravenously to rabbits during the period of organogenesis, no adverse effects on embryofetal development were reported. The high dose, which was not associated with evidence of maternal toxicity, is approximately 4 times the MRHD on a mg/m2 basis.
When midazolam (0, 0.2, 1, or 4 mg/kg/day) was administered intravenously to female rats during late gestation and throughout lactation, no clear adverse effects were noted in the offspring. The high dose, which was not associated with evidence of maternal toxicity, is approximately 4 times the MRHD on a mg/m2 basis.
In published animal studies, administration of benzodiazepines, including midazolam, or other drugs that enhance GABAergic neurotransmission to neonatal rats has been reported to result in widespread apoptotic neurodegeneration in the developing brain at plasma concentrations relevant for seizure control in humans. The window of vulnerability to these changes in rats (postnatal days 0-14) includes a period of brain development corresponding to that taking place during the third trimester of pregnancy in humans.
Midazolam is excreted in human milk. Studies assessing the effects of midazolam in the breastfed infant or on milk production/excretion have not been performed. Postmarketing experience suggests that breastfed infants of mothers taking benzodiazepines, such as NAYZILAM, may have effects of lethargy, somnolence, and poor sucking.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NAYZILAM and any potential adverse effects on the breastfed infant from midazolam or from the underlying maternal condition.
Safety and effectiveness of NAYZILAM have been evaluated in the age group 12 to 17 years. Use of NAYZILAM in this age group is supported by evidence from an adequate and well-controlled study of NAYZILAM in adults and adolescents with seizure clusters [see Clinical Studies] and pharmacokinetic and safety data from adult and pediatric patients [see CLINICAL PHARMACOLOGY].
Safety and effectiveness in pediatric patients below the age of 12 years have not been established.
Safety and efficacy studies of NAYZILAM did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Geriatric patients have longer elimination half-lives for midazolam and its metabolites, which may result in prolonged drug exposure. Geriatric patients may have altered drug distribution; diminished hepatic and/or renal function; and subjects over 70 years of age may be particularly sensitive [see CLINICAL PHARMACOLOGY]. Administration of intramuscular (IM) midazolam to elderly patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression [see WARNINGS AND PRECAUTIONS]. In most of these cases, the patients also received other CNS depressants capable of depressing respiration, especially narcotics [see WARNINGS AND PRECAUTIONS]. Close monitoring of geriatric patients is recommended.
Based on a population pharmacokinetic analysis of patients administered NAYZILAM, midazolam and 1-OH midazolam pharmacokinetics are expected to be similar in subjects with mild renal impairment when compared to normal subjects. Safety and efficacy studies of NAYZILAM did not include patients with severe renal impairment and there were not enough subjects with moderate renal impairment in clinical studies for population pharmacokinetic analysis. Patients with moderate and severe renal impairment may have slower elimination of midazolam and its metabolites, which may result in prolonged drug exposure [see CLINICAL PHARMACOLOGY].
Congestive Heart Failure
Patients with congestive heart failure eliminate midazolam more slowly, which may result in prolonged drug exposure [see CLINICAL PHARMACOLOGY].