`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
` These highlights do not include all the information needed to use
`
` NAYZILAM® safely and effectively. See full prescribing information
`
`
`for NAYZILAM®.
`
`NAYZILAM® (midazolam) nasal spray, CIV
`
`
`
`
`Initial U.S. Approval: 1985
`
`
`
`
` WARNING: RISKS FROM CONCOMITANT USE WITH
`
`OPIOIDS
`
`
`
`
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`
` Concomitant use of benzodiazepines and opioids may result in
`profound sedation, respiratory depression, coma, and death (5.1,
`
` 7.2)
`---------------------------INDICATIONS AND USAGE----------------------­
`
`
`
`
` NAYZILAM is a benzodiazepine indicated 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 patients with epilepsy 12 years of age and older. (1)
`
`
`
`----------------------DOSAGE AND ADMINISTRATION-----------------­
`
`
`
`
`Administer NAYZILAM by the nasal route only. (2.2)
`
`
`
`
`
`
`Initial Dose: Administer one spray (5 mg dose) into one nostril. (2.2)
`Second Dose: One additional spray (5 mg dose) into the opposite nostril
`
`
`
`
` may be administered after 10 minutes if the patient has not responded to
`
`
`
`
`
`
` the initial dose. (2.2)
`
`Maximum Dosage and Treatment Frequency: Do not use more than 2
`
`
`
`
`doses of NAYZILAM to treat a seizure cluster. It is recommended that
`
`
`
`NAYZILAM be used to treat no more than one episode every three days
`
`
`
`
`
`
`
`
`
`
`and treat no more than five episodes per month. (2.2)
`
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS----------------­
`
`
`
`
`Single-dose nasal spray unit containing 5 mg midazolam per 0.1 mL
`
`
`
`
`
`solution. (3)
`
`
`-----------------------------CONTRAINDICATIONS-------------------------­
`Patients with hypersensitivity to midazolam (4)
`
`
`
`
`Patients with acute narrow-angle glaucoma (4)
`
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS
`
`
`1
`INDICATIONS AND USAGE
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Instructions Prior to Dosing
`
`
`2.2 Dosage Information
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`
`
`5.1 Risks from Concomitant Use with Opioids
`
`
`
`
`
`5.2 Risks of Cardiorespiratory Adverse Reactions
`
`
`5.3 CNS Depression from Concomitant Use with Other CNS
`
`
`
`
`
`
`
`
`Depressants, or Moderate or Strong CYP3A4 Inhibitors
`
`
`5.4 Suicidal Behavior and Ideation
`
`
`5.5 Impaired Cognitive Function
`
`
`5.6 Glaucoma
`
`5.7 Other Adverse Reactions
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 CYP3A4 Inhibitors
`
`
`7.2 Opioids
`
`
`
`7.3 Other CNS Depressants
`
`
`
`
`
`Reference ID: 4434795
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`
` CNS Depression From Concomitant Use With Other CNS Depressants or
`
`
`
` Moderate or Strong CYP3A4 Inhibitors: May cause an increased CNS-
`
`
`
` depressant effect when used with alcohol or other CNS depressants.
`
`
`
` Concomitant use with moderate or strong CYP3A4 inhibitors may result
`
`
`
`
`
`
` in prolonged sedation because of a decrease in plasma clearance of
`
`
`
`
` midazolam. (5.3, 7.3)
`
`
`
` Suicidal Behavior and Ideation: Antiepileptic drugs increase the risk of
`
` suicidal ideation and behavior. (5.4)
`
`
`
`
`
`
`Impaired Cognitive Function: Midazolam is associated with a high
`
`
`
`incidence of partial or complete impairment of recall for the next several
`
`
`hours. (5.5)
`---------------------------ADVERSE REACTIONS----------------------------------­
`
`
`
`
`
`
`The most common adverse reactions (≥5% in any NAYZILAM treatment group)
`
`
`were somnolence, headache, nasal discomfort, throat irritation, and rhinorrhea
`
`(6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Proximagen at
`
`
`
`1-844-599-2273 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`----------------------------DRUG INTERACTIONS----------------------------------­
`
`
`
`
`
`CYP3A4 Inhibitors: Avoid co-administration of NAYZILAM with
`
`
`
`
`
`moderate or strong CYP3A4 inhibitors. NAYZILAM should be used with
`
`
`caution when co-administered with mild CYP3A4 inhibitors. (7.1)
`
`
`
`
`Opioids: Risk of respiratory depression is increased. (7.2)
`
`Other CNS Depressants: May increase the risks of hypoventilation, airway
`
`
`
`obstruction, desaturation, or apnea and may contribute to profound and/or
`
`
`prolonged drug effect. (7.3)
`----------------------USE IN SPECIFIC POPULATIONS-------------------------­
`
`
`
`
`
`
`Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`
`
`
`
`
`
`
`
`
` Lactation: Midazolam is excreted in human milk. Caution should be
`
`
`
` exercised when NAYZILAM is administered to a nursing woman. (8.2)
`
`
`
`
`
`
`Renal Impairment: Patients with renal impairment may have longer
` elimination half-lives for midazolam and its metabolites which may result
`
`
`
`
`
`
` in prolonged exposure. (8.6)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`
`
`Revised: 5/2019
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`8.2 Lactation
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Renal Impairment
`
`
`8.7 Congestive Heart Failure
`
`
`9 DRUG ABUSE AND DEPENDENCE
`
`
`9.1 Controlled Substance
`
`
`9.2 Abuse
`
`9.3 Dependence
`
`9.4 Chronic Use
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`
`16 HOW SUPPLIED / STORAGE AND HANDLING
`
`
`16.1 How Supplied
`
`16.2 Storage and Handling
`
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`listed
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`Page 1 of 23
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`

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`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
` WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS
`
`
`
`
`
` Concomitant use of benzodiazepines and opioids may result in profound sedation,
` respiratory depression, coma, and death [see Warnings and Precautions (5.1), Drug
`
`
`Interactions (7.2)].
` • 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.
`
`
`
`
`
`
`
`
`1 INDICATIONS AND USAGE
`
`
`
`NAYZILAM is indicated 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 patients with epilepsy 12 years of age and older.
`
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`Instructions Prior to Dosing
`2.1
`
`
`NAYZILAM prescribers should consider the following prior to initiation of treatment:
`
`
`For patients at increased risk of respiratory depression from benzodiazepines, administration
`
`of NAYZILAM under healthcare professional supervision should be considered prior to
`
`
`treatment with NAYZILAM; this administration may be performed in the absence of a
`
`
`
`seizure episode [see Warnings and Precautions (5.2)].
`
`
`
`
`Prior to treatment, the healthcare professional should instruct the individual administering
`
`
`NAYZILAM on how to identify seizure clusters and use the product appropriately [see
`
`
`Patient Counseling Information: Administration Information (17)]. Patients and caregivers
`
`
`
`should be counseled to read carefully the “Instructions for Use” for complete directions on
`
`how to properly administer NAYZILAM.
`
`
`Dosage Information
`2.2
`
`
`
`
`Administer NAYZILAM by the nasal route only.
`
`
`
`
`Initial Dose: Administer one spray (5 mg dose) into one nostril.
`
`
`
`
`
`
`
`Second Dose (if needed): One additional spray (5 mg dose) into the opposite nostril may be
`
`
`
`
`
`
`administered after 10 minutes if the patient has not responded to the initial dose.
`
`
`
`
`
`
`Reference ID: 4434795
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` A second dose of NAYZILAM should not be administered if the patient has trouble breathing
`
` or if there is excessive sedation that is uncharacteristic of the patient during a seizure cluster
`
`
` episode [see Warnings and Precautions (5.2)].
`
`
`
`
` Maximum Dosage and Treatment Frequency: Do not use more than 2 doses of NAYZILAM
` to treat a single episode.
`
`
`
`
` It is recommended that NAYZILAM be used to treat no more than one episode every three
`
`
`
`
` days and no more than 5 episodes per month [see Drug Abuse and Dependence (9.4)].
`
`
`
`
`
`
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
`
` NAYZILAM is supplied as a single-dose nasal spray unit containing 5 mg of midazolam in
`
`
` 0.1 mL solution.
`
`
`
`
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
`
`
`
`
` NAYZILAM is contraindicated in patients with:
` • Known hypersensitivity to midazolam.
`
`
` • Acute narrow-angle glaucoma [see Warnings and Precautions (5.6)].
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
`
`
`
`
`
`
`
`
` 5.1 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 (7.2)].
`
`
`
`
`
`
`
`
` 5.2 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
`
`
`
`
`
`Reference ID: 4434795
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` 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 (8.5)]; 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 (6.1)]. Cardiac or respiratory arrest caused by NAYZILAM was
` not reported during clinical trials.
`
`
`
`
`
` 5.3 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 Warnings and
`
`
`Precautions (5.1) and Drug Abuse and Dependence (9.3)].
`
`
`
`
`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 (7.3)].
`
`
`
`
`
`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 (7.2) and Clinical Pharmacology (12.2)].
`
`
`
`
`5.4 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
`
`
`
`Reference ID: 4434795
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`
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` 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
`Drug
`Relative Risk:
`
` Risk Difference:
`
` Indication
`Additional Drug
`Patients
`Patients
`Incidence of Drug
`
`
`Patients with
`with
`with Events
`Events in Drug
`
`
`
`
`Events per 1000
`Events/100
`per 1000
`Patients /Incidence
`
`
` 0 Patients
` Patients
`
`
` in Placebo Patients
` Patients
`
` 1.0
`
` 3.4
`
` 3.5
`
` 2.4
`
` 5.7
`
` 8.5
`
` 1.5
`
` 2.9
`
` 1.0
`
` 1.8
`
` 1.9
`
` 0.9
`
` 2.4
`
` 4.3
`
` 1.8
`
` 1.9
`
`
`
`
`
`
`
` Epilepsy
`
` Psychiatric
`
` Other
`
` Total
`
` 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.
`
`
`
`
`
`
` 5.5 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.
`
`
`
`
`
`Reference ID: 4434795
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`5.6 Glaucoma
`
`
`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.
`
`
` 5.7 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.
`
`
`
` 6 ADVERSE REACTIONS
`
`
`
`
`
`
`
` The following serious adverse reactions are discussed in more detail in other sections of the
`
` labeling:
`  Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)]
`
`
`
`
`
`
`
`
`  Risks of Cardiorespiratory Adverse Reactions [see Warnings and Precautions (5.2)]
`
`
`
`
`
`  CNS Depression from Concomitant Use with Other CNS Depressants or Moderate or
`
`
`
`
`
` Strong CYP3A4 Inhibitors [see Warnings and Precautions (5.3)]
`
`
`
`  Suicidal Behavior and Ideation [see Warnings and Precautions (5.4)]
`
`
`
`
`
`  Impaired Cognitive Function [see Warnings and Precautions (5.5)]
`
`
`
`
`  Glaucoma [see Warnings and Precautions (5.6)]
`
`
`
`
`
`  Other Adverse Reactions [see Warnings and Precautions (5.7)]
`
`
`
`
`
`
`
`
`
`
` 6.1 Clinical Trials Experience
`
` Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`
`
`
` observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
` trials of another drug and may not reflect the rates observed in clinical practice.
`
`
`
`
`
`
`
`
` NAYZILAM was studied for the outpatient treatment of a single seizure cluster in 292 adult
` and adolescent patients with epilepsy (Study 1) [see Clinical Studies (14)]. The study was
`
`
`
`
`
` conducted in two phases; an open-label Test Dose Phase followed by a double-blind,
` placebo-controlled, Comparative Phase. The mean age of patients enrolled in the
`
`
`
`
` Comparative Phase (N=201) was 33 years, 51% were female, and 95% were White.
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4434795
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`

`

` Table 2 lists the adverse reactions occurring in 2% or more of the NAYZILAM-treated
`
`
`
`
`
` patients and at a rate greater than the placebo-treated patients in the Comparative Phase of
`
`Study 1.
`
`
`
` Table 2: Adverse Reactionsa that Occurred in ≥2% of Patients (Any NAYZILAM) and
`
`
`
`
`Greater than Placebo in the Comparative Phase of Study 1
`
`
`
`
`
`
`
` Body System/Adverse
`Reaction
`
`
`Placebo
`
`
` N = 26
`
` %
`
`
`
` NAYZILAM
`5 mg
`
`
` N = 91
`
`
` %
`
`
`
`NAYZILAMb
`
`
` Placebo +
` NAYZILAM
`5 mg
`
` N = 41
`
`
` %
`
`
` NAYZILAM
`5 mg + 5 mg
`
`
`
` N = 43
`
` %
`
`
` Any NAYZILAM
`Treatment Group
`
`
` N = 175
`
` %
`
`
`
`
`
`
`
` 10
`
`
` 4
`
` 2
`
`
` 9
`
` 3
`
` 3
`
`
`
` 2
`
`
`
` 2
`
`
`
` Nervous System
`
` Somnolence
`
` Headache
` Dysarthria
`
` Application Site
`
`
` Nasal Discomfort
`
`
` Throat Irritation
` Rhinorrhea
`
`Product Taste
` 0
`
`
` Abnormal
`Eye Disorders
`
`
` 2
` 2
` 1
` 0
` Lacrimation Increased
`
`
`
`
`
`
`
`
`
` a Adverse reactions that occurred within 2 days after NAYZILAM administration are included
`
`
`
`
`
`
`b Patients in Study 1 were permitted to take a second, open-label dose of NAYZILAM 5 mg between 10 minutes
`
`
`
`
`and 6 hours following the initial blinded dose of NAYZILAM 5 mg or placebo if they experience seizure
`
`
`
`
`recurrence or an incomplete resolution of the episode. The Placebo + NAYZILAM 5 mg and NAYZILAM 5
`
`
`
`
`mg + 5 mg columns represent patients who received a second dose of NAYZILAM 5 mg and received a blinded
`
`
`initial dose of placebo or NAYZILAM 5 mg, respectively.
`
`
`
`
`
`
` 4
`
` 0
`
` 0
`
`
` 8
`
` 0
`
` 0
`
`
` 10
`
` 7
`
` 2
`
`
` 5
`
` 2
`
` 3
`
`
`
` 4
`
`
`
`
`
`
`
` 10
`
`
` 0
`
` 2
`
`
` 7
`
` 2
`
` 0
`
`
`
` 0
`
`
`
`
`
`
`
`
` 9
`
` 2
`
` 2
`
`
` 16
`
` 7
`
` 5
`
`
`
` 0
`
`
`
`
`
`
`
` For patients who experienced a decrease in peripheral oxygen saturation in the Test Dose
`
`
`
`
`
`
` Phase of Study 1, the decreases were generally transitory. Two patients (one with a history
` of sleep apnea and one with intercurrent seizure) with decreases in peripheral oxygen
`
`
`
`
`
`
` saturation in the Test Dose Phase required therapeutic supplemental oxygen.
`
`
`
`
`
`Reference ID: 4434795
`
`
`Page 7 of 23
`
`
`AQUESTIVE EXHIBIT 1072 Page 0007
`
`

`

`
`
` 7 DRUG INTERACTIONS
`
`
`
`
`
`
`
` Table 3: Clinically Significant Drug Interactions With NAYZILAM
` 7.1 CYP3A4 Inhibitors
`
`
` Clinical Impact: Concomitant use of CYP3A4 inhibitors may result in prolonged
`
` sedation because of a decrease in plasma clearance of
`
` midazolam.
`
` Intervention: Avoid co-administration of NAYZILAM with moderate or
`
`
` strong CYP3A4 inhibitors. NAYZILAM should be used with
`
` caution when co-administered with mild CYP3A4 inhibitors.
`
` Examples: Moderate CYP3A4 inhibitors: erythromycin, diltiazem,
`
` verapamil
`Strong CYP3A4 inhibitors: ketoconazole, itraconazole,
`clarithromycin
`
`
`
`
`
`
`
`
`
`
`
`
`7.2 Opioids
`
` Clinical Impact: The concomitant use of benzodiazepines and opioids increases
`
`
`
` the risk of respiratory depression because of actions at different
` receptor sites in the CNS that control respiration.
`
`
`
` Benzodiazepines interact at GABAA sites and opioids interact
`
`
` primarily at mu receptors. When benzodiazepines and opioids
`
` are combined, the potential for benzodiazepines to significantly
`
`
` worsen opioid-related respiratory depression exists.
` Intervention: 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 [see
`
` Warnings and Precautions (5.1)].
` Examples: Morphine, hydrocodone, oxymorphone, codeine, fentanyl
`
`7.3 Other Central Nervous System (CNS) Depressants
`
` Clinical Impact: 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.
`
` Intervention: 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 [see
`
` Warnings and Precautions (5.3)].
` Examples: Other benzodiazepines and sedatives/hypnotics, anxiolytics,
`
` tranquilizers, muscle relaxants, general anesthetics,
`
` antipsychotics, opioids, alcohol.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4434795
`
`
`Page 8 of 23
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`AQUESTIVE EXHIBIT 1072 Page 0008
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`

`

`
`
` 8 USE IN SPECIFIC POPULATIONS
`
`
` 8.1 Pregnancy
` 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/.
`
`
`Risk Summary
`
`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.
`
`
`Clinical Considerations
`
`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
`
`
`
`
`Reference ID: 4434795
`
`
`Page 9 of 23
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`
`AQUESTIVE EXHIBIT 1072 Page 0009
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`

`

`
`
`
`
` 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.
`
`Data
`
`Human Data
`
`Congenital Anomalies
`
`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.
`
`
`
`
`
`
`Reference ID: 4434795
`
`
`Page 10 of 23
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`AQUESTIVE EXHIBIT 1072 Page 0010
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`

`

`
`
` Animal Data
`
` 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.
`
`8.2 Lactation
`
`Risk Summary
`
`
`
`
`Mid