Midazolam in sodium chloride injection is indicated:

{ "type": "p", "children": [], "text": "Midazolam in sodium chloride injection is indicated:" }

{ "type": "ul", "children": [ "Continuous intravenous infusion for sedation of intubated and mechanically ventilated adult, pediatric, and neonatal patients as a component of anesthesia or during treatment in a critical care setting." ], "text": "" }

Midazolam must never be used without individualization of dosage particularly when used with other medications capable of producing central nervous system depression [Warnings and Precautions (5.2)].

Midazolam in sodium chloride injection can cause respiratory depression. It is a potent sedative agent that requires slow administration and individualization of dosage. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. Continuously monitor patients for early signs of hypoventilation, airway obstruction, and apnea using capnography, pulse oximetry, and clinical assessment [see Warnings and Precautions (5.3)].

Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric patients [see Warnings and Precautions (5.4)].

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. If solution is discolored or particulate matter is present, do not use.

Individualize dosing and titrate to desired clinical response, taking into account patient age, clinical status, and concomitant use of other CNS depressants. Titrate to effect with multiple small doses while continuously monitoring respiratory and cardiac function (i.e., pulse oximetry). To minimize the potential for oversedation, allow adequate time between doses to achieve peak central nervous system effect (3 to 5 minutes).

Adults and Pediatrics:

Sedation guidelines recommend a careful presedation history to determine how a patient's underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

Pediatrics:

Pediatric patients generally require higher dosages of midazolam (mg/kg) than adults. For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Elderly and Debilitated Patients

Intravenous doses of midazolam should be decreased for elderly and for debilitated patients [see Warnings and Precautions (5.6)]. These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia [see Warnings and Precautions (5.8)].

Monitoring

Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Continuously monitor vital signs during sedation and through the recovery period [see Warnings and Precautions (5.1)].

Table 1 provides dosing recommendations for adult, pediatric, and neonatal patients.

Table 1. Dosing Recommendations for Continuous Intravenous Infusion in Adult, Pediatric, and Neonatal Patients

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0"> <col width="172.4pt"/> <col width="362.8pt"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">ADULT PATIENTS</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">If a loading dose is necessary to rapidly initiate sedation, 0.01 mg/kg to 0.05 mg/kg (approximately 0.5 mg to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 mg/kg/hr to 0.10 mg/kg/hr (1 mg/hr to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients. Use the lowest recommended doses in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids.</p> <p>Individual response to midazolam is variable. Titrate the infusion rate to the desired level of sedation, taking into account the patient's age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation. Assess sedation at regular intervals and adjust the midazolam infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">PEDIATRIC PATIENTS</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients. In obese pediatric patients, calculate the dose based on ideal body weight.</p> <p>Titrate the dose to the desired level of sedation. Assess for desired level of sedation and vital signs at regular intervals.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">PRETERM AND TERM</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Based on pharmacokinetic parameters and reported clinical experience in</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">NEONATAL PATIENTS</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">preterm and term neonates WHOSE TRACHEA WAS INTUBATED, initiate continuous intravenous infusions of midazolam in sodium chloride injection at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates &lt;32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates &gt;32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. Frequently assess the rate of infusion, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly.</p> <p>When sedating preterm and former preterm neonates WHOSE TRACHEA WAS NOT INTUBATED, monitor respiratory parameters due to an increased risk of apnea.</p> </td> </tr> </tbody> </table></div>

If midazolam in sodium chloride injection is administered long-term (for several days to weeks), do not abruptly discontinue. Gradually taper the dosage in physically-dependent patients using a tapering schedule that is individualized to the patient. (see Warnings and Precautions (5.5).

Midazolam in Sodium Chloride Injection, 50 mg per 50 mL (1 mg/mL) and 100 mg per 100 mL (1 mg/ mL), is a clear, colorless solution supplied in single-dose bags with an aluminum overwrap.

{ "type": "p", "children": [], "text": "Midazolam in Sodium Chloride Injection, 50 mg per 50 mL (1 mg/mL) and 100 mg per 100 mL (1 mg/ mL), is a clear, colorless solution supplied in single-dose bags with an aluminum overwrap." }

Midazolam in sodium chloride injection is contraindicated in patients with:

{ "type": "p", "children": [], "text": "Midazolam in sodium chloride injection is contraindicated in patients with:" }

{ "type": "ul", "children": [ "Known hypersensitivity to midazolam", "Acute narrow-angle glaucoma" ], "text": "" }

Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Monitor patients for respiratory depression and sedation [see Warnings and Precautions (5.2) and Drug Interactions (7.1)].

Titrate the dose of midazolam in sodium chloride injection when administered with opioid analgesics and sedative- hypnotics to the desired clinical response.

Continuously monitor sedated patients for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation. These cardiorespiratory effects may be more likely to occur in patients with obstructive sleep apnea, the elderly, and ASA-PS III or IV patients.

Concomitant use of barbiturates, 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 effect. Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.

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 adult or pediatric patients with hemodynamic instability. Hypotension occurred more frequently in the sedation studies in patients premedicated with an opioid.

Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. When used for sedation/anxiolysis/amnesia, midazolam should always be titrated slowly in adult or pediatric patients. Adverse hemodynamic events have been reported in pediatric patients with cardiovascular instability; rapid intravenous administration should also be avoided in this population. Continuously monitor patients for early signs of hypoventilation, airway obstruction, and apnea using capnography, pulse oximetry, and clinical assessment [see Dosage and Administration (2.2)].

Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. These reactions may be due to inadequate or excessive dosing or improper administration of midazolam; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions. Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric patients.

The continued use of benzodiazepines for several days to weeks may lead to clinically significant physical dependence. If used for long-term use (i.e., for several days to weeks), abrupt discontinuation or rapid dosage reduction of midazolam, or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening.

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use.

After extended therapy, do not abruptly discontinue midazolam in sodium chloride injection. When discontinuing midazolam in a physically-dependent patient, gradually taper the dosage using a tapering schedule that is individualized to the patient [see Dosage and Administration (2.3), Dependence (9.3)].

Higher risk adult and pediatric surgical patients, elderly patients and debilitated adult and pediatric patients require lower dosages, whether or not concomitant sedating medications have been administered. Adult or pediatric patients with COPD are unusually sensitive to the respiratory depressant effect of midazolam. Pediatric and adult patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction. Adult and pediatric patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly [see Clinical Pharmacology (12.3)]. Because elderly patients frequently have inefficient function of one or more organ systems and because dosage requirements have been shown to decrease with age, reduced initial dosage of midazolam is recommended, and the possibility of profound and/or prolonged effect should be considered.

Do not administer midazolam in sodium chloride injection to adult or pediatric patients in shock or coma, or in acute alcohol intoxication with depression of vital signs. Particular care should be exercised in the use of intravenous midazolam in adult or pediatric patients with uncompensated acute illnesses, such as severe fluid or electrolyte disturbances.

There have been limited reports of intra-arterial injection of midazolam. Adverse events have included local reactions, as well as isolated reports of seizure activity in which no clear causal relationship was established. Precautions against unintended intra-arterial injection should be taken. Extravasation should also be avoided.

The safety and efficacy of midazolam in sodium chloride injection following nonintravenous routes of administration have not been established. Midazolam in sodium chloride injection  should only be administered intravenously.

Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours. The decision as to when patients who have received injectable midazolam, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized. Gross tests of recovery from the effects of midazolam [see Clinical Pharmacology (12.3)] 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 or until one full day after anesthesia and surgery, whichever is longer. For pediatric patients, particular care should be taken to assure safe ambulation.

Rapid injection should be avoided in the neonatal population. Midazolam administered rapidly as an intravenous injection (i.e., less than 2 minutes) has been associated with severe hypotension in neonates, particularly when the patient has also received fentanyl. Likewise, severe hypotension has been observed in neonates receiving a continuous infusion of midazolam who then receive a rapid intravenous injection of fentanyl. Seizures have been reported in several neonates following rapid intravenous administration.

The neonate also has reduced and/or immature organ function and is also vulnerable to profound and/or prolonged respiratory effects of midazolam.

Receiving midazolam in sodium chloride injection late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate. Monitor neonates exposed to midazolam in sodium chloride injection during pregnancy or labor for signs of sedation and manage these neonates accordingly [see Use in Specific Populations (8.1)].

Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see Nonclinical Pharmacology (13.2)].

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

Benzodiazepines, including midazolam in sodium chloride injection, 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. Midazolam in sodium chloride injection 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 midazolam in sodium chloride injection. Midazolam in sodium chloride injection is contraindicated in patients with narrow-angle glaucoma.

The following serious adverse reactions are discussed in greater detail in other sections:

{ "type": "p", "children": [], "text": "The following serious adverse reactions are discussed in greater detail in other sections:" }

{ "type": "ul", "children": [ "Cardiorespiratory Adverse Reactions [see Warnings and Precautions (5.3)]\n", "Paradoxical Behavior [see Warnings and Precautions (5.4)]\n", "Dependence and Withdrawal [see Warnings and Precautions (5.5)]\n", "Impaired Cognitive Function [see Warnings and Precautions (5.8)]\n", "Hypotension and Seizure in Preterm Infants and Neonates [see Warnings and Precautions (5.9)]\n", "Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.10), Use in Specific Populations (8.1)]\n", "Pediatric Neurotoxicity [see Warnings and Precautions (5.11)]\n" ], "text": "" }

The following adverse reactions have been identified from literature or postmarketing reports of midazolam. Because some of these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

{ "type": "p", "children": [], "text": "The following adverse reactions have been identified from literature or postmarketing reports of midazolam. Because some of these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure." }

Fluctuations in vital signs were the most frequently seen findings following parenteral administration of midazolam in adults and included decreased tidal volume and/or respiratory rate decrease (23.3% of patients following intravenous administration) and apnea (15.4% of patients following intravenous administration), as well as variations in blood pressure and pulse rate. The majority of serious adverse reactions, particularly those associated with oxygenation and ventilation, have been reported when midazolam is administered with other medications capable of depressing the central nervous system. The incidence of such events is higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube, (e.g., upper endoscopy and dental procedures).

{ "type": "p", "children": [], "text": "Fluctuations in vital signs were the most frequently seen findings following parenteral administration of midazolam in adults and included decreased tidal volume and/or respiratory rate decrease (23.3% of patients following intravenous administration) and apnea (15.4% of patients following intravenous administration), as well as variations in blood pressure and pulse rate. The majority of serious adverse reactions, particularly those associated with oxygenation and ventilation, have been reported when midazolam is administered with other medications capable of depressing the central nervous system. The incidence of such events is higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube, (e.g., upper endoscopy and dental procedures)." }

Adults

{ "type": "p", "children": [], "text": "\nAdults\n" }

Table 2: Additional Adverse Reactions Reported Subsequent to Intravenous Administration as a Single Sedative/anxiolytic/amnestic Agent in Adult Patients:

{ "type": "p", "children": [], "text": "\nTable 2: Additional Adverse Reactions Reported Subsequent to Intravenous Administration as a Single Sedative/anxiolytic/amnestic Agent in Adult Patients:\n" }

hiccoughs (3.9%)                                                 Local effects at the intravenous site

{ "type": "p", "children": [], "text": "hiccoughs (3.9%)                                                 Local effects at the intravenous site\n" }

nausea (2.8%)                                                      tenderness (5.6%)

{ "type": "p", "children": [], "text": "nausea (2.8%)                                                      tenderness (5.6%)" }

vomiting (2.6%)                                                   pain during injection (5%)

{ "type": "p", "children": [], "text": "vomiting (2.6%)                                                   pain during injection (5%)" }

coughing (1.3%)                                                  redness (2.6%)

{ "type": "p", "children": [], "text": "coughing (1.3%)                                                  redness (2.6%)" }

"oversedation" (1.6%)                                          induration (1.7%)

{ "type": "p", "children": [], "text": "\"oversedation\" (1.6%)                                          induration (1.7%)" }

headache (1.5%)                                                  phlebitis (0.4%)

{ "type": "p", "children": [], "text": "headache (1.5%)                                                  phlebitis (0.4%)" }

 drowsiness (1.2%)      

{ "type": "p", "children": [], "text": "  drowsiness (1.2%)      " }

Pediatric Patients

{ "type": "p", "children": [], "text": "\nPediatric Patients\n" }

The following adverse events related to the use of intravenous midazolam in pediatric patients were reported in the medical literature: desaturation 4.6%, apnea 2.8%, hypotension 2.7%, paradoxical reactions 2%, hiccough 1.2%, seizure-like activity 1.1% and nystagmus 1.1%. The majority of airway-related events occurred in patients receiving other CNS depressing medications and in patients where midazolam was not used as a single sedating agent.

{ "type": "p", "children": [], "text": "The following adverse events related to the use of intravenous midazolam in pediatric patients were reported in the medical literature: desaturation 4.6%, apnea 2.8%, hypotension 2.7%, paradoxical reactions 2%, hiccough 1.2%, seizure-like activity 1.1% and nystagmus 1.1%. The majority of airway-related events occurred in patients receiving other CNS depressing medications and in patients where midazolam was not used as a single sedating agent." }

Neonates

{ "type": "p", "children": [], "text": "\nNeonates\n" }

There have been reports of hypotensive episodes and seizures following the administration of midazolam to neonates, [see Warnings and Precautions (5.9)].

{ "type": "p", "children": [], "text": "There have been reports of hypotensive episodes and seizures following the administration of midazolam to neonates, [see Warnings and Precautions (5.9)].\n" }

Other Adverse Reactions Occurring at an Incidence of <1% Following Intravenous Injection as a Single Sedative/Anxiolytic/Amnesia Agent

{ "type": "p", "children": [], "text": "\nOther Adverse Reactions Occurring at an Incidence of <1% Following Intravenous Injection as a Single Sedative/Anxiolytic/Amnesia Agent\n" }

Respiratory: Laryngospasm, bronchospasm, dyspnea, hyperventilation, wheezing, shallow respirations, airway obstruction, tachypnea

{ "type": "p", "children": [], "text": "\nRespiratory: Laryngospasm, bronchospasm, dyspnea, hyperventilation, wheezing, shallow respirations, airway obstruction, tachypnea" }

Cardiovascular: Bigeminy, premature ventricular contractions, vasovagal episode, bradycardia, tachycardia, nodal rhythm

{ "type": "p", "children": [], "text": "\nCardiovascular: Bigeminy, premature ventricular contractions, vasovagal episode, bradycardia, tachycardia, nodal rhythm" }

Gastrointestinal: Acid taste, excessive salivation, retching

{ "type": "p", "children": [], "text": "\nGastrointestinal: Acid taste, excessive salivation, retching" }

CNS/Neuromuscular: Retrograde amnesia, euphoria, hallucination, confusion, argumentativeness, nervousness, anxiety, grogginess, restlessness, emergence delirium or agitation, prolonged emergence from anesthesia, dreaming during emergence, sleep disturbance, insomnia, nightmares, athetoid movements, seizure-like activity, ataxia, dizziness, dysphoria, slurred speech, dysphonia, paresthesia

{ "type": "p", "children": [], "text": "\nCNS/Neuromuscular: Retrograde amnesia, euphoria, hallucination, confusion, argumentativeness, nervousness, anxiety, grogginess, restlessness, emergence delirium or agitation, prolonged emergence from anesthesia, dreaming during emergence, sleep disturbance, insomnia, nightmares, athetoid movements, seizure-like activity, ataxia, dizziness, dysphoria, slurred speech, dysphonia, paresthesia" }

Special Senses: Blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic movements of eyelids, visual disturbance, difficulty focusing eyes, ears blocked, loss of balance, light-headedness

{ "type": "p", "children": [], "text": "\nSpecial Senses: Blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic movements of eyelids, visual disturbance, difficulty focusing eyes, ears blocked, loss of balance, light-headedness" }

Integumentary: Hive-like elevation at injection site, swelling or feeling of burning, warmth or coldness at injection site

{ "type": "p", "children": [], "text": "\nIntegumentary: Hive-like elevation at injection site, swelling or feeling of burning, warmth or coldness at injection site" }

Hypersensitivity: Allergic reactions including anaphylactic reactions, hives, rash, pruritus

{ "type": "p", "children": [], "text": "\nHypersensitivity: Allergic reactions including anaphylactic reactions, hives, rash, pruritus" }

Miscellaneous: Yawning, lethargy, chills, weakness, toothache, faint feeling, hematoma

{ "type": "p", "children": [], "text": "\nMiscellaneous: Yawning, lethargy, chills, weakness, toothache, faint feeling, hematoma" }

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. Monitor patients closely for respiratory depression and sedation.

The sedative effect of intravenous midazolam is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly opioids (e.g., morphine, meperidine and fentanyl) and also secobarbital and droperidol. Consequently, the dosage of midazolam should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response [see Dosage and Administration (2)].

Concomitant administration with drugs that are known to inhibit the P450-3A4 enzyme system, such as cimetidine (not ranitidine), erythromycin, diltiazem, verapamil, ketoconazole and itraconazole, may result in prolonged sedation due to a decrease in plasma clearance of midazolam.

The effect of single oral doses of 800 mg cimetidine and 300 mg ranitidine on steady-state concentrations of midazolam was examined in a randomized crossover study (n=8). Cimetidine increased the mean midazolam steady-state concentration from 57 to 71 ng/mL. Ranitidine increased the mean steady-state concentration to 62 ng/mL. No change in choice reaction time or sedation index was detected after dosing with the H2 receptor antagonists.

In a placebo-controlled study, erythromycin administered as a 500 mg dose, three times a day, for 1 week (n=6), reduced the clearance of midazolam following a single 0.5 mg/kg intravenous dose. The half-life was approximately doubled.

The effects of diltiazem (60 mg three times a day) and verapamil (80 mg three times a day) on the pharmacokinetics and pharmacodynamics of oral midazolam were investigated in a three-way crossover study (n=9). The half-life of midazolam increased from 5 to 7 hours when midazolam was taken in conjunction with verapamil or diltiazem. No interaction was observed in healthy subjects between midazolam and nifedipine.

In a placebo-controlled study, saquinavir administered as a 1200 mg dose, tid, for 5 days (n=12), a 56% reduction in the clearance of midazolam following a single 0.05 mg/kg intravenous dose was observed. The half-life was approximately doubled.

A moderate reduction in induction dosage requirements of thiopental (about 15%) has been noted following use of intramuscular midazolam for premedication in adults.

The intravenous administration of midazolam decreases the minimum alveolar concentration (MAC) of halothane required for general anesthesia. This decrease correlates with the dose of midazolam administered; no similar studies have been carried out in pediatric patients but there is no scientific reason to expect that pediatric patients would respond differently than adults.

Although the possibility of minor interactive effects has not been fully studied, midazolam and pancuronium have been used together in patients without noting clinically significant changes in dosage, onset or duration in adults. Midazolam does not protect against the characteristic circulatory changes noted after administration of succinylcholine or pancuronium and does not protect against the increased intracranial pressure noted following administration of succinylcholine. Midazolam does not cause a clinically significant change in dosage, onset or duration of a single intubating dose of succinylcholine; no similar studies have been carried out in pediatric patients but there is no scientific reason to expect that pediatric patients would respond differently than adults.

No significant adverse interactions with commonly used premedications or drugs used during anesthesia and surgery (including atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, d-tubocurarine, succinylcholine and other nondepolarizing muscle relaxants) or topical local anesthetics (including lidocaine, dyclonine HCl and Cetacaine) have been observed in adults or pediatric patients. In neonates, however, severe hypotension has been reported with concomitant administration of fentanyl. This effect has been observed in neonates on an infusion of midazolam who received a rapid injection of fentanyl and in patients on an infusion of fentanyl who have received a rapid injection of midazolam.

Midazolam has not been shown to interfere with results obtained in clinical laboratory tests.

Risk Summary

Neonates born to mothers using benzodiazepines, including midazolam, late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.10), and Clinical Considerations]. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data).

Available data from randomized controlled trials, cohort studies and case reports over several decades with midazolam use in pregnant women for anesthesia have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Most of the reported exposures to midazolam occurred at the time of cesarean delivery. Rare case reports of the prolonged use of midazolam in pregnant women for sedation in a critical care setting are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes (see Data).

In pregnant rats and rabbits, midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons.

Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to midazolam during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to midazolam during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.2)].

Data

Human Data

Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Animal Data

Pregnant rats were treated with midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 through 15). Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose. All doses produced slight to moderate ataxia. The high dose produced a 5% decrease in maternal body weight gain compared to control.

Pregnant rabbits were treated with midazolam using intravenous doses of 0.2, 0.6, and 2 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 to 18). Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose. The high dose was associated with findings of ataxia and sedation but no evidence of maternal toxicity.

Pregnant rats were administered midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during late gestation and through lactation (Gestation Day 15 through Lactation Day 21). All doses produced ataxia. The high dose produced a slight decrease in maternal body weight gain compared to control. There were no clear adverse effects noted in the offspring. The study included no functional assessments of the pups, such as learning and memory testing or reproductive capacity.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits [see Warnings and Precautions (5.8), Use in Specific Populations (8.4), Nonclinical Pharmacology (13.2)].

Risk Summary

There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk. Based on data from published studies, midazolam is present in human milk in low levels (see Data). There are no data on the effects of midazolam on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for midazolam in sodium chloride injection and any potential adverse effects on the breastfed infant from midazolam in sodium chloride injection or from the underlying maternal condition.

Clinical Considerations

Infants exposed to midazolam through breast milk should be monitored for sedation, poor feeding, and poor weight gain. A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment for a range of at least 4 to 8 hours after midazolam administration in order to minimize drug exposure to a breastfed infant.

Data

Published clinical lactation studies describe the presence of midazolam in human milk at low levels 4 to 8 hours after midazolam administration. These lactation studies have limitations including poor methodology and lack of validated analytical methods. Published study guidelines recommend pumping and discarding breast milk for a range of at least 4 to 8 hours after treatment with midazolam. No safety signals have been identified in breastfed infants exposed to midazolam.

The safety and efficacy of midazolam for sedation/anxiolysis/amnesia following continuous infusion have been established in pediatric and neonatal patients. UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require closer monitoring. In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

Midazolam should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid intravenous administration, particularly, with concomitant use of fentanyl.

Animal Data

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as midazolam in sodium chloride injection, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data [see Warnings and Precautions (5.8) and Nonclinical Pharmacology (13.2)].

Because geriatric patients may have altered drug distribution and diminished hepatic and/or renal function, reduced doses of midazolam are recommended. Doses of midazolam in sodium chloride injection should be decreased for elderly and for debilitated patients [see Warnings and Precautions (5.6) and Dosage and Administration (2)] and subjects over 70 years of age may be particularly sensitive. These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia. Administration of intravenous midazolam to elderly and/or high-risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially opioids [see Dosage and Administration (2)].

Midazolam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Midazolam in sodium chloride injection contains  midazolam, a Schedule IV controlled substance.

Midazolam in sodium chloride injection contains the benzodiazepine, midazolam. Benzodiazepines are a class of sedative drugs with a known potential for abuse. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Both abuse and misuse may lead to addiction. Midazolam was actively self-administered in primate models used to assess the positive reinforcing effects of psychoactive drugs. Midazolam produced physical dependence of a mild to moderate intensity in cynomolgus monkeys after 5 to 10 weeks of administration. Available data concerning the drug abuse and dependence potential of midazolam suggest that its abuse potential is at least equivalent to that of diazepam.

Midazolam may produce physical dependence after long-term use. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. If midazolam in sodium chloride injection is administered long­-term (i.e., for several days to weeks), abrupt discontinuation or rapid dosage reduction, or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.5)].

To reduce the risk of withdrawal reactions, after extended therapy, do not abruptly discontinue midazolam in sodium chloride injection. Gradually taper the dosage using a tapering schedule that is individualized to the patient.

Acute Withdrawal Signs and Symptoms

Acute withdrawal signs and symptoms have included abnormal involuntary movements, anxiety, blurred vision, cognitive disorder, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, homicidal thoughts, mania, psychosis, and suicidality

Protracted Withdrawal Syndrome

Protracted withdrawal syndrome is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months.

Tolerance

Midazolam may produce tolerance after long-term use. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance may develop within days or weeks of the therapeutic effects of Midazolam; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

Clinical Presentation

{ "type": "p", "children": [], "text": "\nClinical Presentation\n" }

Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions (5.2)]. Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. No evidence of specific organ toxicity from midazolam overdosage has been reported.

{ "type": "p", "children": [], "text": " Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions (5.2)]. Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. No evidence of specific organ toxicity from midazolam overdosage has been reported." }

Management of Overdosage

{ "type": "p", "children": [], "text": "\nManagement of Overdosage\n" }

In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information.

{ "type": "p", "children": [], "text": "In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information." }

Consider contacting the Poison Help Line (1-800-222-1222) or medical toxicologist for additional overdosage management for recommendations.

{ "type": "p", "children": [], "text": "Consider contacting the Poison Help Line (1-800-222-1222) or medical toxicologist for additional overdosage management for recommendations." }

Midazolam in Sodium Chloride Injection is a benzodiazepine available as a sterile, preservative-free, nonpyrogenic solution of midazolam and sodium chloride in water for injection for intravenous use. Each single-dose bag of Midazolam in Sodium Chloride Injection contains either 50 mg/50 mL (1 mg/mL) or 100 mg/100 mL (1 mg/mL) of midazolam and 9 mg/mL of sodium chloride in water for injection. Midazolam in Sodium Chloride Injection may contain hydrochloric acid and/or sodium hydroxide for pH adjustment. The pH is approximately 2.5 to 3.5.

{ "type": "p", "children": [], "text": "Midazolam in Sodium Chloride Injection is a benzodiazepine available as a sterile, preservative-free, nonpyrogenic solution of midazolam and sodium chloride in water for injection for intravenous use. Each single-dose bag of Midazolam in Sodium Chloride Injection contains either 50 mg/50 mL (1 mg/mL) or 100 mg/100 mL (1 mg/mL) of midazolam and 9 mg/mL of sodium chloride in water for injection. Midazolam in Sodium Chloride Injection may contain hydrochloric acid and/or sodium hydroxide for pH adjustment. The pH is approximately 2.5 to 3.5." }

Midazolam is a white to light yellow crystalline compound, insoluble in water, freely soluble in ethanol, soluble in methanol. Chemically, midazolam is 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine. Midazolam has the empirical formula C18H13ClFN3, a calculated molecular weight of 325.77 and the following structural formula:

{ "type": "p", "children": [], "text": "Midazolam is a white to light yellow crystalline compound, insoluble in water, freely soluble in ethanol, soluble in methanol. Chemically, midazolam is 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine. Midazolam has the empirical formula C18H13ClFN3, a calculated molecular weight of 325.77 and the following structural formula:" }

{ "type": "", "children": [], "text": "" }

Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant.

The effects of midazolam on the CNS are dependent on the dose administered, the route of administration, and the presence or absence of other medications.

Time to Onset

Sedation in adult and pediatric patients is achieved within 3 to 5 minutes after intravenous injection; the time of onset is affected by total dose administered and the concurrent administration of opioid premedication. Seventy-one percent of the adult patients in endoscopy studies had no recall of introduction of the endoscope; 82% of the patients had no recall of withdrawal of the endoscope. In one study of pediatric patients undergoing lumbar puncture or bone marrow aspiration, 88% of patients had impaired recall vs 9% of the placebo controls. In another pediatric oncology study, 91% of midazolam treated patients were amnestic compared with 35% of patients who had received fentanyl alone.

When midazolam is given intravenous as an anesthetic induction agent, induction of anesthesia occurs in approximately 1.5 minutes when opioid premedication has been administered and in 2 to 2.5 minutes without opioid premedication or other sedative premedication. Some impairment in a test of memory was noted in 90% of the patients studied.

Midazolam, used as directed, does not delay awakening from general anesthesia in adults. Gross tests of recovery after awakening (orientation, ability to stand and walk, suitability for discharge from the recovery room, return to baseline Trieger competency) usually indicate recovery within 2 hours but recovery may take up to 6 hours in some cases. When compared with patients who received thiopental, patients who received midazolam generally recovered at a slightly slower rate. Recovery from anesthesia or sedation for procedures in pediatric patients depends on the dose of midazolam administered, coadministration of other medications causing CNS depression and duration of the procedure.

In patients without intracranial lesions, induction of general anesthesia with intravenous midazolam is associated with a moderate decrease in cerebrospinal fluid pressure (lumbar puncture measurements), similar to that observed following intravenous thiopental. Preliminary data in neurosurgical patients with normal intracranial pressure but decreased compliance (subarachnoid screw measurements) show comparable elevations of intracranial pressure with midazolam and with thiopental during intubation. No similar studies have been reported in pediatric patients.

Intravenous induction doses of midazolam depress the ventilatory response to carbon dioxide stimulation for 15 minutes or more beyond the duration of ventilatory depression following administration of thiopental in adults. Impairment of ventilatory response to carbon dioxide is more marked in adult patients with chronic obstructive pulmonary disease (COPD). Sedation with intravenous midazolam does not adversely affect the mechanics of respiration (resistance, static recoil, most lung volume measurements); total lung capacity and peak expiratory flow decrease significantly but static compliance and maximum expiratory flow at 50% of awake total lung capacity (Vmax) increase.

In cardiac hemodynamic studies in adults, intravenous induction of general anesthesia with midazolam was associated with a slight to moderate decrease in mean arterial pressure, cardiac output, stroke volume and systemic vascular resistance. Slow heart rates (less than 65/minute), particularly in patients taking propranolol for angina, tended to rise slightly; faster heart rates (e.g., 85/minute) tended to slow slightly. In pediatric patients, a comparison of intravenous midazolam (500 mcg/kg) with propofol (2.5 mg/kg) revealed a mean 15% decrease in systolic blood pressure in patients who had received intravenous midazolam vs a mean 25% decrease in systolic blood pressure following propofol.

Plasma Concentration-Efficacy Relationships

Concentration-efficacy relationships (after an intravenous dose) have been demonstrated for a variety of pharmacodynamic measures (eg, reaction time, eye movement, sedation) and are associated with extensive intersubject variability. Logistic regression analysis of sedation scores and steady-state plasma concentration indicated that at plasma concentrations greater than 100 ng/mL there was at least a 50% probability that patients would be sedated, but respond to verbal commands (sedation score=3). At 200 ng/mL there was at least a 50% probability that patients would be asleep, but respond to glabellar tap (sedation score=4).

Midazolam's activity is primarily due to the parent drug. Elimination of the parent drug takes place via hepatic metabolism of midazolam to hydroxylated metabolites that are conjugated and excreted in the urine. Six single-dose pharmacokinetic studies involving healthy adults yield pharmacokinetic parameters for midazolam in the following ranges: volume of distribution (Vd), 1 to 3.1 L/kg; elimination half-life, 1.8 to 6.4 hours (mean approximately 3 hours); total clearance (Cl), 0.25 to 0.54 L/hr/kg. In a parallel group study, there was no difference in the clearance, in subjects administered 0.15 mg/kg (n=4) and 0.30 mg/kg (n=4) intravenous doses indicating linear kinetics. The clearance was successively reduced by approximately 30% at doses of 0.45 mg/kg (n=4) and 0.6 mg/kg (n=5) indicating non-linear kinetics in this dose range.

Absorption

Following intramuscular administration, Cmax for midazolam and its 1-hydroxy metabolite were approximately one-half of those achieved after intravenous injection.

Distribution

The volume of distribution (Vd) determined from six single-dose pharmacokinetic studies involving healthy adults ranged from 1 to 3.1 L/kg. Female gender, old age, and obesity are associated with increased values of midazolam Vd. In humans, midazolam has been shown to cross the placenta and enter into fetal circulation and has been detected in human milk and CSF (see Clinical Pharmacology, Special Populations).

In adults and pediatric patients older than 1 year, midazolam is approximately 97% bound to plasma protein, principally albumin and that for 1-hydroxy metabolite is about 89%.

Elimination

Metabolism

In vitro studies with human liver microsomes indicate that the biotransformation of midazolam is mediated by cytochrome P450-3A4. This cytochrome also appears to be present in gastrointestinal tract mucosa as well as liver. Sixty to seventy percent of the biotransformation products is 1-hydroxy-midazolam (also termed alpha-hydroxy-midazolam) while 4­-hydroxy-midazolam constitutes 5% or less. Small amounts of a dihydroxy derivative have also been detected but not quantified. The principal urinary excretion products are glucuronide conjugates of the hydroxylated derivatives.

Drugs that inhibit the activity of cytochrome P450-3A4 may inhibit midazolam clearance and elevate steady-state midazolam concentrations.

Studies of the intravenous administration of 1-hydroxy-midazolam in humans suggest that 1-hydroxy-midazolam is at least as potent as the parent compound and may contribute to the net pharmacologic activity of midazolam. In vitro studies have demonstrated that the affinities of 1- and 4-hydroxy-midazolam for the benzodiazepine receptor are approximately 20% and 7%, respectively, relative to midazolam.

Excretion

Clearance of midazolam is reduced in association with old age, congestive heart failure, liver disease (cirrhosis) or conditions which diminish cardiac output and hepatic blood flow.

The principal urinary excretion product is 1-hydroxy-midazolam in the form of a glucuronide conjugate; smaller amounts of the glucuronide conjugates of 4-hydroxy- and dihydroxy-midazolam are detected as well. The amount of midazolam excreted unchanged in the urine after a single intravenous dose is less than 0.5% (n=5). Following a single intravenous infusion in 5 healthy volunteers, 45% to 57% of the dose was excreted in the urine as 1-hydroxymethyl midazolam conjugate.

Pharmacokinetics-Continuous Infusion

The pharmacokinetic profile of midazolam following continuous infusion, based on 282 adult subjects, has been shown to be similar to that following single-dose administration for subjects of comparable age, gender, body habitus and health status. However, midazolam can accumulate in peripheral tissues with continuous infusion. The effects of accumulation are greater after long-term infusions than after short-term infusions. The effects of accumulation can be reduced by maintaining the lowest midazolam infusion rate that produces satisfactory sedation.

Infrequent hypotensive episodes have occurred during continuous infusion; however, neither the time to onset nor the duration of the episode appeared to be related to plasma concentrations of midazolam or alpha-hydroxy-midazolam. Further, there does not appear to be an increased chance of occurrence of a hypotensive episode with increased loading doses.

Patients with renal impairment may have longer elimination half-lives for midazolam [see Clinical Pharmacology (12.3)].

Specific Populations

Changes in the pharmacokinetic profile of midazolam due to drug interactions, physiological variables, etc., may result in changes in the plasma concentration-time profile and pharmacological response to midazolam in these patients. For example, patients with acute renal failure appear to have a longer elimination half-life for midazolam and may experience delayed recovery [see Clinical Pharmacology (12.3)]. In other groups, the relationship between prolonged half-life and duration of effect has not been established.

Age: Pediatrics and Neonates

In pediatric patients aged 1 year and older, the pharmacokinetic properties following a single dose of midazolam reported in 10 separate studies of midazolam are similar to those in adults. Weight-normalized clearance is similar or higher (0.19 to 0.80 L/hr/kg) than in adults and the terminal elimination half-life (0.78 to 3.3 hours) is similar to or shorter than in adults. The pharmacokinetic properties during and following continuous intravenous infusion in pediatric patients in the operating room as an adjunct to general anesthesia and in the intensive care environment are similar to those in adults.

In seriously ill neonates, however, the terminal elimination half-life of midazolam is substantially prolonged (6.5 to 12 hours) and the clearance reduced (0.07 to 0.12 L/hr/kg) compared to healthy adults or other groups of pediatric patients. It cannot be determined if these differences are due to age, immature organ function or metabolic pathways, underlying illness or debility.

Age: Geriatric

In three parallel group studies, the pharmacokinetics of midazolam administered intravenous or intramuscular were compared in young (mean age 29, n=52) and healthy elderly subjects (mean age 73, n=53). Plasma half-life was approximately two-fold higher in the elderly. The mean Vd based on total body weight increased consistently between 15% to 100% in the elderly. The mean Cl decreased approximately 25% in the elderly in two studies and was similar to that of the younger patients in the other.

Obese

In a study comparing normals (n=20) and obese patients (n=20) the mean half-life was greater in the obese group (5.9 vs 2.3 hrs). This was due to an increase of approximately 50% in the Vd corrected for total body weight. The clearance was not significantly different between groups.

Congestive Heart Failure

In patients suffering from congestive heart failure, there appeared to be a two-fold increase in the elimination half-life, a 25% decrease in the plasma clearance and a 40% increase in the volume of distribution of midazolam.

Hepatic Impairment

Midazolam pharmacokinetics were studied after an intravenous single dose (0.075 mg/kg) was administered to 7 patients with biopsy proven alcoholic cirrhosis and 8 control patients. The mean half-life of midazolam increased 2.5-fold in the alcoholic patients. Clearance was reduced by 50% and the Vd increased by 20%. In another study in 21 male patients with cirrhosis, without ascites and with normal kidney function as determined by creatinine clearance, no changes in the pharmacokinetics of midazolam or 1-hydroxy-midazolam were observed when compared to healthy individuals.

Renal Impairment

Patients with renal impairment may have longer elimination half-lives for midazolam and its metabolites which may result in slower recovery.

Midazolam and 1-hydroxy-midazolam pharmacokinetics in 6 ICU patients who developed acute renal failure (ARF) were compared with a normal renal function control group. Midazolam was administered as an infusion (5 to 15 mg/hours). Midazolam clearance was reduced (1.9 vs 2.8 mL/min/kg) and the half-life was prolonged (7.6 vs 13 hours) in the ARF patients. The renal clearance of the 1-hydroxy-midazolam glucuronide was prolonged in the ARF group (4 vs 136 mL/min) and the half-life was prolonged (12 vs >25 hours). Plasma levels accumulated in all ARF patients to about ten times that of the parent drug. The relationship between accumulating metabolite levels and prolonged sedation is unclear.

In a study of chronic renal failure patients (n=15) receiving a single intravenous dose, there was a two-fold increase in the clearance and volume of distribution but the half-life remained unchanged. Metabolite levels were not studied.

Carcinogenesis

Midazolam maleate was administered with diet in mice and rats for 2 years at dosages of 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. Dosages of 9 mg/kg/day of midazolam maleate (4 times a human induction dose of 0.35 mg/kg based on body surface area comparison) do not increase the incidence of tumors. 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.

Mutagenesis

Midazolam did not have mutagenic activity in Salmonella typhimurium (5 bacterial strains), Chinese hamster lung cells (V79), human lymphocytes or in the micronucleus test in mice.

Impairment of Fertility

Male rats were treated orally with 1, 4, or 16 mg/kg midazolam beginning 62 days prior to mating with female rats treated with the same doses for 14 days prior to mating to Gestation Day 13 or Lactation Day 21. The high dose produced an equivalent exposure (AUC) as 4 mg/kg intravenous midazolam (1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparison). There were no adverse effects on either male or female fertility noted.

Published studies in animals demonstrate that the use of anesthetic agents during the period of rapid brain growth or synaptogenesis results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of an anesthetic regimen that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and health care providers should balance the benefits of appropriate anesthesia in neonates and young children who require procedures against the potential risks suggested by the nonclinical data [Warnings and Precautions (5.8)].

Midazolam in Sodium Chloride Injection is a clear, colorless solution supplied in single-dose bags with an aluminum overwrap available as:

{ "type": "p", "children": [], "text": "Midazolam in Sodium Chloride Injection is a clear, colorless solution supplied in single-dose bags with an aluminum overwrap available as:" }

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0"> <col width="175.25pt"/> <col width="1.25in"/> <col width="130.5pt"/> <col width="135pt"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Total Strength per Total Volume</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Strength per mL</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">10 single-dose bags NDC</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Bag and Overwrap NDC</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">50 mg per 50 mL</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1 mg/mL</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0143-9379-10</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0143-9379-01</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">100 mg per 100 mL</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1 mg/mL</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0143-9380-10</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0143-9380-01</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table border=\"0\" cellpadding=\"0\" cellspacing=\"0\">\n<col width=\"175.25pt\"/>\n<col width=\"1.25in\"/>\n<col width=\"130.5pt\"/>\n<col width=\"135pt\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Total Strength per Total Volume</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Strength per mL</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">10 single-dose bags NDC</span>\n</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">\n<span class=\"Bold\">Bag and Overwrap NDC</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">50 mg per 50 mL</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">1 mg/mL</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">0143-9379-10</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">0143-9379-01</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">100 mg per 100 mL</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">1 mg/mL</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">0143-9380-10</p>\n</td><td class=\"Botrule Lrule Rrule Toprule\">\n<p class=\"First\">0143-9380-01</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Protect from Freezing. Individual containers may be used up to 48 hours after initial penetration. Discard unused portion.

{ "type": "p", "children": [], "text": "Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Protect from Freezing. Individual containers may be used up to 48 hours after initial penetration. Discard unused portion." }

Alcohol and Current Medication

{ "type": "p", "children": [], "text": "\nAlcohol and Current Medication\n" }

Advise patients to notify their healthcare provider about alcohol or medication use, especially blood pressure medication and antibiotics. Alcohol and other CNS depressants, such as opioid analgesic and benzodiazepines, can have an additive effect when administered with midazolam in sodium chloride injection [see Warnings and Precautions (5.2), Drug Interactions (7.1)].

{ "type": "p", "children": [], "text": "Advise patients to notify their healthcare provider about alcohol or medication use, especially blood pressure medication and antibiotics. Alcohol and other CNS depressants, such as opioid analgesic and benzodiazepines, can have an additive effect when administered with midazolam in sodium chloride injection [see Warnings and Precautions (5.2), Drug Interactions (7.1)]." }

Effect of Anesthetic and Sedation Drugs on Early Brain Development

{ "type": "p", "children": [], "text": "\nEffect of Anesthetic and Sedation Drugs on Early Brain Development\n" }

Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)]." }

Pregnancy

{ "type": "p", "children": [], "text": "\nPregnancy\n" }

Advise pregnant females exposed to midazolam late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns. Instruct patients to inform their healthcare provider if they are pregnant during treatment with midazolam in sodium chloride injection [see Warnings and Precautions (5.10), Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Advise pregnant females exposed to midazolam late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns. Instruct patients to inform their healthcare provider if they are pregnant during treatment with midazolam in sodium chloride injection [see Warnings and Precautions (5.10), Use in Specific Populations (8.1)]." }

Lactation

{ "type": "p", "children": [], "text": "\nLactation\n" }

Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients receiving midazolam to monitor infants for excessive sedation, poor feeding, and poor weight gain, and to seek medical attention if they notice these signs. A lactating woman may consider pumping and discarding breastmilk for at least 4 to 8 hours after receiving midazolam for sedation or anesthesia to minimize drug exposure to a breastfed infant [see Use in Specific Populations (8.2)].

{ "type": "p", "children": [], "text": "Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients receiving midazolam to monitor infants for excessive sedation, poor feeding, and poor weight gain, and to seek medical attention if they notice these signs. A lactating woman may consider pumping and discarding breastmilk for at least 4 to 8 hours after receiving midazolam for sedation or anesthesia to minimize drug exposure to a breastfed infant [see Use in Specific Populations (8.2)]." }

Residual Sedation and Amnesia

{ "type": "p", "children": [], "text": "\nResidual Sedation and Amnesia\n" }

Advise patients that they may experience residual sedation and amnesia. The decision as to when patients who have received injectable midazolam, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery, or drive a motor vehicle must be individualized [see Warnings and Precautions (5.8)].

{ "type": "p", "children": [], "text": "Advise patients that they may experience residual sedation and amnesia. The decision as to when patients who have received injectable midazolam, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery, or drive a motor vehicle must be individualized [see Warnings and Precautions (5.8)]." }

Withdrawal

{ "type": "p", "children": [], "text": "\nWithdrawal\n" }

Advise patients that receive midazolam in a critical care setting over an extended period of time that they may experience symptoms of withdrawal following abrupt discontinuation.

{ "type": "p", "children": [], "text": "Advise patients that receive midazolam in a critical care setting over an extended period of time that they may experience symptoms of withdrawal following abrupt discontinuation." }

Discard unused portion.

{ "type": "p", "children": [], "text": "Discard unused portion." }

Manufactured by

{ "type": "p", "children": [], "text": "\nManufactured by\n" }

HIKMA FARMACÊUTICA (PORTUGAL), S.A.

{ "type": "p", "children": [], "text": "HIKMA FARMACÊUTICA (PORTUGAL), S.A." }

Estrada do Rio da Mó, 8, 8A e 8B – Fervença – 2705-906 Terrugem SNT, PORTUGAL

{ "type": "p", "children": [], "text": "Estrada do Rio da Mó, 8, 8A e 8B – Fervença – 2705-906 Terrugem SNT, PORTUGAL" }

Distributed by

{ "type": "p", "children": [], "text": "\nDistributed by\n" }

Hikma Pharmaceuticals USA Inc.

{ "type": "p", "children": [], "text": "Hikma Pharmaceuticals USA Inc. " }

Berkeley Heights, NJ 07922

{ "type": "p", "children": [], "text": "Berkeley Heights, NJ 07922 " }

Revised January 2023

{ "type": "p", "children": [], "text": "Revised January 2023" }

PIN517-WES/1

{ "type": "p", "children": [], "text": "PIN517-WES/1" }

High Alert Medication

{ "type": "p", "children": [], "text": "High Alert Medication" }

NDC 0143-9379-01 Rx only

{ "type": "p", "children": [], "text": "NDC 0143-9379-01 Rx only" }

Midazolam in 0.9% Sodium Chloride Injection CIV

{ "type": "p", "children": [], "text": "\nMidazolam in 0.9% Sodium Chloride Injection CIV\n" }

50 mg per 50 mL (1 mg/mL)

{ "type": "p", "children": [], "text": "\n50 mg per 50 mL (1 mg/mL)\n" }

For Intravenous Use ONLY  - Do Not Dilute

{ "type": "p", "children": [], "text": "\nFor Intravenous Use ONLY  - Do Not Dilute\n" }

High Alert Medication

{ "type": "p", "children": [], "text": "High Alert Medication" }

NDC 0143-9380-01 Rx only

{ "type": "p", "children": [], "text": "NDC 0143-9380-01 Rx only" }

Midazolam in 0.9% Sodium Chloride Injection CIV

{ "type": "p", "children": [], "text": "\nMidazolam in 0.9% Sodium Chloride Injection CIV\n" }

100 mg per 100 mL (1 mg/mL)

{ "type": "p", "children": [], "text": "\n100 mg per 100 mL (1 mg/mL)\n" }

For Intravenous Use ONLY - Do Not Dilute

{ "type": "p", "children": [], "text": "For Intravenous Use ONLY - Do Not Dilute" }

Representative Serialization Image

{ "type": "p", "children": [], "text": "Representative Serialization Image" }

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.

{ "type": "p", "children": [], "text": "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." }

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 (5.4)].

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.

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.

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 (5.4)].

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)].

NAYZILAM is supplied as a single-dose nasal spray unit containing 5 mg of midazolam in 0.1 mL solution.

{ "type": "p", "children": [], "text": "NAYZILAM is supplied as a single-dose nasal spray unit containing 5 mg of midazolam in 0.1 mL solution." }

NAYZILAM is contraindicated in patients with:

{ "type": "p", "children": [], "text": "NAYZILAM is contraindicated in patients with:" }

{ "type": "ul", "children": [ " Known hypersensitivity to midazolam.", " Acute narrow-angle glaucoma [see Warnings and Precautions (5.8)].\n" ], "text": "" }

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 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)].

The use of benzodiazepines, including NAYZILAM, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death [see Drug Abuse and Dependence (9.2)].

Before prescribing NAYZILAM and throughout treatment, assess each patient's risk for abuse, misuse, and addiction. Use of NAYZILAM, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of NAYZILAM along with monitoring for signs and symptoms of abuse, misuse, and addiction. Do not exceed the recommended dosing frequency; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

For patients using NAYZILAM more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue NAYZILAM (a patient-specific plan should be used to taper the dose). Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.

Acute Withdrawal Reactions

The continued use of benzodiazepines may lead to clinically significant physical dependence. Although NAYZILAM is indicated only for intermittent use [see Indications and Usage (1) and Dosage and Administration (2)], if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of NAYZILAM, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) [see Drug Abuse and Dependence (9.3)].

Protracted Withdrawal Syndrome

In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Drug Abuse and Dependence (9.3)].

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 (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.

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)].

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.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 1. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis</span> </caption> <col align="left" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> <thead> <tr class="Botrule First Last"> <th align="left" class="Lrule Rrule">Indication</th><th align="center" class="Rrule">Placebo Patients with Events/1000 Patients</th><th align="center" class="Rrule">Drug Patients with Events per 1000 Patients</th><th align="center" class="Rrule">Relative Risk: Incidence of Drug Events in Drug Patients /Incidence in Placebo Patients</th><th align="center" class="Rrule">Risk Difference: Additional Drug Patients with Events per 1000 Patients</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Epilepsy</td><td align="center" class="Rrule">1.0</td><td align="center" class="Rrule">3.4</td><td align="center" class="Rrule">3.5</td><td align="center" class="Rrule">2.4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Psychiatric</td><td align="center" class="Rrule">5.7</td><td align="center" class="Rrule">8.5</td><td align="center" class="Rrule">1.5</td><td align="center" class="Rrule">2.9</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Other</td><td align="center" class="Rrule">1.0</td><td align="center" class="Rrule">1.8</td><td align="center" class="Rrule">1.9</td><td align="center" class="Rrule">0.9</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Total</td><td align="center" class="Rrule">2.4</td><td align="center" class="Rrule">4.3</td><td align="center" class="Rrule">1.8</td><td align="center" class="Rrule">1.9</td> </tr> </tbody> </table></div>

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.

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.

Use of NAYZILAM late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate [see Use in Specific Populations (8.1)]. Monitor neonates exposed to NAYZILAM during pregnancy or labor for signs of sedation and monitor neonates exposed to NAYZILAM during pregnancy for signs of withdrawal; manage these neonates accordingly.

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.

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.

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.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 2: Adverse Reactions<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> that Occurred in ≥2% of Patients (Any NAYZILAM) and Greater than Placebo in the Comparative Phase of Study 1</span> </caption> <col align="left" valign="bottom" width="20%"/> <col align="center" valign="bottom" width="12%"/> <col align="center" valign="bottom" width="17%"/> <col align="center" valign="bottom" width="17%"/> <col align="center" valign="bottom" width="17%"/> <col align="center" valign="bottom" width="17%"/> <thead> <tr class="Botrule First"> <th align="left" class="Lrule Rrule" rowspan="2">Body System/Adverse Reaction </th><th align="center" class="Rrule" rowspan="2">Placebo</th><th align="center" class="Rrule" colspan="4">NAYZILAM<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a></th> </tr> <tr class="Botrule"> <th align="center" class="Rrule"> NAYZILAM<br/>5 mg </th><th align="center" class="Rrule"> Placebo + NAYZILAM<br/>5 mg </th><th align="center" class="Rrule"> NAYZILAM<br/>5 mg + 5 mg </th><th align="center" class="Rrule"> Any NAYZILAM Treatment Group </th> </tr> <tr class="Botrule Last"> <th align="left" class="Lrule Rrule"></th><th align="center" class="Rrule">N = 26<br/>%</th><th align="center" class="Rrule">N = 91<br/>%</th><th align="center" class="Rrule">N = 41<br/>%</th><th align="center" class="Rrule">N = 43<br/>%</th><th align="center" class="Rrule">N = 175<br/>%</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="6"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Adverse reactions that occurred within 2 days after NAYZILAM administration are included</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>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. </dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="Bold">Nervous System </span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Somnolence</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">10</td><td align="center" class="Rrule">10</td><td align="center" class="Rrule">9</td><td align="center" class="Rrule">10</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Headache</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Dysarthria</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Application Site </span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Nasal Discomfort</td><td align="center" class="Rrule">8</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">16</td><td align="center" class="Rrule">9</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Throat Irritation</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Rhinorrhea</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">  Product Taste Abnormal</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="Bold">Eye Disorders</span></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">  Lacrimation Increased</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">2</td> </tr> </tbody> </table></div>

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.

<div class="scrollingtable"><table width="80%"> <caption> <span>Table 3: Clinically Significant Drug Interactions With NAYZILAM</span> </caption> <col align="right" valign="top" width="30%"/> <col align="left" valign="top" width="70%"/> <tbody class="Headless"> <tr class="Botrule First"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold"><a name="S7.1"></a>7.1 CYP3A4 Inhibitors</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Rrule">Concomitant use of CYP3A4 inhibitors may result in prolonged sedation because of a decrease in plasma clearance of midazolam.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Intervention:</span></td><td align="left" class="Rrule">Avoid co-administration of NAYZILAM with moderate or strong CYP3A4 inhibitors. NAYZILAM should be used with caution when co-administered with mild CYP3A4 inhibitors.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Examples:</span></td><td align="left" class="Rrule">Moderate CYP3A4 inhibitors: erythromycin, diltiazem, verapamil<br/>Strong CYP3A4 inhibitors: ketoconazole, itraconazole, clarithromycin</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold"><a name="S7.2"></a>7.2 Opioids</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Rrule">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 GABA<span class="Sub">A </span>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.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Intervention:</span></td><td align="left" class="Rrule">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 <span class="Italics">[see <a href="#S5.1">Warnings and Precautions (5.1)</a>].</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Examples:</span></td><td align="left" class="Rrule">Morphine, hydrocodone, oxymorphone, codeine, fentanyl</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="2"><span class="Bold"><a name="S7.3"></a>7.3 Other Central Nervous System (CNS) Depressants</span></td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Clinical Impact:</span></td><td align="left" class="Rrule">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.</td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule"><span class="Italics">Intervention:</span></td><td align="left" class="Rrule">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 <span class="Italics">[see <a href="#S5.5">Warnings and Precautions (5.5)</a>]</span>.</td> </tr> <tr class="Last"> <td align="right" class="Lrule Rrule"><span class="Italics">Examples:</span></td><td align="left" class="Rrule">Other benzodiazepines and sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, opioids, alcohol.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"80%\">\n<caption>\n<span>Table 3: Clinically Significant Drug Interactions With NAYZILAM</span>\n</caption>\n<col align=\"right\" valign=\"top\" width=\"30%\"/>\n<col align=\"left\" valign=\"top\" width=\"70%\"/>\n<tbody class=\"Headless\">\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\"><a name=\"S7.1\"></a>7.1 CYP3A4 Inhibitors</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Rrule\">Concomitant use of CYP3A4 inhibitors may result in prolonged sedation because of a decrease in plasma clearance of midazolam.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Rrule\">Avoid co-administration of NAYZILAM with moderate or strong CYP3A4 inhibitors. NAYZILAM should be used with caution when co-administered with mild CYP3A4 inhibitors.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Rrule\">Moderate CYP3A4 inhibitors: erythromycin, diltiazem, verapamil<br/>Strong CYP3A4 inhibitors: ketoconazole, itraconazole, clarithromycin</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\"><a name=\"S7.2\"></a>7.2 Opioids</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Rrule\">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 GABA<span class=\"Sub\">A </span>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.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Rrule\">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 <span class=\"Italics\">[see <a href=\"#S5.1\">Warnings and Precautions (5.1)</a>].</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Rrule\">Morphine, hydrocodone, oxymorphone, codeine, fentanyl</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"2\"><span class=\"Bold\"><a name=\"S7.3\"></a>7.3 Other Central Nervous System (CNS) Depressants</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Clinical Impact:</span></td><td align=\"left\" class=\"Rrule\">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.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Intervention:</span></td><td align=\"left\" class=\"Rrule\">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 <span class=\"Italics\">[see <a href=\"#S5.5\">Warnings and Precautions (5.5)</a>]</span>.</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"right\" class=\"Lrule Rrule\"><span class=\"Italics\">Examples:</span></td><td align=\"left\" class=\"Rrule\">Other benzodiazepines and sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, opioids, alcohol.</td>\n</tr>\n</tbody>\n</table></div>" }

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. Healthcare providers are encouraged to recommend that pregnant women who are taking NAYZILAM during pregnancy enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.

Risk Summary

Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.9) and Clinical Considerations]. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see 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.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to NAYZILAM during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to NAYZILAM during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.9)].

Data

Human Data

Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

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.

Risk Summary

Midazolam is excreted in human milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. There are no data on the effects of midazolam on milk production.

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 NAYZILAM or from the underlying maternal condition.

Clinical Considerations

Infants exposed to NAYZILAM through breast milk should be monitored for sedation, poor feeding and poor weight gain.

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 (14)] and pharmacokinetic and safety data from adult and pediatric patients [see Clinical Pharmacology (12.3)].

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 (12.3)]. 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 (5.4)]. In most of these cases, the patients also received other CNS depressants capable of depressing respiration, especially narcotics [see Warnings and Precautions (5.1, 5.5)]. 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 (12.3)].

Patients with congestive heart failure eliminate midazolam more slowly, which may result in prolonged drug exposure [see Clinical Pharmacology (12.3)].

NAYZILAM contains midazolam, a Schedule IV controlled substance.

NAYZILAM is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction.

Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2)].

The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.

The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

Midazolam was actively self-administered in primate models used to assess the positive reinforcing effects of psychoactive drugs. Midazolam produced physical dependence of a mild to moderate intensity in cynomolgus monkeys after 5 to 10 weeks of administration.

Assessment of the abuse-related subjective effects comparing NAYZILAM to oral midazolam syrup was conducted in adult subjects with a history of benzodiazepine recreational drug use. No statistically significant or clinically-relevant differences in subjective positive effects (i.e., Drug Liking, Overall Drug Liking, Take Drug Again, and High) were observed between NAYZILAM and oral midazolam syrup. However, subjective positive effects on all these measures were significantly greater for NAYZILAM than for placebo confirming that NAYZILAM has abuse potential. Somnolence occurred at a similar rate in both midazolam groups, but euphoric mood occurred at a greater rate in NAYZILAM (4 to 16%) compared to the oral midazolam syrup (4 to 8.5%).

Physical Dependence After Use of NAYZILAM More Frequently Than Recommended

NAYZILAM may produce physical dependence if used more frequently than recommended. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Although NAYZILAM is indicated only for intermittent use [see Indications and Usage (1) and Dosage and Administration (2)], if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3)]. For patients using NAYZILAM more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue NAYZILAM [see Warnings and Precautions (5.3)].

Acute Withdrawal Signs and Symptoms

Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality.

Protracted Withdrawal Syndrome

Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.

Tolerance

Tolerance to NAYZILAM may develop after use more frequently than recommended. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Tolerance to the therapeutic effect of benzodiazepines may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

NAYZILAM is not recommended for chronic, daily use as an anticonvulsant because of the potential for development of tolerance to midazolam. In clinical trials, patients were treated with NAYZILAM no more frequently than every 3 days.

Chronic daily use of benzodiazepines may increase the frequency and/or severity of tonic-clonic seizures, requiring an increase in the dosage of standard anticonvulsant medication. In such cases, abrupt withdrawal of chronic benzodiazepines may also be associated with a temporary increase in the frequency and/or severity of seizures.

Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions (5.2)]. Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.

{ "type": "p", "children": [], "text": "Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions (5.2)]. Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage." }

In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway maintenance. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information.

{ "type": "p", "children": [], "text": "In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway maintenance. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information." }

Consider contacting the Poison Help line (1-800-222-1222) or medical toxicologist for additional overdosage management recommendations.

{ "type": "p", "children": [], "text": "Consider contacting the Poison Help line (1-800-222-1222) or medical toxicologist for additional overdosage management recommendations." }

NAYZILAM contains midazolam, a compound of the benzodiazepine class. Midazolam is chemically designated as 8-Chloro-6-(ο-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine, and it has the following structure:

{ "type": "p", "children": [], "text": "NAYZILAM contains midazolam, a compound of the benzodiazepine class. Midazolam is chemically designated as 8-Chloro-6-(ο-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine, and it has the following structure:" }

The empirical formula is C18H13ClFN3 representing a molecular weight of 325.8. Midazolam, USP is a white or yellowish, crystalline powder that is practically insoluble in water, soluble in methanol, and freely soluble in acetone and in alcohol.

{ "type": "p", "children": [], "text": "The empirical formula is C18H13ClFN3 representing a molecular weight of 325.8. Midazolam, USP is a white or yellowish, crystalline powder that is practically insoluble in water, soluble in methanol, and freely soluble in acetone and in alcohol." }

NAYZILAM nasal spray is a clear, colorless to yellowish colored liquid. Each single-dose NAYZILAM unit is for nasal administration and delivers 5 mg of midazolam in 0.1 mL of solution containing ethanol; PEG-6 methyl ether; polyethylene glycol 400; propylene glycol; and purified water.

{ "type": "p", "children": [], "text": "NAYZILAM nasal spray is a clear, colorless to yellowish colored liquid. Each single-dose NAYZILAM unit is for nasal administration and delivers 5 mg of midazolam in 0.1 mL of solution containing ethanol; PEG-6 methyl ether; polyethylene glycol 400; propylene glycol; and purified water." }

The pH range of solution is approximately 5.0 to 9.0.

{ "type": "p", "children": [], "text": "The pH range of solution is approximately 5.0 to 9.0." }

The exact mechanism of action for midazolam is not fully understood, but it is thought to involve potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABAA receptor.

The pharmacodynamic properties of midazolam and its metabolites, are similar to those of other benzodiazepines, including sedative, anxiolytic, amnestic, and hypnotic activities. The effects of midazolam on the CNS are dependent on the dose administered, the route of administration, and the presence or absence of other medications.

Treatment with NAYZILAM was associated with effects on measures of sedation and measures of psychomotor performance [see Warnings and Precautions (5.5)]. Sedation and psychomotor impairment effects generally began to occur within 10 minutes post dose with peak effects observed within 30 minutes to 2 hours post dose. The pharmacodynamic effects generally returned to near baseline levels by 4 hours post-dose.

Pharmacokinetics

Based on a population pharmacokinetic analysis, plasma exposures (Cmax and AUC) of midazolam in epilepsy patients increase approximately proportional to dose from 5.0 mg to 15 mg, 0.5 and 1.5 times the recommended maximum total dose (5 mg Initial Dose + 5 mg Second Dose), respectively.

Absorption

Following nasal administration of a single 5 mg midazolam dose to healthy adults, midazolam was absorbed with median Tmax (range) of 17.3 (7.8 to 28.2) minutes; midazolam mean (±SD) Cmax and AUC0-∞ were 54.7 (±30.4) ng/mL and 126.2 (±59) ng∙hr/mL, respectively. The mean absolute bioavailability is approximately 44%.

Distribution

In adults and pediatric patients, midazolam is approximately 97% bound to plasma protein, principally albumin. In healthy volunteers, 1-hydroxy midazolam is bound to the extent of 89%.

The estimated total volume of distribution of midazolam is 226.5 L.

In humans, midazolam has been shown to cross the placenta and enter into fetal circulation and has been detected in human milk and CSF [see Use in Specific Populations (8.1, 8.2)].

Elimination

Following administration of NAYZILAM in clinical trials, median midazolam and 1-hydroxy-midazolam elimination half-lives ranged from 2.1 to 6.2 hours and 2.7 to 7.2 hours, respectively, independent of dose.

Metabolism

Midazolam is primarily metabolized by liver and intestinal cytochrome P450 3A4 (CYP3A4) to its pharmacologic active metabolite, 1-hydroxy midazolam (also termed α-hydroxy-midazolam). Midazolam is also metabolized to two other minor metabolites: 4-hydroxy metabolite and 1,4-dihydroxy metabolite. The principal urinary excretion products are glucuronide conjugates of the hydroxylated derivatives.

Studies of the intravenous administration of 1-hydroxy-midazolam in humans suggest that 1-hydroxy-midazolam is at least as potent as the parent compound and may contribute to the net pharmacologic activity of midazolam.

Excretion

The principal urinary excretion product is 1-OH midazolam in the form of a glucuronide conjugate. Smaller amounts of the glucuronide conjugates of 4-hydroxy- and dihydroxy-midazolam are detected as well.

Specific Populations

Geriatric Patients

In a parallel group study of 2.5 mg and 5 mg doses of NAYZILAM, mean systemic exposure (AUC) and peak plasma concentrations (Cmax) of midazolam were 21 to 45% higher in geriatric subjects (> 65 years old) as compared to non-geriatric subjects. The terminal half-life was increased by approximately 2 hours in the geriatric subjects because of a decrease in clearance [see Use in Specific Populations (8.5)].

Obesity

In a study comparing normal (n=20) and obese patients (n=20), the mean half-life of midazolam administered by parental route was greater in the obese group (5.9 versus 2.3 hours). This was because of an increase of approximately 50% in the volume of distribution (Vd) corrected for total body weight. The clearance was not significantly different between groups.

Patients with Renal Impairment

Patients with renal impairment may have longer elimination half-lives for midazolam and its metabolites [see Use in Specific Populations (8.6)].

Midazolam and 1-hydroxy-midazolam pharmacokinetics in 6 ICU patients who developed acute renal failure (ARF) were compared with a normal renal function control group. Midazolam was administered as an infusion (5 to 15 mg/hr). Midazolam clearance was reduced (1.9 vs 2.8 mL/min/kg) and the half-life was prolonged (7.6 vs 13 hours) in the ARF patients. The renal clearance of the 1-hydroxy-midazolam glucuronide was prolonged in the ARF group (4 vs 136 mL/min) and the half-life was prolonged (12 vs >25 hours). Plasma levels accumulated in all ARF patients to about ten times that of the parent drug. The relationship between accumulating metabolite levels and prolonged sedation is unclear.

In a study of chronic renal failure patients (n=15) receiving a single intravenous dose of midazolam, there was a 2-fold increase in the clearance and volume of distribution, but the half-life remained unchanged.

Patients with Hepatic Impairment

Midazolam pharmacokinetics were studied after an intravenous single dose (0.075 mg/kg) was administered to patients with biopsy proven alcoholic cirrhosis (n=7) and control patients (n=8). The mean half-life of midazolam increased 2.5-fold in the patients with cirrhosis. Clearance was reduced by 50% and the Vd increased by 20%. In another study in male patients with cirrhosis (n=21) without ascites and with normal kidney function as determined by creatinine clearance, no changes in the pharmacokinetics of midazolam or 1-hydroxy-midazolam were observed when compared to healthy individuals. The clinical significance of these findings is unknown.

Patients with Congestive Heart Failure

In patients suffering from congestive heart failure, a 2-fold increase in the elimination half-life, a 25% decrease in the plasma clearance, and a 40% increase in the volume of distribution of midazolam were observed.

Drug Interaction Studies

Since NAYZILAM is metabolized by CYP3A4, interactions with drugs that inhibit or induce CYP3A4 are likely.

Inhibitors of CYP3A4 Isozymes

Coadministration of CYP3A4 inhibitors with NAYZILAM has not been studied. However, the effects of inhibitors on midazolam exposure following NAYZILAM administration are expected to be similar to those following IV midazolam administration. Concomitant use of CYP3A4 inhibitors may result in prolonged sedation because of a decrease in plasma clearance of midazolam [Warnings and Precautions (5.5) and Drug Interactions (7.1)].

Inducers of CYP3A4 Isozymes

Exposures (e.g., combined Cmax or AUC of midazolam and the 1-OH-midazolam active metabolite) are decreased 16 to 26% when NAYZILAM is co-administered with anti-epileptic drugs that are strong CYP3A4 inducers (e.g., phenytoin, phenobarbital, primidone, carbamazepine). Exposures (e.g., combined Cmax or AUC of midazolam and the 1-OH-midazolam active metabolite) are decreased 8 to 15% when NAYZILAM is co-administered with anti-epileptic drugs that are weak to moderate CYP3A4 inducers (e.g., clobazam, eslicarbazepine, felbamate, oxcarbazepine, rufinamide, topiramate). These changes in exposures are not expected to be clinically significant.

Carcinogenesis

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.

Mutagenesis

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.

The effectiveness of NAYZILAM 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 was established in a randomized, double-blind, placebo-controlled trial (Study 1; NCT 01390220).

{ "type": "p", "children": [], "text": "The effectiveness of NAYZILAM 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 was established in a randomized, double-blind, placebo-controlled trial (Study 1; NCT 01390220)." }

Study 1 enrolled patients with epilepsy on a stable regimen of antiepileptic drugs who were identified by their physicians as having intermittent, stereotypic episodes of frequent seizure activity that were distinct from the patient's usual seizure pattern.

{ "type": "p", "children": [], "text": "Study 1 enrolled patients with epilepsy on a stable regimen of antiepileptic drugs who were identified by their physicians as having intermittent, stereotypic episodes of frequent seizure activity that were distinct from the patient's usual seizure pattern." }

Study 1 was conducted in two phases: an open-label Test Dose Phase followed by a randomized, double-blind, placebo-controlled, Comparative Phase. In the Test Dose Phase, tolerability was assessed in 292 patients who, in the absence of a seizure, received two 5 mg doses of NAYZILAM (10 mg total dosage) separated by 10 minutes. Patients were excluded from participation in the Comparative Phase if they failed to meet pre-defined blood pressure, heart rate, sedation, electrocardiogram, and peripheral oxygen saturation criteria.

{ "type": "p", "children": [], "text": "Study 1 was conducted in two phases: an open-label Test Dose Phase followed by a randomized, double-blind, placebo-controlled, Comparative Phase. In the Test Dose Phase, tolerability was assessed in 292 patients who, in the absence of a seizure, received two 5 mg doses of NAYZILAM (10 mg total dosage) separated by 10 minutes. Patients were excluded from participation in the Comparative Phase if they failed to meet pre-defined blood pressure, heart rate, sedation, electrocardiogram, and peripheral oxygen saturation criteria." }

In the Comparative Phase, 201 patients treated a single seizure cluster episode in an outpatient setting with either a blinded dose of NAYZILAM 5 mg (134 patients) or placebo (67 patients). If the seizure activity persisted or recurred, patients in both groups had the option to receive a subsequent unblinded dose of NAYZILAM 5 mg to be used between 10 minutes and 6 hours after administration of the initial blinded dose of study drug.

{ "type": "p", "children": [], "text": "In the Comparative Phase, 201 patients treated a single seizure cluster episode in an outpatient setting with either a blinded dose of NAYZILAM 5 mg (134 patients) or placebo (67 patients). If the seizure activity persisted or recurred, patients in both groups had the option to receive a subsequent unblinded dose of NAYZILAM 5 mg to be used between 10 minutes and 6 hours after administration of the initial blinded dose of study drug." }

The primary efficacy endpoint for Study 1 was treatment success, defined as the termination of seizures within 10 minutes after the initial blinded dose of study drug and the absence of a recurrence of seizures within 6 hours of the initial blinded dose of study drug. A statistically significantly higher percentage of NAYZILAM-treated patients met the primary efficacy endpoint, as shown in Table 4.

{ "type": "p", "children": [], "text": "The primary efficacy endpoint for Study 1 was treatment success, defined as the termination of seizures within 10 minutes after the initial blinded dose of study drug and the absence of a recurrence of seizures within 6 hours of the initial blinded dose of study drug. A statistically significantly higher percentage of NAYZILAM-treated patients met the primary efficacy endpoint, as shown in Table 4." }

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 4: Primary Endpoint Results: Treatment Success (Study 1) </span> </caption> <col align="left" valign="top" width="50%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"> <br/> </th><th align="center" class="Rrule">NAYZILAM <br/>(N=134)</th><th align="center" class="Rrule">Placebo<br/>(N=67)</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Treatment success (%)</td><td align="center" class="Rrule">53.7</td><td align="center" class="Rrule">34.3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">95% CI</td><td align="center" class="Rrule">(45.3, 62.2)</td><td align="center" class="Rrule">(23.0, 45.7)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">p-value</td><td align="center" class="Rrule" colspan="2">0.011</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"75%\">\n<caption>\n<span>Table 4: Primary Endpoint Results: Treatment Success (Study 1) </span>\n</caption>\n<col align=\"left\" valign=\"top\" width=\"50%\"/>\n<col align=\"center\" valign=\"top\" width=\"25%\"/>\n<col align=\"center\" valign=\"top\" width=\"25%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"left\" class=\"Lrule Rrule\">\n<br/>\n</th><th align=\"center\" class=\"Rrule\">NAYZILAM <br/>(N=134)</th><th align=\"center\" class=\"Rrule\">Placebo<br/>(N=67)</th>\n</tr>\n</thead>\n<tbody>\n<tr class=\"Botrule First\">\n<td align=\"left\" class=\"Lrule Rrule\">Treatment success (%)</td><td align=\"center\" class=\"Rrule\">53.7</td><td align=\"center\" class=\"Rrule\">34.3</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\">95% CI</td><td align=\"center\" class=\"Rrule\">(45.3, 62.2)</td><td align=\"center\" class=\"Rrule\">(23.0, 45.7)</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\">p-value</td><td align=\"center\" class=\"Rrule\" colspan=\"2\">0.011</td>\n</tr>\n</tbody>\n</table></div>" }

Numerical differences in favor of NAYZILAM were observed on each of the components of the treatment success responder definition; termination of seizure(s) within 10 minutes after initial dose of study drug (80.6 versus 70.1%) and the absence of seizure recurrence between 10 minutes and 6 hours after the initial dose of study drug (58.2 versus 37.3%).

{ "type": "p", "children": [], "text": "Numerical differences in favor of NAYZILAM were observed on each of the components of the treatment success responder definition; termination of seizure(s) within 10 minutes after initial dose of study drug (80.6 versus 70.1%) and the absence of seizure recurrence between 10 minutes and 6 hours after the initial dose of study drug (58.2 versus 37.3%). " }

Study 1 also evaluated the occurrence and time to next seizure after the initial blinded dose of study drug. A smaller proportion of NAYZILAM-treated patients experienced the next seizure within 24 hours after the initial blinded dose of study drug (37.3% versus 46.3%). NAYZILAM-treated patients experienced a statistically longer time-to-next-seizure than the placebo group (Figure 1).

{ "type": "p", "children": [], "text": "Study 1 also evaluated the occurrence and time to next seizure after the initial blinded dose of study drug. A smaller proportion of NAYZILAM-treated patients experienced the next seizure within 24 hours after the initial blinded dose of study drug (37.3% versus 46.3%). NAYZILAM-treated patients experienced a statistically longer time-to-next-seizure than the placebo group (Figure 1). " }

FIGURE 1: Kaplan-Meier Analysis of Time-to-Next-Seizure (Study 1)

{ "type": "p", "children": [], "text": "FIGURE 1: Kaplan-Meier Analysis of Time-to-Next-Seizure (Study 1)" }

Analysis by gender revealed no substantial differences in treatment response. Informative subgroup analyses by age and race were not possible because of the small percentage of patients less than 18 years of age or 65 years of age or greater, and of non-White patients in the study.

{ "type": "p", "children": [], "text": "Analysis by gender revealed no substantial differences in treatment response. Informative subgroup analyses by age and race were not possible because of the small percentage of patients less than 18 years of age or 65 years of age or greater, and of non-White patients in the study." }

NAYZILAM is supplied as a solution of midazolam. Each single-dose nasal spray unit delivers 5 mg of midazolam in 0.1 mL of solution.

NAYZILAM is supplied in boxes of 2 nasal spray units (NDC 50474-500-15), each contained within an individual blister pack.

Do not open the blister packaging until ready to use. Do not test or prime before use.

Do not use if the nasal spray unit appears damaged.

Store at controlled room temperature 20°C to 25°C (68°F to 77°F). Excursions permitted to 15°C to 30°C (59°F to 86°F).

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 (5.1)].

Abuse, Misuse, and Addiction

Inform patients that use of NAYZILAM more frequently than recommended, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug [see Warnings and Precautions (5.2) and Drug Abuse and Dependence (9.2)].

Withdrawal Reactions

Inform patients that use of NAYZILAM more frequently than recommended may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of NAYZILAM may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.3)].

Risks of Cardiorespiratory Adverse Reactions

Warn patients and caregivers about the risks of respiratory depression, cardiac and respiratory arrest [see Warnings and Precautions (5.4)].

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 (2.1)].

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 (5.5)].

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 (5.6)].

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 (5.7)].

Pregnancy

Advise pregnant females that the use of NAYZILAM late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1)]. Instruct patients to inform their healthcare provider if they are pregnant. 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 (8.1)].

Lactation

Counsel patients that midazolam, the active ingredient in NAYZILAM, is excreted in breast milk. Instruct patients to inform their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients who take NAYZILAM to monitor their infants for excessive sedation, poor feeding and poor weight gain, and to seek medical attention if they notice these signs [see Use in Specific Populations (8.2)].

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 (2.1)].

Advise patients and caregivers on how frequently they can treat successive seizure cluster episodes over time.

Administration Information

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.

Manufactured for: UCB, Inc., Smyrna, GA 30080

{ "type": "p", "children": [], "text": "Manufactured for: UCB, Inc., Smyrna, GA 30080" }

NAYZILAM® is a registered trademark of the UCB Group of Companies. ©2022. All rights reserved.

{ "type": "p", "children": [], "text": "NAYZILAM® is a registered trademark of the UCB Group of Companies. ©2022. All rights reserved. \n" }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="5%"/> <col align="left" valign="top" width="52%"/> <col align="left" valign="top" width="43%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule" colspan="3">MEDICATION GUIDE <br/>NAYZILAM<span class="Sup">®</span> (NAY-zil-am) <br/>(midazolam) nasal spray, CIV</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="2" valign="top">This Medication Guide has been approved by the U.S. Food and Drug Administration</td><td align="right" valign="top">Issued: 1/2023      </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold"><a name="whatis"></a>What is the most important information I should know about NAYZILAM? </span> <ul> <li> <span class="Bold">NAYZILAM is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma, and death.</span> </li> <li>Get emergency medical help right away if any of the following happens:<ul class="Circle"> <li>shallow or slowed breathing</li> <li>breathing stops (which may lead to the heart stopping)</li> <li>excessive sleepiness (sedation)<br/>Do not drive or operate heavy machinery until you know how taking NAYZILAM with opioids may affect you. </li> </ul> </li> <li> <span class="Bold">Risk of abuse, misuse, and addiction.</span> There is a risk of abuse, misuse, and addiction with benzodiazepines, including NAYZILAM, which can lead to overdose and serious side effects including coma and death. <ul class="Circle"> <li> <span class="Bold">Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including midazolam (the active ingredient in NAYZILAM).</span> These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. <span class="Bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of these serious side effects.</span> </li> <li> <span class="Bold">You can develop an addiction even if you use NAYZILAM as prescribed by your healthcare provider.</span> </li> <li> <span class="Bold">Use NAYZILAM exactly as your healthcare provider prescribed. </span> </li> <li> <span class="Bold">Do not share your NAYZILAM with other people</span>. </li> <li> <span class="Bold">Keep NAYZILAM in a safe place and away from children.</span> </li> </ul> </li> <li> <span class="Bold">Physical dependence and withdrawal reactions</span>. Benzodiazepines, including NAYZILAM, can cause physical dependence and withdrawal reactions, especially if you use NAYZILAM daily. NAYZILAM is not intended for daily use.<ul class="Circle"> <li> <span class="Bold">Do not suddenly stop using NAYZILAM without talking to your healthcare provider</span>. Stopping NAYZILAM suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. <span class="Bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of these symptoms.</span> </li> <li> <span class="Bold">Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months</span>, including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.</li> <li>Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. </li> <li> <span class="Bold">Do not use more NAYZILAM than prescribed or use NAYZILAM more often than prescribed.</span> </li> </ul> </li> <li> <span class="Bold">NAYZILAM can make you sleepy or dizzy and can slow your thinking and motor skills.</span> <ul class="Circle"> <li>Do not drive, operate heavy machinery, or do other dangerous activities until you know how NAYZILAM affects you.</li> <li>Do not drink alcohol or take other drugs that may make you sleepy or dizzy while using NAYZILAM without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, NAYZILAM may make your sleepiness or dizziness worse.</li> </ul> </li> <li> <span class="Bold">Like other antiepileptic medicines, NAYZILAM may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:</span> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left"> <ul class="Circle"> <li>thoughts about suicide or dying</li> <li>feeling agitated or restless</li> <li>acting aggressive, being angry, or violent</li> <li>attempts to commit suicide</li> <li>panic attacks</li> <li>acting on dangerous impulses</li> <li>new or worse depression</li> </ul> </td><td align="left" class="Rrule"> <ul class="Circle"> <li>trouble sleeping (insomnia)</li> <li>an extreme increase in activity and talking (mania)</li> <li>new or worse anxiety</li> <li>new or worse irritability</li> <li>other unusual changes in behavior or mood</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">How can I watch for early symptoms of suicidal thoughts or actions?</span> <ul class="Circle"> <li>Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings.</li> <li>Keep all follow-up visits with your healthcare provider as scheduled.</li> </ul>Call your healthcare provider between visits as needed, especially if you are worried about symptoms. <br/>Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">What is NAYZILAM?</span> <ul> <li>NAYZILAM is a prescription medicine used for the short-term treatment of seizure clusters (also known as "acute repetitive seizures") in people 12 years of age and older.</li> <li> <span class="Bold">NAYZILAM is a federally controlled substance (CIV) because it contains midazolam that can be abused or lead to dependence</span>. Keep NAYZILAM in a safe place to prevent misuse and abuse. Selling or giving away NAYZILAM may harm others and is against the law. Tell your healthcare provider if you have ever abused or been dependent on alcohol, prescription drugs, or street drugs.</li> <li>It is not known if NAYZILAM is safe and effective in children under 12 years of age.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold"><a name="donot"></a>Do not use NAYZILAM if you</span>:<ul> <li>are allergic to midazolam.</li> <li>have an eye problem called acute narrow-angle glaucoma.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">Before you use NAYZILAM, tell your healthcare provider about all your medical conditions, including if you</span>:<ul> <li>have a history of depression, mood problems or suicidal thoughts or behavior.</li> <li>have asthma, emphysema, bronchitis, chronic obstructive pulmonary disease, or other breathing problems. </li> <li>have kidney or liver problems.</li> <li>have congestive heart failure.</li> <li>have a history of drug or alcohol abuse.</li> <li>are pregnant or plan to become pregnant. <ul class="Circle"> <li>Taking NAYZILAM late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems).</li> <li>Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with NAYZILAM.</li> <li>If you become pregnant while using NAYZILAM, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. You can register by calling 1-888-233-2334. For more information about the registry, go to http://www.aedpregnancyregistry.org. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.</li> </ul> </li> <li>are breastfeeding or plan to breastfeed. Midazolam passes into your breast milk and may harm your baby.<ul class="Circle"> <li>Breastfeeding during treatment with NAYZILAM may cause your baby to have sleepiness, feeding problems, and decreased weight gain.</li> <li>Talk to your healthcare provider about the best way to feed your baby while you take NAYZILAM.</li> </ul> </li> </ul> <span class="Bold">Tell your healthcare provider about all the medicines you take</span>, including prescription and over-the-counter medicines, vitamins and herbal supplements. Using NAYZILAM with certain other medicines can affect each other, causing side effects. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each time you get a new medicine. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">How should I use NAYZILAM?</span> <ul> <li>Use NAYZILAM in the nose only.</li> <li> <span class="Bold">Use NAYZILAM exactly as your healthcare provider tells you to use it</span> and follow the Instructions for Use that comes with this Medication Guide.</li> <li>Your healthcare provider has prescribed NAYZILAM to treat a type of seizure called a "seizure cluster". </li> <li>If the seizure cluster is continuing <span class="Bold">10 minutes</span> after the first dose of NAYZILAM, a second dose of NAYZILAM <span class="Bold">may be used if you have been told to do so by your healthcare provider</span>.</li> <li>If a second dose of NAYZILAM is used, give the second dose in the other nostril.</li> <li> <span class="Bold">Do not</span> give more than 2 doses of NAYZILAM to treat a seizure cluster.</li> <li> <span class="Bold">If the seizures do not stop</span> after NAYZILAM is used, get emergency medical help right away.</li> <li> <span class="Bold">Do not</span> use NAYZILAM for more than 1 seizure cluster episode every 3 days. <span class="Bold">Do not</span> use NAYZILAM for more than 5 seizure cluster episodes per month.</li> <li>If benzodiazepines are stopped after a person takes them daily, they can cause withdrawal symptoms. Stopping benzodiazepines suddenly can cause seizures that will not stop (status epilepticus), hearing or seeing things that are not there (hallucinations), shaking, nervousness, and stomach and muscle cramps. NAYZILAM is not intended to be used daily.</li> <li>If you use too much NAYZILAM, call your healthcare provider or go to the nearest emergency room right away.</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">What should I avoid while using NAYZILAM?<br/>See "<a href="#whatis">What is the most important information I should know about NAYZILAM?</a>"</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">What are the possible side effects of NAYZILAM? <br/>NAYZILAM may cause serious side effects, including:</span> <ul> <li>See "<span class="Bold"><a href="#whatis">What is the most important information I should know about NAYZILAM?</a></span>"</li> <li> <span class="Bold">Increase in eye pressure in people with acute narrow-angle glaucoma</span>. See "<span class="Bold"><a href="#donot">Do not use NAYZILAM if you:</a></span>"</li> </ul> <span class="Bold">The most common side effects of NAYZILAM include</span>:</td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left"> <ul> <li>sleepiness</li> <li>headache</li> <li>runny nose</li> </ul> </td><td align="left" class="Rrule"> <ul> <li>nasal discomfort</li> <li>throat irritation</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3">These are not all the possible side effects of NAYZILAM. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">How should I store NAYZILAM?</span> <ul> <li>Store NAYZILAM at room temperature between 68°F to 77°F (20°C to 25°C).</li> <li>Keep NAYZILAM in the blister package until ready to use.</li> </ul> <span class="Bold">Keep NAYZILAM and all medicines out of the reach of children.</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">General information about the safe and effective use of NAYZILAM.</span> <br/>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NAYZILAM for a condition for which it was not prescribed. Do not give NAYZILAM to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about NAYZILAM that is written for health professionals.</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="3"><span class="Bold">What are the ingredients in NAYZILAM?</span> <br/> <span class="Bold">Active ingredient</span>: midazolam <br/> <span class="Bold">Inactive ingredients</span>: ethanol, PEG-6 methyl ether, polyethylene glycol 400, propylene glycol and purified water <br/>Manufactured for UCB, Inc., Smyrna, GA 30080.<br/>NAYZILAM<span class="Sup">®</span> is a registered trademark of the UCB Group of Companies.<br/> ©2022. All rights reserved.<br/>For more information, go to www.nayzilam.com or call 1-844-599-2273.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"5%\"/>\n<col align=\"left\" valign=\"top\" width=\"52%\"/>\n<col align=\"left\" valign=\"top\" width=\"43%\"/>\n<thead>\n<tr class=\"First Last\">\n<th align=\"center\" class=\"Lrule Rrule\" colspan=\"3\">MEDICATION GUIDE <br/>NAYZILAM<span class=\"Sup\">®</span> (NAY-zil-am) <br/>(midazolam) nasal spray, CIV</th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First Last\">\n<td align=\"left\" colspan=\"2\" valign=\"top\">This Medication Guide has been approved by the U.S. Food and Drug Administration</td><td align=\"right\" valign=\"top\">Issued: 1/2023      </td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"First\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\"><span class=\"Bold\"><a name=\"whatis\"></a>What is the most important information I should know about NAYZILAM? </span>\n<ul>\n<li>\n<span class=\"Bold\">NAYZILAM is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma, and death.</span>\n</li>\n<li>Get emergency medical help right away if any of the following happens:<ul class=\"Circle\">\n<li>shallow or slowed breathing</li>\n<li>breathing stops (which may lead to the heart stopping)</li>\n<li>excessive sleepiness (sedation)<br/>Do not drive or operate heavy machinery until you know how taking NAYZILAM with opioids may affect you. </li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">Risk of abuse, misuse, and addiction.</span> There is a risk of abuse, misuse, and addiction with benzodiazepines, including NAYZILAM, which can lead to overdose and serious side effects including coma and death. <ul class=\"Circle\">\n<li>\n<span class=\"Bold\">Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including midazolam (the active ingredient in NAYZILAM).</span> These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. <span class=\"Bold\">Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of these serious side effects.</span>\n</li>\n<li>\n<span class=\"Bold\">You can develop an addiction even if you use NAYZILAM as prescribed by your healthcare provider.</span>\n</li>\n<li>\n<span class=\"Bold\">Use NAYZILAM exactly as your healthcare provider prescribed. </span>\n</li>\n<li>\n<span class=\"Bold\">Do not share your NAYZILAM with other people</span>. \t\t\t\t\t\t\t\t\t\t\t\t\t</li>\n<li>\n<span class=\"Bold\">Keep NAYZILAM in a safe place and away from children.</span>\n</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">Physical dependence and withdrawal reactions</span>. Benzodiazepines, including NAYZILAM, can cause physical dependence and withdrawal reactions, especially if you use NAYZILAM daily. NAYZILAM is not intended for daily use.<ul class=\"Circle\">\n<li>\n<span class=\"Bold\">Do not suddenly stop using NAYZILAM without talking to your healthcare provider</span>. Stopping NAYZILAM suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. <span class=\"Bold\">Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of these symptoms.</span>\n</li>\n<li>\n<span class=\"Bold\">Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months</span>, including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.</li>\n<li>Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. </li>\n<li>\n<span class=\"Bold\">Do not use more NAYZILAM than prescribed or use NAYZILAM more often than prescribed.</span>\n</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">NAYZILAM can make you sleepy or dizzy and can slow your thinking and motor skills.</span>\n<ul class=\"Circle\">\n<li>Do not drive, operate heavy machinery, or do other dangerous activities until you know how NAYZILAM affects you.</li>\n<li>Do not drink alcohol or take other drugs that may make you sleepy or dizzy while using NAYZILAM without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, NAYZILAM may make your sleepiness or dizziness worse.</li>\n</ul>\n</li>\n<li>\n<span class=\"Bold\">Like other antiepileptic medicines, NAYZILAM may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\">\n<ul class=\"Circle\">\n<li>thoughts about suicide or dying</li>\n<li>feeling agitated or restless</li>\n<li>acting aggressive, being angry, or violent</li>\n<li>attempts to commit suicide</li>\n<li>panic attacks</li>\n<li>acting on dangerous impulses</li>\n<li>new or worse depression</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\">\n<ul class=\"Circle\">\n<li>trouble sleeping (insomnia)</li>\n<li>an extreme increase in activity and talking (mania)</li>\n<li>new or worse anxiety</li>\n<li>new or worse irritability</li>\n<li>other unusual changes in behavior or mood</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\"><span class=\"Bold\">How can I watch for early symptoms of suicidal thoughts or actions?</span>\n<ul class=\"Circle\">\n<li>Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings.</li>\n<li>Keep all follow-up visits with your healthcare provider as scheduled.</li>\n</ul>Call your healthcare provider between visits as needed, especially if you are worried about symptoms. <br/>Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\"><span class=\"Bold\">What is NAYZILAM?</span>\n<ul>\n<li>NAYZILAM is a prescription medicine used for the short-term treatment of seizure clusters (also known as \"acute repetitive seizures\") in people 12 years of age and older.</li>\n<li>\n<span class=\"Bold\">NAYZILAM is a federally controlled substance (CIV) because it contains midazolam that can be abused or lead to dependence</span>. Keep NAYZILAM in a safe place to prevent misuse and abuse. Selling or giving away NAYZILAM may harm others and is against the law. Tell your healthcare provider if you have ever abused or been dependent on alcohol, prescription drugs, or street drugs.</li>\n<li>It is not known if NAYZILAM is safe and effective in children under 12 years of age.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\"><span class=\"Bold\"><a name=\"donot\"></a>Do not use NAYZILAM if you</span>:<ul>\n<li>are allergic to midazolam.</li>\n<li>have an eye problem called acute narrow-angle glaucoma.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\"><span class=\"Bold\">Before you use NAYZILAM, tell your healthcare provider about all your medical conditions, including if you</span>:<ul>\n<li>have a history of depression, mood problems or suicidal thoughts or behavior.</li>\n<li>have asthma, emphysema, bronchitis, chronic obstructive pulmonary disease, or other breathing problems. </li>\n<li>have kidney or liver problems.</li>\n<li>have congestive heart failure.</li>\n<li>have a history of drug or alcohol abuse.</li>\n<li>are pregnant or plan to become pregnant. \t\t\t\t\t\t\t\t\t\t\t<ul class=\"Circle\">\n<li>Taking NAYZILAM late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems).</li>\n<li>Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with NAYZILAM.</li>\n<li>If you become pregnant while using NAYZILAM, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. You can register by calling 1-888-233-2334. For more information about the registry, go to http://www.aedpregnancyregistry.org. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.</li>\n</ul>\n</li>\n<li>are breastfeeding or plan to breastfeed. Midazolam passes into your breast milk and may harm your baby.<ul class=\"Circle\">\n<li>Breastfeeding during treatment with NAYZILAM may cause your baby to have sleepiness, feeding problems, and decreased weight gain.</li>\n<li>Talk to your healthcare provider about the best way to feed your baby while you take NAYZILAM.</li>\n</ul>\n</li>\n</ul>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take</span>, including prescription and over-the-counter medicines, vitamins and herbal supplements. Using NAYZILAM with certain other medicines can affect each other, causing side effects. Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each time you get a new medicine. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\"><span class=\"Bold\">How should I use NAYZILAM?</span>\n<ul>\n<li>Use NAYZILAM in the nose only.</li>\n<li>\n<span class=\"Bold\">Use NAYZILAM exactly as your healthcare provider tells you to use it</span> and follow the Instructions for Use that comes with this Medication Guide.</li>\n<li>Your healthcare provider has prescribed NAYZILAM to treat a type of seizure called a \"seizure cluster\". </li>\n<li>If the seizure cluster is continuing <span class=\"Bold\">10 minutes</span> after the first dose of NAYZILAM, a second dose of NAYZILAM <span class=\"Bold\">may be used if you have been told to do so by your healthcare provider</span>.</li>\n<li>If a second dose of NAYZILAM is used, give the second dose in the other nostril.</li>\n<li>\n<span class=\"Bold\">Do not</span> give more than 2 doses of NAYZILAM to treat a seizure cluster.</li>\n<li>\n<span class=\"Bold\">If the seizures do not stop</span> after NAYZILAM is used, get emergency medical help right away.</li>\n<li>\n<span class=\"Bold\">Do not</span> use NAYZILAM for more than 1 seizure cluster episode every 3 days. <span class=\"Bold\">Do not</span> use NAYZILAM for more than 5 seizure cluster episodes per month.</li>\n<li>If benzodiazepines are stopped after a person takes them daily, they can cause withdrawal symptoms. Stopping benzodiazepines suddenly can cause seizures that will not stop (status epilepticus), hearing or seeing things that are not there (hallucinations), shaking, nervousness, and stomach and muscle cramps. NAYZILAM is not intended to be used daily.</li>\n<li>If you use too much NAYZILAM, call your healthcare provider or go to the nearest emergency room right away.</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\"><span class=\"Bold\">What should I avoid while using NAYZILAM?<br/>See \"<a href=\"#whatis\">What is the most important information I should know about NAYZILAM?</a>\"</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\"><span class=\"Bold\">What are the possible side effects of NAYZILAM? <br/>NAYZILAM may cause serious side effects, including:</span>\n<ul>\n<li>See \"<span class=\"Bold\"><a href=\"#whatis\">What is the most important information I should know about NAYZILAM?</a></span>\"</li>\n<li>\n<span class=\"Bold\">Increase in eye pressure in people with acute narrow-angle glaucoma</span>. See \"<span class=\"Bold\"><a href=\"#donot\">Do not use NAYZILAM if you:</a></span>\"</li>\n</ul>\n<span class=\"Bold\">The most common side effects of NAYZILAM include</span>:</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\">\n<ul>\n<li>sleepiness</li>\n<li>headache</li>\n<li>runny nose</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\">\n<ul>\n<li>nasal discomfort</li>\n<li>throat irritation</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\">These are not all the possible side effects of NAYZILAM. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\"><span class=\"Bold\">How should I store NAYZILAM?</span>\n<ul>\n<li>Store NAYZILAM at room temperature between 68°F to 77°F (20°C to 25°C).</li>\n<li>Keep NAYZILAM in the blister package until ready to use.</li>\n</ul>\n<span class=\"Bold\">Keep NAYZILAM and all medicines out of the reach of children.</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\"><span class=\"Bold\">General information about the safe and effective use of NAYZILAM.</span>\n<br/>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NAYZILAM for a condition for which it was not prescribed. Do not give NAYZILAM to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about NAYZILAM that is written for health professionals.</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"3\"><span class=\"Bold\">What are the ingredients in NAYZILAM?</span>\n<br/>\n<span class=\"Bold\">Active ingredient</span>: midazolam <br/>\n<span class=\"Bold\">Inactive ingredients</span>: ethanol, PEG-6 methyl ether, polyethylene glycol 400, propylene glycol and purified water <br/>Manufactured for UCB, Inc., Smyrna, GA 30080.<br/>NAYZILAM<span class=\"Sup\">®</span> is a registered trademark of the UCB Group of Companies.<br/> ©2022. All rights reserved.<br/>For more information, go to www.nayzilam.com or call 1-844-599-2273.</td>\n</tr>\n</tbody>\n</table></div>" }

Instructions for Use NAYZILAM® (NAY-zil-am) (midazolam) nasal spray, CIV

{ "type": "p", "children": [], "text": "\nInstructions for Use NAYZILAM® (NAY-zil-am)\n(midazolam) nasal spray, CIV" }

You and your family members or caregivers should read this Instructions for Use before you start using NAYZILAM nasal spray and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you and your family members or caregivers have any questions about NAYZILAM, ask your healthcare provider or pharmacist.

{ "type": "p", "children": [], "text": "You and your family members or caregivers should read this Instructions for Use before you start using NAYZILAM nasal spray and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you and your family members or caregivers have any questions about NAYZILAM, ask your healthcare provider or pharmacist." }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="center" valign="middle" width="53%"/> <col align="left" valign="middle" width="47%"/> <tbody class="Headless"> <tr> <td align="center" colspan="2"></td> </tr> <tr> <td align="left" colspan="2"></td> </tr> <tr> <td align="center"><img alt="Figure" src="/dailymed/image.cfm?name=nayzilam-03.jpg&amp;setid=2b29422e-54d5-4a49-8522-e9cf752368c3"/></td><td align="left"><span class="Bold">Important</span>: <span class="Bold">NAYZILAM is for use in the nose only</span>.<ul> <li> <span class="Bold">There is only 1 dose of NAYZILAM in the nasal spray unit</span>. </li> <li> <span class="Bold">Do not</span> try to test or prime the nasal spray unit before use. You will lose the dose. </li> <li> <span class="Bold">Do not</span> open the blister packaging until ready to use.</li> <li> <span class="Bold">Do not</span> use if the nasal spray unit appears damaged.</li> <li> <span class="Bold">Do not</span> use past the expiration date printed on the blister packaging.</li> <li>Throw away (dispose of) the nasal spray unit after use.</li> </ul> </td> </tr> <tr> <td align="center" valign="baseline"><a name="fig1"></a><img alt="Figure 1" src="/dailymed/image.cfm?name=nayzilam-04.jpg&amp;setid=2b29422e-54d5-4a49-8522-e9cf752368c3"/></td><td align="left"><span class="Bold">How to use NAYZILAM nasal spray: <br/>Step 1: Peel open the blister packaging</span> <ul> <li>When ready to use, open the blister packaging.</li> <li>Hold blister packaging in the palm of your hand.</li> <li>On the foil backing, find the "<span class="Bold">Peel Here</span>" tab and pull down <span class="Bold">(see <a href="#fig1">Figure 1</a>)</span>.</li> <li>Remove the nasal spray unit carefully.</li> </ul> </td> </tr> <tr> <td align="center"><a name="fig2"></a><img alt="Figure 2" src="/dailymed/image.cfm?name=nayzilam-05.jpg&amp;setid=2b29422e-54d5-4a49-8522-e9cf752368c3"/></td><td align="left"><span class="Bold">Step 2: Hold the nasal spray unit</span> <ul> <li>Hold the nasal spray unit with your thumb on the plunger and your middle and index fingers on each side of the nozzle (<span class="Bold">see <a href="#fig2">Figure 2</a></span>). </li> <li> <span class="Bold">Do not press the plunger yet. If you press the plunger now, you will lose the dose. </span> </li> </ul> </td> </tr> <tr> <td align="center"><a name="fig3"></a><img alt="Figure 3" src="/dailymed/image.cfm?name=nayzilam-06.jpg&amp;setid=2b29422e-54d5-4a49-8522-e9cf752368c3"/></td><td align="left"><span class="Bold">Step 3: Place the tip into 1 nostril</span> <ul> <li>Place the tip of the nozzle into 1 nostril until your fingers on either side of the nozzle touches the bottom of the nose <span class="Bold">(see <a href="#fig3">Figure 3</a>)</span>.</li> </ul> </td> </tr> <tr> <td align="center"><a name="fig4"></a><img alt="Figure 4" src="/dailymed/image.cfm?name=nayzilam-07.jpg&amp;setid=2b29422e-54d5-4a49-8522-e9cf752368c3"/></td><td align="left"><span class="Bold">Step 4: Press the plunger</span> <ul> <li>Press the plunger firmly to deliver the dose of NAYZILAM nasal spray <span class="Bold">(see <a href="#fig4">Figure 4</a>)</span>.</li> <li>Make sure to firmly press the plunger using 1 motion.</li> </ul> <span class="Bold">The patient does not need to breathe deeply when you give them the medicine.</span></td> </tr> <tr> <td align="center"></td><td align="left"><span class="Bold">What to do after the NAYZILAM nasal spray has been used:</span> <br/>Remove the nozzle from the nostril after giving the dose.<br/> <span class="Bold">Note:</span> The plunger will remain inside the nasal spray unit after the dose is given.<br/>Throw away (dispose of) the nasal spray unit and blister packaging in the trash.<br/> <span class="Bold">What to do if a Second Dose is needed:</span> <br/> <span class="Bold">Important:</span> If the seizure cluster is continuing <span class="Bold">10 minutes</span> after the first dose of NAYZILAM, a second dose of NAYZILAM <span class="Bold">may be used if you have been told to do so by your healthcare provider</span>.<br/>If you need to give a second dose of NAYZILAM, follow the instructions in this Instructions for Use using a new nasal spray unit <span class="Bold">in the other nostril</span>. (Repeat Step 1 through Step 4)</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col align=\"center\" valign=\"middle\" width=\"53%\"/>\n<col align=\"left\" valign=\"middle\" width=\"47%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"center\" colspan=\"2\"></td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"2\"></td>\n</tr>\n<tr>\n<td align=\"center\"><img alt=\"Figure\" src=\"/dailymed/image.cfm?name=nayzilam-03.jpg&amp;setid=2b29422e-54d5-4a49-8522-e9cf752368c3\"/></td><td align=\"left\"><span class=\"Bold\">Important</span>: <span class=\"Bold\">NAYZILAM is for use in the nose only</span>.<ul>\n<li>\n<span class=\"Bold\">There is only 1 dose of NAYZILAM in the nasal spray unit</span>. </li>\n<li>\n<span class=\"Bold\">Do not</span> try to test or prime the nasal spray unit before use. You will lose the dose. </li>\n<li>\n<span class=\"Bold\">Do not</span> open the blister packaging until ready to use.</li>\n<li>\n<span class=\"Bold\">Do not</span> use if the nasal spray unit appears damaged.</li>\n<li>\n<span class=\"Bold\">Do not</span> use past the expiration date printed on the blister packaging.</li>\n<li>Throw away (dispose of) the nasal spray unit after use.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"center\" valign=\"baseline\"><a name=\"fig1\"></a><img alt=\"Figure 1\" src=\"/dailymed/image.cfm?name=nayzilam-04.jpg&amp;setid=2b29422e-54d5-4a49-8522-e9cf752368c3\"/></td><td align=\"left\"><span class=\"Bold\">How to use NAYZILAM nasal spray: <br/>Step 1: Peel open the blister packaging</span>\n<ul>\n<li>When ready to use, open the blister packaging.</li>\n<li>Hold blister packaging in the palm of your hand.</li>\n<li>On the foil backing, find the \"<span class=\"Bold\">Peel Here</span>\" tab and pull down <span class=\"Bold\">(see <a href=\"#fig1\">Figure 1</a>)</span>.</li>\n<li>Remove the nasal spray unit carefully.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"center\"><a name=\"fig2\"></a><img alt=\"Figure 2\" src=\"/dailymed/image.cfm?name=nayzilam-05.jpg&amp;setid=2b29422e-54d5-4a49-8522-e9cf752368c3\"/></td><td align=\"left\"><span class=\"Bold\">Step 2: Hold the nasal spray unit</span>\n<ul>\n<li>Hold the nasal spray unit with your thumb on the plunger and your middle and index fingers on each side of the nozzle (<span class=\"Bold\">see <a href=\"#fig2\">Figure 2</a></span>). </li>\n<li>\n<span class=\"Bold\">Do not press the plunger yet. If you press the plunger now, you will lose the dose. </span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"center\"><a name=\"fig3\"></a><img alt=\"Figure 3\" src=\"/dailymed/image.cfm?name=nayzilam-06.jpg&amp;setid=2b29422e-54d5-4a49-8522-e9cf752368c3\"/></td><td align=\"left\"><span class=\"Bold\">Step 3: Place the tip into 1 nostril</span>\n<ul>\n<li>Place the tip of the nozzle into 1 nostril until your fingers on either side of the nozzle touches the bottom of the nose <span class=\"Bold\">(see <a href=\"#fig3\">Figure 3</a>)</span>.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"center\"><a name=\"fig4\"></a><img alt=\"Figure 4\" src=\"/dailymed/image.cfm?name=nayzilam-07.jpg&amp;setid=2b29422e-54d5-4a49-8522-e9cf752368c3\"/></td><td align=\"left\"><span class=\"Bold\">Step 4: Press the plunger</span>\n<ul>\n<li>Press the plunger firmly to deliver the dose of NAYZILAM nasal spray <span class=\"Bold\">(see <a href=\"#fig4\">Figure 4</a>)</span>.</li>\n<li>Make sure to firmly press the plunger using 1 motion.</li>\n</ul>\n<span class=\"Bold\">The patient does not need to breathe deeply when you give them the medicine.</span></td>\n</tr>\n<tr>\n<td align=\"center\"></td><td align=\"left\"><span class=\"Bold\">What to do after the NAYZILAM nasal spray has been used:</span>\n<br/>Remove the nozzle from the nostril after giving the dose.<br/>\n<span class=\"Bold\">Note:</span> The plunger will remain inside the nasal spray unit after the dose is given.<br/>Throw away (dispose of) the nasal spray unit and blister packaging in the trash.<br/>\n<span class=\"Bold\">What to do if a Second Dose is needed:</span>\n<br/>\n<span class=\"Bold\">Important:</span> If the seizure cluster is continuing <span class=\"Bold\">10 minutes</span> after the first dose of NAYZILAM, a second dose of NAYZILAM <span class=\"Bold\">may be used if you have been told to do so by your healthcare provider</span>.<br/>If you need to give a second dose of NAYZILAM, follow the instructions in this Instructions for Use using a new nasal spray unit <span class=\"Bold\">in the other nostril</span>. (Repeat Step 1 through Step 4)</td>\n</tr>\n</tbody>\n</table></div>" }

<div class="scrollingtable"><table class="Noautorules" width="80%"> <col align="left" valign="top" width="50%"/> <col align="left" valign="top" width="50%"/> <tbody class="Headless"> <tr> <td align="left" class="Lrule Rrule Toprule" colspan="2" valign="middle"> <p class="First"> <img alt="Figure" src="/dailymed/image.cfm?name=nayzilam-08.jpg&amp;setid=2b29422e-54d5-4a49-8522-e9cf752368c3"/><span class="Bold">Call for help if any of the following happens:</span> </p> </td> </tr> <tr> <td align="left" class="Lrule" valign="top"> <ul> <li>Seizure or seizures continue after giving NAYZILAM to the person as instructed by the healthcare provider.</li> </ul> </td><td align="left" class="Rrule" valign="top"><span class="Bold">Local Emergency Number:________________________</span></td> </tr> <tr> <td align="left" class="Lrule" valign="top"> <ul> <li>Seizure behavior in the person is different from other episodes. </li> </ul> </td><td align="left" class="Rrule" valign="top"><span class="Bold">Healthcare Provider's Number:_______________________</span></td> </tr> <tr> <td align="left" class="Lrule" valign="top"> <ul> <li>You are alarmed by the number or severity of the seizure or seizures in the person.</li> </ul> </td><td align="left" class="Rrule" valign="bottom"><span class="Bold">Information for Emergency Responder</span></td> </tr> <tr> <td align="left" class="Botrule Lrule" rowspan="2"> <ul> <li>You are alarmed by the color or breathing of the person.</li> </ul> </td><td align="left" class="Rrule">Time of first NAYZILAM dose:________________</td> </tr> <tr> <td align="left" class="Botrule Rrule">Time of second NAYZILAM dose (if given):_________________________</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"80%\">\n<col align=\"left\" valign=\"top\" width=\"50%\"/>\n<col align=\"left\" valign=\"top\" width=\"50%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\" class=\"Lrule Rrule Toprule\" colspan=\"2\" valign=\"middle\">\n<p class=\"First\">\n<img alt=\"Figure\" src=\"/dailymed/image.cfm?name=nayzilam-08.jpg&amp;setid=2b29422e-54d5-4a49-8522-e9cf752368c3\"/><span class=\"Bold\">Call for help if any of the following happens:</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" valign=\"top\">\n<ul>\n<li>Seizure or seizures continue after giving NAYZILAM to the person as instructed by the healthcare provider.</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" valign=\"top\"><span class=\"Bold\">Local Emergency Number:________________________</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" valign=\"top\">\n<ul>\n<li>Seizure behavior in the person is different from other episodes. </li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" valign=\"top\"><span class=\"Bold\">Healthcare Provider's Number:_______________________</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\" valign=\"top\">\n<ul>\n<li>You are alarmed by the number or severity of the seizure or seizures in the person.</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" valign=\"bottom\"><span class=\"Bold\">Information for Emergency Responder</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Lrule\" rowspan=\"2\">\n<ul>\n<li>You are alarmed by the color or breathing of the person.</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\">Time of first NAYZILAM dose:________________</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Botrule Rrule\">Time of second NAYZILAM dose (if given):_________________________</td>\n</tr>\n</tbody>\n</table></div>" }

Manufactured for UCB, Inc., Smyrna, GA 30080.NAYZILAM® is a registered trademark of the UCB Group of Companies. ©2022. All rights reserved.For more information, go to www.nayzilam.com or call 1-844-599-2273.This Instructions for Use has been approved by the U.S. Food and Drug AdministrationIssued: 1/2023

{ "type": "p", "children": [], "text": "Manufactured for UCB, Inc., Smyrna, GA 30080.NAYZILAM® is a registered trademark of the UCB Group of Companies. ©2022. All rights reserved.For more information, go to www.nayzilam.com or call 1-844-599-2273.This Instructions for Use has been approved by the U.S. Food and Drug AdministrationIssued: 1/2023" }

NDC 50474-500-15Rx only

{ "type": "p", "children": [], "text": "NDC 50474-500-15Rx only" }

Nayzilam® CIV(midazolam) nasal spray5 mg

{ "type": "p", "children": [], "text": "Nayzilam® CIV(midazolam) nasal spray5 mg" }

FOR NASAL USE ONLY2 Nasal Spray Units(1 dose per unit)

{ "type": "p", "children": [], "text": "FOR NASAL USE ONLY2 Nasal Spray Units(1 dose per unit)" }

DO NOT test or prime before use.

{ "type": "p", "children": [], "text": "DO NOT test or prime before use." }

Midazolam in 0.9% Sodium Chloride Injection is indicated:

{ "type": "p", "children": [], "text": "Midazolam in 0.9% Sodium Chloride Injection is indicated:\n" }

{ "type": "ul", "children": [ "Continuous intravenous infusion for sedation of intubated and mechanically ventilated adult, pediatric, and neonatal patients as a component of anesthesia or during treatment in a critical care setting.\n" ], "text": "" }

Midazolam must never be used without individualization of dosage particularly when used with other medications capable of producing central nervous system depression [see Warnings and Precautions (5.2)].

Midazolam in 0.9% Sodium Chloride Injection can cause respiratory depression. It is a potent sedative agent that requires slow administration and individualization of dosage. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. Continuously monitor patients for early signs of hypoventilation, airway obstruction, and apnea using capnography, pulse oximetry, and clinical assessment [see Warnings and Precautions (5.3)].

Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric patients [see Warnings and Precautions (5.4)].

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. If solution is discolored or particulate matter is present, do not use.

Individualize dosing and titrate to desired clinical response, taking into account patient age, clinical status, and concomitant use of other CNS depressants. Titrate to effect with multiple small doses while continuously monitoring respiratory and cardiac function (i.e., pulse oximetry). To minimize the potential for oversedation, allow adequate time between doses to achieve peak central nervous system effect (3 to 5 minutes).

Adults and Pediatrics:

Sedation guidelines recommend a careful presedation history to determine how a patient's underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting.

Pediatrics:

Pediatric patients generally require higher dosages of midazolam (mg/kg) than adults. For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

Elderly and Debilitated Patients

Intravenous doses of midazolam should be decreased for elderly and for debilitated patients [see Warnings and Precautions (5.6)]. These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia [see Warnings and Precautions (5.8)].

Monitoring

Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Continuously monitor vital signs during sedation and through the recovery period [see Warnings and Precautions (5.1)].

Table 1 provides dosing recommendations for adult, pediatric, and neonatal patients.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1. Dosing Recommendations for Continuous Intravenous Infusion in Adult, Pediatric, and Neonatal Patients </span> </caption> <col align="left" width="32.050%"/> <col align="left" width="67.950%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Botrule Lrule Rrule Toprule" valign="top"><span class="Bold">ADULT PATIENTS</span></td><td align="justify" class="Botrule Rrule Toprule" valign="top">If a loading dose is necessary to rapidly initiate sedation, 0.01 mg/kg to 0.05 mg/kg (approximately 0.5 mg to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 mg/kg/hr to 0.10 mg/kg/hr (1 mg/hr to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients. Use the lowest recommended doses in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids.<br/> <br/>Individual response to midazolam is variable. Titrate the infusion rate to the desired level of sedation, taking into account the patient's age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation. Assess sedation at regular intervals and adjust the midazolam infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. </td> </tr> <tr> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">PEDIATRIC PATIENTS</span></td><td align="justify" class="Botrule Rrule" valign="top">UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients. In obese pediatric patients, calculate the dose based on ideal body weight.<br/> <br/>Titrate the dose to the desired level of sedation. Assess for desired level of sedation and vital signs at regular intervals. </td> </tr> <tr class="Last"> <td align="left" class="Botrule Lrule Rrule" valign="top"><span class="Bold">PRETERM AND TERM</span> <br/> <span class="Bold">NEONATAL PATIENTS</span> <br/> </td><td align="justify" class="Botrule Rrule" valign="top">Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, initiate continuous intravenous infusions of Midazolam in 0.9% Sodium Chloride Injection at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates &lt;32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates &gt;32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. Frequently assess the rate of infusion, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly.<br/> <br/>When sedating preterm and former preterm neonates WHOSE TRACHEA WAS NOT INTUBATED, monitor respiratory parameters due to an increased risk of apnea. </td> </tr> </tbody> </table></div>

If Midazolam in 0.9% Sodium Chloride Injection is administered long-term (for several days to weeks), do not abruptly discontinue. Gradually taper the dosage in physically-dependent patients using a tapering schedule that is individualized to the patient [see Warnings and Precautions (5.5)].

Midazolam in 0.9% Sodium Chloride Injection, 50 mg per 50 mL (1 mg per mL) and 100 mg per 100 mL (1 mg per mL), is a clear, colorless solution supplied in single-dose bags with an aluminum overwrap.

{ "type": "p", "children": [], "text": "Midazolam in 0.9% Sodium Chloride Injection, 50 mg per 50 mL (1 mg per mL) and 100 mg per 100 mL (1 mg per mL), is a clear, colorless solution supplied in single-dose bags with an aluminum overwrap.\n" }

Midazolam in 0.9% Sodium Chloride Injection is contraindicated in patients with:

{ "type": "p", "children": [], "text": "Midazolam in 0.9% Sodium Chloride Injection is contraindicated in patients with:\n" }

{ "type": "ul", "children": [ "Known hypersensitivity to midazolam\n", "Acute narrow-angle glaucoma\n" ], "text": "" }

Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Monitor patients for respiratory depression and sedation [see Warnings and Precautions (5.2) and Drug Interactions (7.1)].

Titrate the dose of Midazolam in 0.9% Sodium Chloride Injection when administered with opioid analgesics and sedative-hypnotics to the desired clinical response.

Continuously monitor sedated patients for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation. These cardiorespiratory effects may be more likely to occur in patients with obstructive sleep apnea, the elderly, and ASA‑PS III or IV patients.

Concomitant use of barbiturates, 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 effect. Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.

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 adult or pediatric patients with hemodynamic instability. Hypotension occurred more frequently in the sedation studies in patients premedicated with an opioid. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. When used for sedation/anxiolysis/amnesia, midazolam should always be titrated slowly in adult or pediatric patients. Adverse hemodynamic events have been reported in pediatric patients with cardiovascular instability; rapid intravenous administration should also be avoided in this population. Continuously monitor patients for early signs of hypoventilation, airway obstruction, and apnea using capnography, pulse oximetry, and clinical assessment [see Dosage and Administration (2.2)].

Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. These reactions may be due to inadequate or excessive dosing or improper administration of midazolam; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions. Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric patients.

The continued use of benzodiazepines for several days to weeks may lead to clinically significant physical dependence. If used for long-term use (i.e., for several days to weeks), abrupt discontinuation or rapid dosage reduction of midazolam, or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening.

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use.

After extended therapy, do not abruptly discontinue Midazolam in 0.9% Sodium Chloride Injection. When discontinuing midazolam in a physically-dependent patient, gradually taper the dosage using a tapering schedule that is individualized to the patient [see Dosage and Administration (2.3), Dependence (9.3)].

Higher risk adult and pediatric surgical patients, elderly patients and debilitated adult and pediatric patients require lower dosages, whether or not concomitant sedating medications have been administered. Adult or pediatric patients with COPD are unusually sensitive to the respiratory depressant effect of midazolam. Pediatric and adult patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction. Adult and pediatric patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly [see Clinical Pharmacology (12.3)]. Because elderly patients frequently have inefficient function of one or more organ systems and because dosage requirements have been shown to decrease with age, reduced initial dosage of midazolam is recommended, and the possibility of profound and/or prolonged effect should be considered.

Do not administer Midazolam in 0.9% Sodium Chloride Injection to adult or pediatric patients in shock or coma, or in acute alcohol intoxication with depression of vital signs. Particular care should be exercised in the use of intravenous midazolam in adult or pediatric patients with uncompensated acute illnesses, such as severe fluid or electrolyte disturbances.

There have been limited reports of intra-arterial injection of midazolam. Adverse events have included local reactions, as well as isolated reports of seizure activity in which no clear causal relationship was established. Precautions against unintended intra-arterial injection should be taken. Extravasation should also be avoided.

The safety and efficacy of Midazolam in 0.9% Sodium Chloride Injection following nonintravenous routes of administration have not been established. Midazolam in 0.9% Sodium Chloride Injection should only be administered intravenously.

Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours. The decision as to when patients who have received injectable midazolam, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized. Gross tests of recovery from the effects of midazolam [see Clinical Pharmacology (12.3)] 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 or until one full day after anesthesia and surgery, whichever is longer. For pediatric patients, particular care should be taken to assure safe ambulation.

Rapid injection should be avoided in the neonatal population. Midazolam administered rapidly as an intravenous injection (i.e., less than 2 minutes) has been associated with severe hypotension in neonates, particularly when the patient has also received fentanyl. Likewise, severe hypotension has been observed in neonates receiving a continuous infusion of midazolam who then receive a rapid intravenous injection of fentanyl. Seizures have been reported in several neonates following rapid intravenous administration.

The neonate also has reduced and/or immature organ function and is also vulnerable to profound and/or prolonged respiratory effects of midazolam.

Receiving Midazolam in 0.9% Sodium Chloride Injection late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate. Monitor neonates exposed to Midazolam in 0.9% Sodium Chloride Injection during pregnancy or labor for signs of sedation and manage these neonates accordingly [see Use in Specific Populations (8.1)].

Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see Nonclinical Pharmacology (13.2)].

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

Benzodiazepines, including Midazolam in 0.9% Sodium Chloride Injection, 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. Midazolam in 0.9% Sodium Chloride Injection 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 Midazolam in 0.9% Sodium Chloride Injection. Midazolam in 0.9% Sodium Chloride Injection is contraindicated in patients with narrow-angle glaucoma.

Adults

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 2: Additional Adverse Reactions Reported Subsequent to Intravenous Administration as a Single Sedative/anxiolytic/amnestic Agent in Adult Patients: </span> </caption> <col align="left" width="50.100%"/> <col align="left" width="49.900%"/> <tbody class="Headless"> <tr class="First"> <td align="left" class="Toprule" valign="top">          hiccoughs (3.9%) </td><td align="left" class="Toprule" valign="top"><span class="Bold">Local effects at the intravenous site</span></td> </tr> <tr> <td align="left" valign="top">          nausea (2.8%) </td><td align="left" valign="top">tenderness (5.6%) </td> </tr> <tr> <td align="left" valign="top">          vomiting (2.6%) </td><td align="left" valign="top">pain during injection (5.0%) </td> </tr> <tr> <td align="left" valign="top">          coughing (1.3%) </td><td align="left" valign="top">redness (2.6%) </td> </tr> <tr> <td align="left" valign="top">          "oversedation" (1.6%) </td><td align="left" valign="top">induration (1.7%) </td> </tr> <tr> <td align="left" valign="top">          headache (1.5%) </td><td align="left" valign="top">phlebitis (0.4%) </td> </tr> <tr class="Last"> <td align="left" valign="top">          drowsiness (1.2%) </td><td align="left" valign="top"></td> </tr> </tbody> </table></div>

Pediatric Patients

The following adverse events related to the use of intravenous midazolam in pediatric patients were reported in the medical literature: desaturation 4.6%, apnea 2.8%, hypotension 2.7%, paradoxical reactions 2.0%, hiccough 1.2%, seizure-like activity 1.1% and nystagmus 1.1%. The majority of airway-related events occurred in patients receiving other CNS depressing medications and in patients where midazolam was not used as a single sedating agent.

Neonates

There have been reports of hypotensive episodes and seizures following the administration of midazolam to neonates, [see Warnings and Precautions (5.9)].

Other Adverse Reactions Occurring at an Incidence of <1.0% Following Intravenous Injection as a Single Sedative/Anxiolytic/Amnesia Agent

Respiratory: Laryngospasm, bronchospasm, dyspnea, hyperventilation, wheezing, shallow respirations, airway obstruction, tachypnea

Cardiovascular: Bigeminy, premature ventricular contractions, vasovagal episode, bradycardia, tachycardia, nodal rhythm

Gastrointestinal: Acid taste, excessive salivation, retching

CNS/Neuromuscular: Retrograde amnesia, euphoria, hallucination, confusion, argumentativeness, nervousness, anxiety, grogginess, restlessness, emergence delirium or agitation, prolonged emergence from anesthesia, dreaming during emergence, sleep disturbance, insomnia, nightmares, athetoid movements, seizure-like activity, ataxia, dizziness, dysphoria, slurred speech, dysphonia, paresthesia

Special Senses: Blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic movements of eyelids, visual disturbance, difficulty focusing eyes, ears blocked, loss of balance, light-headedness

Integumentary: Hive-like elevation at injection site, swelling or feeling of burning, warmth or coldness at injection site

Hypersensitivity: Allergic reactions including anaphylactic reactions, hives, rash, pruritus

Miscellaneous: Yawning, lethargy, chills, weakness, toothache, faint feeling, hematoma

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. Monitor patients closely for respiratory depression and sedation.

The sedative effect of intravenous midazolam is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly opioids (e.g., morphine, meperidine and fentanyl) and also secobarbital and droperidol. Consequently, the dosage of midazolam should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response [see Dosage and Administration (2)].

Concomitant administration with drugs that are known to inhibit the P450-3A4 enzyme system, such as cimetidine (not ranitidine), erythromycin, diltiazem, verapamil, ketoconazole and itraconazole, may result in prolonged sedation due to a decrease in plasma clearance of midazolam.

The effect of single oral doses of 800 mg cimetidine and 300 mg ranitidine on steady-state concentrations of midazolam was examined in a randomized crossover study (n=8). Cimetidine increased the mean midazolam steady-state concentration from 57 to 71 ng/mL. Ranitidine increased the mean steady-state concentration to 62 ng/mL. No change in choice reaction time or sedation index was detected after dosing with the H2 receptor antagonists.

In a placebo-controlled study, erythromycin administered as a 500 mg dose, three times a day, for 1 week (n=6), reduced the clearance of midazolam following a single 0.5 mg/kg intravenous dose. The half-life was approximately doubled.

The effects of diltiazem (60 mg three times a day) and verapamil (80 mg three times a day) on the pharmacokinetics and pharmacodynamics of oral midazolam were investigated in a three-way crossover study (n=9). The half-life of midazolam increased from 5 to 7 hours when midazolam was taken in conjunction with verapamil or diltiazem. No interaction was observed in healthy subjects between midazolam and nifedipine.

In a placebo-controlled study, saquinavir administered as a 1200 mg dose, tid, for 5 days (n=12), a 56% reduction in the clearance of midazolam following a single 0.05 mg/kg intravenous dose was observed. The half-life was approximately doubled.

A moderate reduction in induction dosage requirements of thiopental (about 15%) has been noted following use of intramuscular midazolam for premedication in adults.

The intravenous administration of midazolam decreases the minimum alveolar concentration (MAC) of halothane required for general anesthesia. This decrease correlates with the dose of midazolam administered; no similar studies have been carried out in pediatric patients but there is no scientific reason to expect that pediatric patients would respond differently than adults.

Although the possibility of minor interactive effects has not been fully studied, midazolam and pancuronium have been used together in patients without noting clinically significant changes in dosage, onset or duration in adults. Midazolam does not protect against the characteristic circulatory changes noted after administration of succinylcholine or pancuronium and does not protect against the increased intracranial pressure noted following administration of succinylcholine. Midazolam does not cause a clinically significant change in dosage, onset or duration of a single intubating dose of succinylcholine; no similar studies have been carried out in pediatric patients but there is no scientific reason to expect that pediatric patients would respond differently than adults.

No significant adverse interactions with commonly used premedications or drugs used during anesthesia and surgery (including atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, d-tubocurarine, succinylcholine and other nondepolarizing muscle relaxants) or topical local anesthetics (including lidocaine, dyclonine HCl and Cetacaine) have been observed in adults or pediatric patients. In neonates, however, severe hypotension has been reported with concomitant administration of fentanyl. This effect has been observed in neonates on an infusion of midazolam who received a rapid injection of fentanyl and in patients on an infusion of fentanyl who have received a rapid injection of midazolam.

Midazolam has not been shown to interfere with results obtained in clinical laboratory tests.

Risk Summary

Neonates born to mothers using benzodiazepines, including midazolam, late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.10), and Clinical Considerations]. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data).

Available data from randomized controlled trials, cohort studies and case reports over several decades with midazolam use in pregnant women for anesthesia have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Most of the reported exposures to midazolam occurred at the time of cesarean delivery. Rare case reports of the prolonged use of midazolam in pregnant women for sedation in a critical care setting are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes (see Data).

In pregnant rats and rabbits, midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons.

Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to midazolam during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to midazolam during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.2)].

Data

Human Data

Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Animal Data

Pregnant rats were treated with midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 through 15). Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose. All doses produced slight to moderate ataxia. The high dose produced a 5% decrease in maternal body weight gain compared to control.

Pregnant rabbits were treated with midazolam using intravenous doses of 0.2, 0.6, and 2 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 to 18). Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose. The high dose was associated with findings of ataxia and sedation but no evidence of maternal toxicity.

Pregnant rats were administered midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during late gestation and through lactation (Gestation Day 15 through Lactation Day 21). All doses produced ataxia. The high dose produced a slight decrease in maternal body weight gain compared to control. There were no clear adverse effects noted in the offspring. The study included no functional assessments of the pups, such as learning and memory testing or reproductive capacity.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits [see Warnings and Precautions (5.8), Use in Specific Populations (8.4), Nonclinical Pharmacology (13.2)].

Risk Summary

There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk. Based on data from published studies, midazolam is present in human milk in low levels (see Data). There are no data on the effects of midazolam on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Midazolam in 0.9% Sodium Chloride Injection and any potential adverse effects on the breastfed infant from Midazolam in 0.9% Sodium Chloride Injection or from the underlying maternal condition.

Clinical Considerations

Infants exposed to midazolam through breast milk should be monitored for sedation, poor feeding, and poor weight gain. A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment for a range of at least 4 to 8 hours after midazolam administration in order to minimize drug exposure to a breastfed infant.

Data

Published clinical lactation studies describe the presence of midazolam in human milk at low levels 4 to 8 hours after midazolam administration. These lactation studies have limitations including poor methodology and lack of validated analytical methods. Published study guidelines recommend pumping and discarding breast milk for a range of at least 4 to 8 hours after treatment with midazolam. No safety signals have been identified in breastfed infants exposed to midazolam.

The safety and efficacy of midazolam for sedation/anxiolysis/amnesia following continuous infusion have been established in pediatric and neonatal patients. UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require closer monitoring. In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.

Midazolam should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid intravenous administration, particularly, with concomitant use of fentanyl.

Animal Data

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as Midazolam in 0.9% Sodium Chloride Injection, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data [see Warnings and Precautions (5.8) and Nonclinical Pharmacology (13.2)].

Because geriatric patients may have altered drug distribution and diminished hepatic and/or renal function, reduced doses of midazolam are recommended. Doses of Midazolam in 0.9% Sodium Chloride Injection should be decreased for elderly and for debilitated patients [see Warnings and Precautions (5.6) and Dosage and Administration (2)] and subjects over 70 years of age may be particularly sensitive. These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia. Administration of intravenous midazolam to elderly and/or high-risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially opioids [see Dosage and Administration (2)].

Midazolam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Midazolam in 0.9% Sodium Chloride Injection contains midazolam, a Schedule IV controlled substance.

Midazolam in 0.9% Sodium Chloride Injection contains the benzodiazepine, midazolam. Benzodiazepines are a class of sedative drugs with a known potential for abuse. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Both abuse and misuse may lead to addiction. Midazolam was actively self-administered in primate models used to assess the positive reinforcing effects of psychoactive drugs. Midazolam produced physical dependence of a mild to moderate intensity in cynomolgus monkeys after 5 to 10 weeks of administration. Available data concerning the drug abuse and dependence potential of midazolam suggest that its abuse potential is at least equivalent to that of diazepam.

Midazolam may produce physical dependence after long-term use. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. If Midazolam in 0.9% Sodium Chloride Injection is administered long-term (i.e., for several days to weeks), abrupt discontinuation or rapid dosage reduction, or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.5)].

To reduce the risk of withdrawal reactions, after extended therapy, do not abruptly discontinue Midazolam in 0.9% Sodium Chloride Injection. Gradually taper the dosage using a tapering schedule that is individualized to the patient.

Acute Withdrawal Signs and Symptoms

Acute withdrawal signs and symptoms have included abnormal involuntary movements, anxiety, blurred vision, cognitive disorder, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, homicidal thoughts, mania, psychosis, and suicidality.

Protracted Withdrawal Syndrome

Protracted withdrawal syndrome is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months.

Tolerance

Midazolam may produce tolerance after long-term use. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance may develop within days or weeks of the therapeutic effects of Midazolam; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

Clinical Presentation

Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions (5.2)]. Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. No evidence of specific organ toxicity from midazolam overdosage has been reported.

Management of Overdosage

In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information.

Consider contacting the Poison Help Line (1-800-222-1222) or medical toxicologist for additional overdosage management for recommendations.

Midazolam in 0.9% Sodium Chloride Injection is a benzodiazepine available as a sterile, preservative-free, nonpyrogenic solution of midazolam and sodium chloride in water for injection for intravenous use. Each single-dose bag of Midazolam in 0.9% Sodium Chloride Injection contains either 50 mg per 50 mL (1 mg per mL) or 100 mg per 100 mL (1 mg per mL) of midazolam and 9 mg/mL of sodium chloride in water for injection. Midazolam in 0.9% Sodium Chloride Injection may contain hydrochloric acid and/or sodium hydroxide for pH adjustment. The pH is approximately 2.5 to 3.5.

{ "type": "p", "children": [], "text": "Midazolam in 0.9% Sodium Chloride Injection is a benzodiazepine available as a sterile, preservative-free, nonpyrogenic solution of midazolam and sodium chloride in water for injection for intravenous use. Each single-dose bag of Midazolam in 0.9% Sodium Chloride Injection contains either 50 mg per 50 mL (1 mg per mL) or 100 mg per 100 mL (1 mg per mL) of midazolam and 9 mg/mL of sodium chloride in water for injection. Midazolam in 0.9% Sodium Chloride Injection may contain hydrochloric acid and/or sodium hydroxide for pH adjustment. The pH is approximately 2.5 to 3.5.\n" }

Midazolam is a white or yellowish powder, practically insoluble in water, Chemically, midazolam is 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]-benzodiazepine. Midazolam has the empirical formula C18 H13ClFN3, a calculated molecular weight of 325.8 and the following structural formula:

{ "type": "p", "children": [], "text": "Midazolam is a white or yellowish powder, practically insoluble in water, Chemically, midazolam is 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]-benzodiazepine. Midazolam has the empirical formula C18 H13ClFN3, a calculated molecular weight of 325.8 and the following structural formula:\n" }

Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant.

The effects of midazolam on the CNS are dependent on the dose administered, the route of administration, and the presence or absence of other medications.

Time to Onset

Sedation in adult and pediatric patients is achieved within 3 to 5 minutes after intravenous injection; the time of onset is affected by total dose administered and the concurrent administration of opioid premedication. Seventy-one percent of the adult patients in endoscopy studies had no recall of introduction of the endoscope; 82% of the patients had no recall of withdrawal of the endoscope. In one study of pediatric patients undergoing lumbar puncture or bone marrow aspiration, 88% of patients had impaired recall vs 9% of the placebo controls. In another pediatric oncology study, 91% of midazolam treated patients were amnestic compared with 35% of patients who had received fentanyl alone.

When midazolam is given intravenous as an anesthetic induction agent, induction of anesthesia occurs in approximately 1.5 minutes when opioid premedication has been administered and in 2 to 2.5 minutes without opioid premedication or other sedative premedication. Some impairment in a test of memory was noted in 90% of the patients studied.

Midazolam, used as directed, does not delay awakening from general anesthesia in adults. Gross tests of recovery after awakening (orientation, ability to stand and walk, suitability for discharge from the recovery room, return to baseline Trieger competency) usually indicate recovery within 2 hours but recovery may take up to 6 hours in some cases. When compared with patients who received thiopental, patients who received midazolam generally recovered at a slightly slower rate. Recovery from anesthesia or sedation for procedures in pediatric patients depends on the dose of midazolam administered, coadministration of other medications causing CNS depression and duration of the procedure.

In patients without intracranial lesions, induction of general anesthesia with intravenous midazolam is associated with a moderate decrease in cerebrospinal fluid pressure (lumbar puncture measurements), similar to that observed following intravenous thiopental. Preliminary data in neurosurgical patients with normal intracranial pressure but decreased compliance (subarachnoid screw measurements) show comparable elevations of intracranial pressure with midazolam and with thiopental during intubation. No similar studies have been reported in pediatric patients.

Intravenous induction doses of midazolam depress the ventilatory response to carbon dioxide stimulation for 15 minutes or more beyond the duration of ventilatory depression following administration of thiopental in adults. Impairment of ventilatory response to carbon dioxide is more marked in adult patients with chronic obstructive pulmonary disease (COPD). Sedation with intravenous midazolam does not adversely affect the mechanics of respiration (resistance, static recoil, most lung volume measurements); total lung capacity and peak expiratory flow decrease significantly but static compliance and maximum expiratory flow at 50% of awake total lung capacity (Vmax) increase.

In cardiac hemodynamic studies in adults, intravenous induction of general anesthesia with midazolam was associated with a slight to moderate decrease in mean arterial pressure, cardiac output, stroke volume and systemic vascular resistance. Slow heart rates (less than 65/minute), particularly in patients taking propranolol for angina, tended to rise slightly; faster heart rates (e.g., 85/minute) tended to slow slightly. In pediatric patients, a comparison of intravenous midazolam (500 mcg/kg) with propofol (2.5 mg/kg) revealed a mean 15% decrease in systolic blood pressure in patients who had received intravenous midazolam vs a mean 25% decrease in systolic blood pressure following propofol.

Plasma Concentration-Efficacy Relationships

Concentration-efficacy relationships (after an intravenous dose) have been demonstrated for a variety of pharmacodynamic measures (e.g., reaction time, eye movement, sedation) and are associated with extensive intersubject variability. Logistic regression analysis of sedation scores and steady-state plasma concentration indicated that at plasma concentrations greater than 100 ng/mL there was at least a 50% probability that patients would be sedated, but respond to verbal commands (sedation score=3). At 200 ng/mL there was at least a 50% probability that patients would be asleep, but respond to glabellar tap (sedation score=4).

Midazolam's activity is primarily due to the parent drug. Elimination of the parent drug takes place via hepatic metabolism of midazolam to hydroxylated metabolites that are conjugated and excreted in the urine. Six single-dose pharmacokinetic studies involving healthy adults yield pharmacokinetic parameters for midazolam in the following ranges: volume of distribution (Vd), 1.0 to 3.1 L/kg; elimination half-life, 1.8 to 6.4 hours (mean approximately 3 hours); total clearance (Cl), 0.25 to 0.54 L/hr/kg. In a parallel group study, there was no difference in the clearance, in subjects administered 0.15 mg/kg (n=4) and 0.30 mg/kg (n=4) intravenous doses indicating linear kinetics. The clearance was successively reduced by approximately 30% at doses of 0.45 mg/kg (n=4) and 0.6 mg/kg (n=5) indicating non-linear kinetics in this dose range.

Absorption

Following intramuscular administration, Cmax for midazolam and its 1-hydroxy metabolite were approximately one-half of those achieved after intravenous injection.

Distribution

The volume of distribution (Vd) determined from six single-dose pharmacokinetic studies involving healthy adults ranged from 1.0 to 3.1 L/kg. Female gender, old age, and obesity are associated with increased values of midazolam Vd. In humans, midazolam has been shown to cross the placenta and enter into fetal circulation and has been detected in human milk and CSF (see Clinical Pharmacology, Specific Populations).

In adults and pediatric patients older than 1 year, midazolam is approximately 97% bound to plasma protein, principally albumin and that for 1-hydroxy metabolite is about 89%.

Elimination

Metabolism

In vitro studies with human liver microsomes indicate that the biotransformation of midazolam is mediated by cytochrome P450-3A4. This cytochrome also appears to be present in gastrointestinal tract mucosa as well as liver. Sixty to seventy percent of the biotransformation products is 1-hydroxy-midazolam (also termed alpha–hydroxy-midazolam) while 4-hydroxy-midazolam constitutes 5% or less. Small amounts of a dihydroxy derivative have also been detected but not quantified. The principal urinary excretion products are glucuronide conjugates of the hydroxylated derivatives.

Drugs that inhibit the activity of cytochrome P450-3A4 may inhibit midazolam clearance and elevate steady-state midazolam concentrations.

Studies of the intravenous administration of 1-hydroxy-midazolam in humans suggest that 1-hydroxy-midazolam is at least as potent as the parent compound and may contribute to the net pharmacologic activity of midazolam. In vitro studies have demonstrated that the affinities of 1- and 4-hydroxy-midazolam for the benzodiazepine receptor are approximately 20% and 7%, respectively, relative to midazolam.

Excretion

Clearance of midazolam is reduced in association with old age, congestive heart failure, liver disease (cirrhosis) or conditions which diminish cardiac output and hepatic blood flow.

The principal urinary excretion product is 1-hydroxy-midazolam in the form of a glucuronide conjugate; smaller amounts of the glucuronide conjugates of 4-hydroxy- and dihydroxy-midazolam are detected as well. The amount of midazolam excreted unchanged in the urine after a single intravenous dose is less than 0.5% (n=5). Following a single intravenous infusion in 5 healthy volunteers, 45% to 57% of the dose was excreted in the urine as 1-hydroxymethyl midazolam conjugate.

Pharmacokinetics-Continuous Infusion

The pharmacokinetic profile of midazolam following continuous infusion, based on 282 adult subjects, has been shown to be similar to that following single-dose administration for subjects of comparable age, gender, body habitus and health status. However, midazolam can accumulate in peripheral tissues with continuous infusion. The effects of accumulation are greater after long-term infusions than after short-term infusions. The effects of accumulation can be reduced by maintaining the lowest midazolam infusion rate that produces satisfactory sedation.

Infrequent hypotensive episodes have occurred during continuous infusion; however, neither the time to onset nor the duration of the episode appeared to be related to plasma concentrations of midazolam or alpha-hydroxy-midazolam. Further, there does not appear to be an increased chance of occurrence of a hypotensive episode with increased loading doses.

Patients with renal impairment may have longer elimination half-lives for midazolam [see Clinical Pharmacology (12.3)].

Specific Populations

Changes in the pharmacokinetic profile of midazolam due to drug interactions, physiological variables, etc., may result in changes in the plasma concentration-time profile and pharmacological response to midazolam in these patients. For example, patients with acute renal failure appear to have a longer elimination half-life for midazolam and may experience delayed recovery [see Clinical Pharmacology (12.3)]. In other groups, the relationship between prolonged half-life and duration of effect has not been established.

Age: Pediatrics and Neonates

In pediatric patients aged 1 year and older, the pharmacokinetic properties following a single dose of midazolam reported in 10 separate studies of midazolam are similar to those in adults. Weight-normalized clearance is similar or higher (0.19 to 0.80 L/hr/kg) than in adults and the terminal elimination half-life (0.78 to 3.3 hours) is similar to or shorter than in adults. The pharmacokinetic properties during and following continuous intravenous infusion in pediatric patients in the operating room as an adjunct to general anesthesia and in the intensive care environment are similar to those in adults.

In seriously ill neonates, however, the terminal elimination half-life of midazolam is substantially prolonged (6.5 to 12.0 hours) and the clearance reduced (0.07 to 0.12 L/hr/kg) compared to healthy adults or other groups of pediatric patients. It cannot be determined if these differences are due to age, immature organ function or metabolic pathways, underlying illness or debility.

Age: Geriatric

In three parallel group studies, the pharmacokinetics of midazolam administered intravenous or intramuscular were compared in young (mean age 29, n=52) and healthy elderly subjects (mean age 73, n=53). Plasma half-life was approximately two-fold higher in the elderly. The mean Vd based on total body weight increased consistently between 15% to 100% in the elderly. The mean Cl decreased approximately 25% in the elderly in two studies and was similar to that of the younger patients in the other.

Obese

In a study comparing normals (n=20) and obese patients (n=20) the mean half-life was greater in the obese group (5.9 vs 2.3 hrs). This was due to an increase of approximately 50% in the Vd corrected for total body weight. The clearance was not significantly different between groups.

Congestive Heart Failure

In patients suffering from congestive heart failure, there appeared to be a two-fold increase in the elimination half-life, a 25% decrease in the plasma clearance and a 40% increase in the volume of distribution of midazolam.

Hepatic Impairment

Midazolam pharmacokinetics were studied after an intravenous single dose (0.075 mg/kg) was administered to 7 patients with biopsy proven alcoholic cirrhosis and 8 control patients. The mean half-life of midazolam increased 2.5-fold in the alcoholic patients. Clearance was reduced by 50% and the Vd increased by 20%. In another study in 21 male patients with cirrhosis, without ascites and with normal kidney function as determined by creatinine clearance, no changes in the pharmacokinetics of midazolam or 1-hydroxy-midazolam were observed when compared to healthy individuals.

Renal Impairment

Patients with renal impairment may have longer elimination half-lives for midazolam and its metabolites which may result in slower recovery.

Midazolam and 1-hydroxy-midazolam pharmacokinetics in 6 ICU patients who developed acute renal failure (ARF) were compared with a normal renal function control group. Midazolam was administered as an infusion (5 to 15 mg/hours). Midazolam clearance was reduced (1.9 vs 2.8 mL/min/kg) and the half-life was prolonged (7.6 vs 13 hours) in the ARF patients. The renal clearance of the 1-hydroxy-midazolam glucuronide was prolonged in the ARF group (4 vs 136 mL/min) and the half-life was prolonged (12 vs >25 hours). Plasma levels accumulated in all ARF patients to about ten times that of the parent drug. The relationship between accumulating metabolite levels and prolonged sedation is unclear.

In a study of chronic renal failure patients (n=15) receiving a single intravenous dose, there was a two-fold increase in the clearance and volume of distribution but the half-life remained unchanged. Metabolite levels were not studied.

Carcinogenesis

Midazolam maleate was administered with diet in mice and rats for 2 years at dosages of 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. Dosages of 9 mg/kg/day of midazolam maleate (4 times a human induction dose of 0.35 mg/kg based on body surface area comparison) do not increase the incidence of tumors. 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.

Mutagenesis

Midazolam did not have mutagenic activity in Salmonella typhimurium (5 bacterial strains), Chinese hamster lung cells (V79), human lymphocytes or in the micronucleus test in mice.

Impairment of Fertility

Male rats were treated orally with 1, 4, or 16 mg/kg midazolam beginning 62 days prior to mating with female rats treated with the same doses for 14 days prior to mating to Gestation Day 13 or Lactation Day 21. The high dose produced an equivalent exposure (AUC) as 4 mg/kg intravenous midazolam (1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparison). There were no adverse effects on either male or female fertility noted.

Published studies in animals demonstrate that the use of anesthetic agents during the period of rapid brain growth or synaptogenesis results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of an anesthetic regimen that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and health care providers should balance the benefits of appropriate anesthesia in neonates and young children who require procedures against the potential risks suggested by the nonclinical data [see Warnings and Precautions (5.8)].

Midazolam in 0.9% Sodium Chloride Injection is a clear, colorless solution supplied in single-dose bags with an aluminum overwrap available as:

{ "type": "p", "children": [], "text": "Midazolam in 0.9% Sodium Chloride Injection is a clear, colorless solution supplied in single-dose bags with an aluminum overwrap available as:\n" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" width="25.567%"/> <col align="left" width="44.167%"/> <col align="left" width="30.267%"/> <tfoot> <tr> <td align="left" colspan="3" valign="top"> <p class="First Footnote">*Partial fill container 50 mL volume in 100 mL container </p> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="justify" valign="top"><span class="Bold">NDC</span></td><td align="justify" valign="top"><span class="Bold">Midazolam in 0.9% Sodium Chloride Injection</span></td><td align="justify" valign="top"><span class="Bold">Package Factor</span></td> </tr> <tr> <td align="justify" valign="top"></td><td align="justify" valign="top"><span class="Bold">(1 mg per mL)</span></td><td align="justify" valign="top"></td> </tr> <tr> <td align="justify" valign="top">25021-688-82 </td><td align="justify" valign="top">*50 mg per 50 mL Single-Dose Bag </td><td align="justify" valign="top">10 bags per carton </td> </tr> <tr> <td align="justify" valign="top">25021-688-87 </td><td align="justify" valign="top">100 mg per 100 mL Single-Dose Bag </td><td align="justify" valign="top">20 bags per carton </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col align=\"left\" width=\"25.567%\"/>\n<col align=\"left\" width=\"44.167%\"/>\n<col align=\"left\" width=\"30.267%\"/>\n<tfoot>\n<tr>\n<td align=\"left\" colspan=\"3\" valign=\"top\">\n<p class=\"First Footnote\">*Partial fill container 50 mL volume in 100 mL container\n</p>\n</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"justify\" valign=\"top\"><span class=\"Bold\">NDC</span></td><td align=\"justify\" valign=\"top\"><span class=\"Bold\">Midazolam in 0.9% Sodium Chloride Injection</span></td><td align=\"justify\" valign=\"top\"><span class=\"Bold\">Package Factor</span></td>\n</tr>\n<tr>\n<td align=\"justify\" valign=\"top\"></td><td align=\"justify\" valign=\"top\"><span class=\"Bold\">(1 mg per mL)</span></td><td align=\"justify\" valign=\"top\"></td>\n</tr>\n<tr>\n<td align=\"justify\" valign=\"top\">25021-688-82\n</td><td align=\"justify\" valign=\"top\">*50 mg per 50 mL Single-Dose Bag\n</td><td align=\"justify\" valign=\"top\">10 bags per carton\n</td>\n</tr>\n<tr>\n<td align=\"justify\" valign=\"top\">25021-688-87\n</td><td align=\"justify\" valign=\"top\">100 mg per 100 mL Single-Dose Bag\n</td><td align=\"justify\" valign=\"top\">20 bags per carton\n</td>\n</tr>\n</tbody>\n</table></div>" }

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.] Individual containers may be used up to 48 hours after initial penetration.

{ "type": "p", "children": [], "text": "Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.] Individual containers may be used up to 48 hours after initial penetration.\n" }

Do not freeze. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free, PVC-free, DEHP-free.The container closure is not made with natural rubber latex.

{ "type": "p", "children": [], "text": "\nDo not freeze.\nDiscard unused portion.\nSterile, Nonpyrogenic, Preservative-free, PVC-free, DEHP-free.The container closure is not made with natural rubber latex.\n" }

Alcohol and Current Medication

Advise patients to notify their healthcare provider about alcohol or medication use, especially blood pressure medication and antibiotics. Alcohol and other CNS depressants, such as opioid analgesic and benzodiazepines, can have an additive effect when administered with Midazolam in 0.9% Sodium Chloride Injection [see Warnings and Precautions (5.2), Drug Interactions (7.1)].

Effect of Anesthetic and Sedation Drugs on Early Brain Development

Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)].

Pregnancy

Advise pregnant females exposed to midazolam late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns. Instruct patients to inform their healthcare provider if they are pregnant during treatment with Midazolam in 0.9% Sodium Chloride Injection [see Warnings and Precautions (5.10), Use in Specific Populations (8.1)].

Lactation

Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients receiving midazolam to monitor infants for excessive sedation, poor feeding, and poor weight gain, and to seek medical attention if they notice these signs. A lactating woman may consider pumping and discarding breastmilk for at least 4 to 8 hours after receiving midazolam for sedation or anesthesia to minimize drug exposure to a breastfed infant [see Use in Specific Populations (8.2)].

Residual Sedation and Amnesia

Advise patients that they may experience residual sedation and amnesia. The decision as to when patients who have received injectable midazolam, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery, or drive a motor vehicle must be individualized [see Warnings and Precautions (5.8)].

Withdrawal

Advise patients that receive midazolam in a critical care setting over an extended period of time that they may experience symptoms of withdrawal following abrupt discontinuation.

sagent® Mfd. for SAGENT PharmaceuticalsSchaumburg, IL 60173 (USA)Made in India©2024 Sagent Pharmaceuticals

October 2024

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Bag Label

{ "type": "p", "children": [], "text": "PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Bag Label\n" }

NDC 25021-688-82

{ "type": "p", "children": [], "text": "NDC 25021-688-82\n" }

Rx only

{ "type": "p", "children": [], "text": "Rx only\n" }

Midazolam in 0.9% Sodium Chloride Injection

{ "type": "p", "children": [], "text": "Midazolam in 0.9% Sodium Chloride Injection\n" }

50 mg per 50 mL

{ "type": "p", "children": [], "text": "50 mg per 50 mL\n" }

(1 mg per mL)

{ "type": "p", "children": [], "text": "(1 mg per mL)\n" }

50 mL Single-Dose Container

{ "type": "p", "children": [], "text": "50 mL Single-Dose Container\n" }

High Alert Medication

{ "type": "p", "children": [], "text": "\nHigh Alert Medication\n" }

For Intravenous Use Only

{ "type": "p", "children": [], "text": "For Intravenous Use Only\n" }

Do Not Dilute

{ "type": "p", "children": [], "text": "Do Not Dilute\n" }

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Bag Label

{ "type": "p", "children": [], "text": "PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Bag Label\n" }

NDC 25021-688-87

{ "type": "p", "children": [], "text": "NDC 25021-688-87\n" }

Rx only

{ "type": "p", "children": [], "text": "Rx only\n" }

Midazolam in 0.9% Sodium Chloride Injection

{ "type": "p", "children": [], "text": "Midazolam in 0.9% Sodium Chloride Injection\n" }

100 mg per 100 mL

{ "type": "p", "children": [], "text": "100 mg per 100 mL\n" }

(1 mg per mL)

{ "type": "p", "children": [], "text": "(1 mg per mL)\n" }

100 mL Single-Dose Container

{ "type": "p", "children": [], "text": "100 mL Single-Dose Container\n" }

High Alert Medication

{ "type": "p", "children": [], "text": "\nHigh Alert Medication\n" }

For Intravenous Use Only

{ "type": "p", "children": [], "text": "For Intravenous Use Only\n" }

Do Not Dilute

{ "type": "p", "children": [], "text": "Do Not Dilute\n" }