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• RISKS FROM CONCOMITANT USE WITH OPIOIDS;
• ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS 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 (5.1), Drug Interactions (7.1)].
• The use of benzodiazepines, including midazolam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death.
• Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with a n increased frequency of serious adverse outcomes.
• Before prescribing Midazolam Injection and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2)].
• The continued use of benzodiazepines may lead to clinically significant physical dependence.
• The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose.
• Although Midazolam Injection 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 Midazolam Injection may precipitate acute withdrawal reactions, which can be life-threatening.
• For patients using Midazolam Injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue Midazolam Injection [see Warnings and Precautions (5.3)].
• WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS;
• ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS See full prescribing information for complete boxed warning.
• Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.
• Monitor patients for respiratory depression and sedation.
• (5.1, 7.1) The use of benzodiazepines, including midazolam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death.
• Before prescribing Midazolam Injection and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction.
• (5.2) Although Midazolam Injection is indicated only for intermitt ent use (1, 2), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of Midazolam Injection may precipitate acute withdrawal reactions, which can be lifethreatening.
• For patients using Midazolam Injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue Midazolam Injection.
• (5.3)

Midazolam Injection is contraindicated in patients with a known hypersensitivity to midazolam. Hypersensitivity to midazolam. (4)

• Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including Midazolam Injection, and opioids may result in profound sedation, respiratory depression, coma, and death.
• If a decision is made to use midazolam concomitantly with opioids, monitor patients closely for respiratory depression and sedation [see Drug Interactions (7.1)].
• Trained personnel administering Midazolam Injection must have the skills necessary to manage serious cardiorespiratory adverse reactions, including skills in airway management.
• Abuse, Misuse, and Addiction The use of benzodiazepines, including Midazolam Injection, 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)].
• Use of Midazolam Injection, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of Midazolam Injection 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.
• Dependence and Withdrawal Reactions After Use of Midazolam Injection More Frequently Than Recommended For patients using Midazolam Injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue Midazolam Injection (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 Midazolam Injection 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 Midazolam Injection, 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)].
• Risks of Cardiorespiratory Adverse Reactions Serious cardiorespiratory adverse reactions have occurred after administration of midazolam.
• These have included respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury.
• There have also been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical manipulations, particularly in patients with hemodynamic instability.
• Hypotension occurs more frequently in patients premedicated with a narcotic.
• The danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve [see Use in Specific Populations (8.5, 8.7)]; patients with COPD are highly sensitive to the respiratory depressant effect of midazolam.
• Midazolam Injection should be administered with caution to patients in shock or coma with depression of vital signs.
• Trained personnel administering Midazolam Injection must have the skills necessary to manage serious cardiorespiratory adverse reactions, including skills in airway management.
• Other Adverse Reactions Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity, and combativeness have been reported with midazolam when used for sedation.
• 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.
• Agitation also occurred in the randomized controlled clinical study of midazolam injection in patients with status epilepticus [see Adverse Reactions (6.1)].
• Risks from Concomitant Use of Central Nervous System Depressants 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.
• Midazolam Injection should be administered with caution to patients in acute alcohol intoxication with depression of vital signs.
• Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.
• The efficacy and safety of midazolam in clinical use are functions of the dose administered, the clinical status of the individual patient, and the use of concomitant medications capable of depressing the central nervous system (CNS).
• Anticipated effects range from mild sedation to deep levels of sedation virtually equivalent to a state of general anesthesia where the patient may require external support of vital functions.
• Trained personnel administering Midazolam Injection must have the skills necessary to manage serious cardiorespiratory adverse reactions, including skills in airway management.
• For information regarding withdrawal, see Drug Abuse and Dependence (9.3).
• Impaired Cognitive Function Midazolam 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.
• Glaucoma Benzodiazepines, including Midazolam 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; patients with glaucoma have not been studied.
• Patients with open-angle glaucoma may need to have their ophthalmologic status evaluated following treatment with Midazolam Injection.
• Midazolam Injection is not recommended in patients with narrow-angle glaucoma.
• Neonatal Sedation and Withdrawal Syndrome Use of Midazolam 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 [see Use in Specific Populations (8.1)].
• Monitor neonates exposed to Midazolam Injection during pregnancy or labor for signs of sedation and monitor neonates exposed to Midazolam Injection during pregnancy for signs of withdrawal; manage these infants accordingly.
• Serious cardiorespiratory adverse reactions have occurred, sometimes resulting in death or permanent neurologic injury, after administration of midazolam.
• (5.4) Other Adverse Reactions: Agitation can occur.
• (5.5) Risks from Concomitant Use of Central Nervous System (CNS) Depressants:
• May increase risk of hypoventilation, airway obstruction, desaturation, or apnea, and may contribute to profound and/or prolonged drug effect.
• Practitioners administering Midazolam Injection must have the skills necessary to manage serious cardiorespiratory adverse reactions, including skills in airway management.
• Because of partial or complete impairment of recall, patients should not operate hazardous machinery or a motor vehicle until drug effects have subsided.
• (5.7) Glaucoma:
• Patients with open-angle glaucoma may need to have their ophthalmologic status evaluated following treatment with Midazolam Injection.
• Midazolam injection is not recommended in patients with narrow-angle glaucoma.
• Midazolam Injection use during pregnancy can result in neonatal sedation and/or neonatal withdrawal.(5.9, 8.1)

• Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as Midazolam Injection, during pregnancy.
• Healthcare providers are encouraged to recommend that pregnant women who are taking Midazolam Injection 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 Infants 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 adverse effects on development (see Animal Data).
• Data for other benzodiazepines suggest the possibility of increased neuronal cell death and long-term effects on neurobehavioral and immunological function based on findings 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 defects, 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 Injection during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems.
• Monitor neonates exposed to Midazolam Injection 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 recommended human dose (RHD) of 10 mg based on body surface area (mg/m 2 ).
• 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 RHD on a mg/m 2 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 RHD on a mg/m 2 basis.
• In published animal studies, administration of benzodiazepines or other drugs that enhance GABAergic inhibition 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 that takes place during the third trimester of pregnancy in humans.
• Lactation 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 Midazolam Injection and any potential adverse effects on the breastfed child from Midazolam Injection or from the underlying maternal condition.
• Clinical Considerations Infants exposed to Midazolam Injection through breast milk should be monitored for sedation, poor feeding and poor weight gain.
• Pediatric Use Safety and effectiveness in pediatric patients have not been established.
• Benzodiazepines are not recognized as a treatment for status epilepticus in neonates and should not be used in this population.
• Geriatric Use Of the total number of patients from the intent-to-treat (ITT) population in the clinical trial of a different midazolam injection, 14.9 percent were 65 years of age and over, while 8.3 percent were 75 years of age and over.
• Geriatric patients may have altered drug distribution; diminished hepatic and/or renal function; longer elimination half-lives for midazolam and its metabolites, and subjects over 70 years of age may be particularly sensitive [see Clinical Pharmacology (12.3)].
• Administration of 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, 5.6)].
• Close monitoring of geriatric patients is recommended.
• Renal Impairment Patients with renal impairment may have a slower elimination of midazolam and its metabolites, which may result in prolonged drug exposure [see Clinical Pharmacology (12.3)].
• Congestive Heart Failure Patients with congestive heart failure eliminate midazolam more slowly, which may result in prolonged drug exposure [see Clinical Pharmacology (12.3)].
• Pregnancy: Based on animal data, may cause fetal harm.
• (8.1) See 17 for PATIENT COUNSELING INFORMATION.

• Effect of Concomitant Use of Benzodiazepines and Opioids 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.
• Limit dosage and duration of concomitant use of benzodiazepines and opioids.
• Monitor patients closely for respiratory depression and sedation.
• Other CNS Depressants and Alcohol The sedative effect of Midazolam Injection is accentuated by concomitantly administered medication that depresses the central nervous system, particularly opioids (e.g., morphine, meperidine, and fentanyl), secobarbital, and droperidol, and also by alcohol [see Warnings and Precautions (5.1, 5.4, 5.6)].
• Cytochrome P450-3A4 Inhibitors Caution is advised when Midazolam Injection is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system (e.g., cimetidine, erythromycin, diltiazem, verapamil, ketoconazole, and itraconazole).
• These drug interactions may result in prolonged sedation caused by a decrease in plasma clearance of midazolam [see Clinical Pharmacology (12.3)].
• Benzodiazepines and Opioids: Risk of respiratory depression is increased.
• (7.1) Other CNS Depressants and Alcohol: Sedative effect of midazolam is increased.
• (7.2) Cytochrome P450-3A4 Inhibitors:
• May result in prolonged sedation due to decreased plasma clearance of midazolam.
• (7.3)

• 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 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 a poison center (1-800-221-2222) or a medical toxicologist for additional overdosage management recommendations.

• Midazolam Injection contains midazolam, a Schedule IV controlled substance.
• Abuse Midazolam 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.
• Available data concerning the drug abuse and dependence potential of midazolam suggest that its abuse potential is at least equivalent to that of diazepam.
• Dependence Physical Dependence After Use of Midazolam Injection More Frequently Than Recommended Midazolam Injection 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 Midazolam Injection 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 Midazolam Injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue Midazolam Injection [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 Midazolam Injection 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.