ABUSE SECTION.

9.2 Abuse. SEIZALAM is benzodiazepine and CNS depressant with potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of drug by an individual in way other than prescribed by health care provider or for whom it was not prescribed. Drug addiction is cluster of behavioral, cognitive, and physiological phenomena that may include strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving 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 mild to moderate intensity in cynomolgus monkeys after 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.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are discussed in greater detail in other sections:Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)] Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2)] Dependence and Withdrawal Reactions After Use of SEIZALAM More Frequently Than Recommended [see Warnings and Precautions (5.3)] Risks of Cardiorespiratory Adverse Reactions [see Warnings and Precautions (5.4)] Other Adverse Reactions [see Warnings and Precautions (5.5)] Risks from Concomitant Use of Central Nervous System Depressants [see Warnings and Precautions (5.6)] Impaired Cognitive Function [see Warnings and Precautions (5.7)] Glaucoma [see Warnings and Precautions (5.8)] Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative [see Warnings and Precautions (5.9)] Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)] Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2)] Dependence and Withdrawal Reactions After Use of SEIZALAM More Frequently Than Recommended [see Warnings and Precautions (5.3)] Risks of Cardiorespiratory Adverse Reactions [see Warnings and Precautions (5.4)] Other Adverse Reactions [see Warnings and Precautions (5.5)] Risks from Concomitant Use of Central Nervous System Depressants [see Warnings and Precautions (5.6)] Impaired Cognitive Function [see Warnings and Precautions (5.7)] Glaucoma [see Warnings and Precautions (5.8)] Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative [see Warnings and Precautions (5.9)] The most common adverse reactions (incidence >3%) in clinical trials in patients with status epilepticus were upper airway obstruction, agitation, and pyrexia. (6.1)The most common adverse reaction (incidence >5%) observed in clinical trials for uses other than that for which SEIZALAM is indicated was decreased tidal volume and/or respiratory rate decrease (11%). (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or www.meridianmeds.com or FDA at 1-800-FDA-1088 or www.fda.gov.medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Adverse Reactions in the Controlled Study of Intramuscular Midazolam in Patients with Status EpilepticusIn double-blind, randomized, active-controlled clinical study, 448 patients were assigned to receive intramuscular (IM) midazolam via an autoinjector, and 445 were assigned to receive intravenous (IV) lorazepam. Approximately 45% of patients were female, and the mean age was 43 years. Patients were administered treatment by healthcare professional (e.g., paramedic) prior to arrival at hospital.Table lists the adverse reactions occurring in 2% or more of the IM midazolam-treated patients and at rate greater than the IV lorazepam-treated patients.Table Adverse Reactions in 2% or More of IM Midazolam-Treated Patients and More Frequent than in IV Lorazepam-Treated Patients in Out of Hospital Treatment of Status EpilepticusAdverse ReactionIM MidazolamN=448(%)IV LorazepamN=445(%)Upper airway obstruction53Agitation43Pyrexia43Mental status changes32Postictal state32Acute renal failure21. Adverse Reactions in Other Midazolam StudiesFluctuations in vital signs were the most frequently seen findings following parenteral administration of midazolam in adults for uses other than that for which SEIZALAM is indicated, and included decreased tidal volume and/or respiratory rate decrease [11% of patients following intramuscular administration], as well as variations in blood pressure and pulse rate. The majority of serious adverse effects, particularly those associated with oxygenation and ventilation, have been reported when midazolam was administered with other medications capable of depressing the CNS. The incidence of such events was higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube (e.g., upper endoscopy and dental procedures).The following additional adverse reactions were reported after intramuscular administration in adults: Headache (1.3%), and local effects at the IM injection site including pain (3.7%), induration (0.5%), redness (0.5%), and muscle stiffness (0.3%).

BOXED WARNING SECTION.

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS. 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 SEIZALAM, 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 an increased frequency of serious adverse outcomes. Before prescribing SEIZALAM and throughout treatment, assess each patients 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 SEIZALAM 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 SEIZALAM may precipitate acute withdrawal reactions, which can be life-threatening. For patients using SEIZALAM more frequently than recommended, to reduce the risk of withdrawal reactions, use gradual taper to discontinue SEIZALAM[see Warnings and Precautions (5.3)].. 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 SEIZALAM, 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 an increased frequency of serious adverse outcomes. Before prescribing SEIZALAM and throughout treatment, assess each patients 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 SEIZALAM 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 SEIZALAM may precipitate acute withdrawal reactions, which can be life-threatening. For patients using SEIZALAM more frequently than recommended, to reduce the risk of withdrawal reactions, use gradual taper to discontinue SEIZALAM[see Warnings and Precautions (5.3)].. WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONSSee 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 SEIZALAM, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing SEIZALAM and throughout treatment, assess each patients risk for abuse, misuse, and addiction. (5.2)Although SEIZALAM is indicated only for intermittent use (1, 2), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of SEIZALAM may precipitate acute withdrawal reactions, which can be life-threatening. For patients using SEIZALAM more frequently than recommended, to reduce the risk of withdrawal reactions, use gradual taper to discontinue SEIZALAM. (5.3). 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 SEIZALAM, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing SEIZALAM and throughout treatment, assess each patients risk for abuse, misuse, and addiction. (5.2). Although SEIZALAM is indicated only for intermittent use (1, 2), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of SEIZALAM may precipitate acute withdrawal reactions, which can be life-threatening. For patients using SEIZALAM more frequently than recommended, to reduce the risk of withdrawal reactions, use gradual taper to discontinue SEIZALAM. (5.3).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The exact mechanism of action for midazolam in the treatment of status epilepticus is not fully understood, but is thought to involve potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABAA receptor.. 12.2 Pharmacodynamics. 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. 12.3 Pharmacokinetics. The pharmacokinetics of midazolam were evaluated in single dose-escalation trial in healthy subjects; following IM injection of midazolam at doses ranging from fixed total amounts of mg to 30 mg (one half to three times the recommended dose) or body weight based dose of 0.10 mg/kg to 0.49 mg/kg, the overall median time to maximum plasma concentration (Tmax) was observed at approximately 0.5 hours after administration. The rate and extent of systemic exposure, as assessed by maximum plasma concentration (Cmax) and area under the plasma drug concentration-time curve from time to infinity (AUC0-), tended to increase proportionally with increasing dose from mg to 30 mg.. AbsorptionFollowing IM administration of single 10 mg midazolam dose to healthy subjects, midazolam was absorbed with median Tmax (range) of 0.5 (0.25 to 0.5) hours; midazolam mean (+-SD) Cmax and AUC0- were 113.9 (+-30.9) ng/mL and 402.7 (+-97.0) nghr/mL, respectively.. DistributionThe mean (+-SD) apparent volume of distribution (Vz/F) of midazolam following single IM dose of 10 mg midazolam was 2117 (+-845.1) mL/kg in healthy subjects.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)]. In adults, midazolam is approximately 97% bound to plasma protein, principally albumin. The 1-hydroxy metabolite is approximately 89% bound to plasma protein.. EliminationElimination of the parent drug takes place via hepatic metabolism of midazolam to hydroxylated metabolites that are conjugated and excreted in the urine.. MetabolismIn vitro studies with human liver microsomes indicate that the biotransformation of midazolam is mediated by the cytochrome P450-3A4 (CYP3A4). This enzyme is present in gastrointestinal tract mucosa, as well as in the liver. The 1-hydroxy-midazolam (also termed alpha-hydroxymidazolam) metabolite comprises 60% to 70% of the biotransformation products of midazolam, while 4-hydroxy-midazolam constitutes 5% or less. Small amounts of dihydroxy derivative have also been detected, but not quantified. 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. 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.. ExcretionFollowing IM administration of 10 mg midazolam, mean (+-SD) elimination half-life and apparent total body clearance (CL/F) of midazolam were 4.2 (+-1.87) hours and 367.3 (+-73.5) mL/hr/kg, respectively.The principal urinary excretion product is 1-hydroxy-midazolam in the form of 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 single IV dose is less than 0.5%. Following single IV infusion in healthy volunteers, 45% to 57% of the dose was excreted in the urine as the 1-hydroxymethyl midazolam conjugate.. Specific PopulationsChanges 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 (ARF) appear to have longer elimination half-life for midazolam [see Use in Specific Populations (8.6)]. In other groups, the relationship between prolonged half-life and duration of effect has not been established.. ObesityIn study comparing normal (n=20) and obese patients (n=20), the mean half-life was greater in the obese group (5.9 versus 2.3 hours). This was due to an increase of approximately 50% in the volume of distribution (Vd) corrected for total body weight. The clearance was not significantly different between groups.. Geriatric PatientsIn three parallel-group studies, the pharmacokinetics of midazolam administered IV or IM were compared in young (mean age 29 years, n=52) and healthy elderly subjects (mean age 73 years, n=53). Plasma half-life was approximately 2-fold higher in the elderly. The mean Vd based on total body weight increased consistently between 15% and 100% in the elderly. The mean CL (total clearance) decreased approximately 25% in the elderly in two studies, and was similar to that of the younger patients in the other [see Use in Specific Populations (8.5)].. Male and Female PatientsNo meaningful differences in midazolam exposures (Cmax and AUC) were observed between male and female adults after IM administration.. Patients with Congestive Heart FailureIn patients suffering from congestive heart failure, 2-fold increase in the elimination half-life, 25% decrease in the plasma clearance, and 40% increase in the volume of distribution of midazolam were observed.. Patients with Renal ImpairmentPatients 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 were compared between intensive care unit (ICU) patients who developed acute renal failure (ARF) and control group of subjects with normal renal function. Midazolam was administered as an IV infusion (5 to 15 mg/hour). Midazolam clearance was reduced (1.9 versus 2.8 mL/min/kg), and the half-life was prolonged (7.6 hours versus 13 hours) in the ARF patients. The renal clearance of the 1-hydroxy-midazolam glucuronide was prolonged in the ARF group (4 versus 136 mL/min), and the half-life was prolonged (12 hours versus >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 study of chronic renal failure patients (n=15) receiving single IV dose of midazolam, there was 2-fold increase in the clearance and volume of distribution, but the half-life remained unchanged. Metabolite levels were not studied.. Patients with Hepatic ImpairmentMidazolam pharmacokinetics were studied after single IV dose (0.075 mg/kg) was administered to patients with biopsy-proven alcoholic cirrhosis and control patients. The mean half-life of midazolam increased 2.5-fold in the patients with cirrhosis. Clearance was reduced by 50% and 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. The clinical significance of these findings is unknown.. Drug Interaction Studies. CYP3A4 InhibitorsDrugs that inhibit the activity of CYP3A4 may inhibit midazolam clearance and elevate midazolam concentrations [see Drug Interactions (7.3)].The effect of single oral doses of 800 mg cimetidine and 300 mg ranitidine on steady-state concentrations oral midazolam was examined in 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 placebo-controlled study, erythromycin administered as 500 mg dose, three times day, for week (n=6), reduced the clearance of midazolam following single 0.5 mg/kg IV dose. The half-life was approximately doubled.The effects of diltiazem (60 mg three times day) and verapamil (80 mg three times day) on the pharmacokinetics and pharmacodynamics of midazolam were investigated in three-way crossover study (n=9). The half-life of midazolam increased from to hours when midazolam was taken in conjunction with verapamil or diltiazem. No interaction was observed in healthy subjects between midazolam and nifedipine.In placebo-controlled study, where saquinavir or placebo was administered orally as 1200 mg dose three times day for days (n=12), 56% reduction in the clearance of midazolam following single 0.05 mg/kg IV dose was observed. The half-life was approximately doubled.. The effect of single oral doses of 800 mg cimetidine and 300 mg ranitidine on steady-state concentrations oral midazolam was examined in 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 placebo-controlled study, erythromycin administered as 500 mg dose, three times day, for week (n=6), reduced the clearance of midazolam following single 0.5 mg/kg IV dose. The half-life was approximately doubled.. The effects of diltiazem (60 mg three times day) and verapamil (80 mg three times day) on the pharmacokinetics and pharmacodynamics of midazolam were investigated in three-way crossover study (n=9). The half-life of midazolam increased from to hours when midazolam was taken in conjunction with verapamil or diltiazem. No interaction was observed in healthy subjects between midazolam and nifedipine.. In placebo-controlled study, where saquinavir or placebo was administered orally as 1200 mg dose three times day for days (n=12), 56% reduction in the clearance of midazolam following single 0.05 mg/kg IV dose was observed. The half-life was approximately doubled.. CYP3A4 InducersDrugs that induce the activity of CYP3A4 may increase midazolam clearance and decrease midazolam concentrations.

DEPENDENCE SECTION.

9.3 Dependence. Physical Dependence After Use of SEIZALAM More Frequently Than RecommendedSEIZALAM may produce physical dependence if used more frequently than recommended. Physical dependence is state that develops as result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dose reduction of drug. Although SEIZALAM 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, 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 SEIZALAM more frequently than recommended, to reduce the risk of withdrawal reactions, use gradual taper to discontinue SEIZALAM [see Warnings and Precautions (5.3)]. Acute Withdrawal Signs and SymptomsAcute 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 SyndromeProtracted 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 to weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.. ToleranceTolerance to SEIZALAM may develop after use more frequently than recommended. Tolerance is physiological state characterized by reduced response to drug after repeated administration (i.e., higher dose of drug is required to produce the same effect that was once obtained at 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.

DRUG ABUSE AND DEPENDENCE SECTION.

9 DRUG ABUSE AND DEPENDENCE. 9.1 Controlled Substance. SEIZALAM contains midazolam hydrochloride, Schedule IV controlled substance.. 9.2 Abuse. SEIZALAM is benzodiazepine and CNS depressant with potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of drug by an individual in way other than prescribed by health care provider or for whom it was not prescribed. Drug addiction is cluster of behavioral, cognitive, and physiological phenomena that may include strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving 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 mild to moderate intensity in cynomolgus monkeys after 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.. 9.3 Dependence. Physical Dependence After Use of SEIZALAM More Frequently Than RecommendedSEIZALAM may produce physical dependence if used more frequently than recommended. Physical dependence is state that develops as result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dose reduction of drug. Although SEIZALAM 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, 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 SEIZALAM more frequently than recommended, to reduce the risk of withdrawal reactions, use gradual taper to discontinue SEIZALAM [see Warnings and Precautions (5.3)]. Acute Withdrawal Signs and SymptomsAcute 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 SyndromeProtracted 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 to weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.. ToleranceTolerance to SEIZALAM may develop after use more frequently than recommended. Tolerance is physiological state characterized by reduced response to drug after repeated administration (i.e., higher dose of drug is required to produce the same effect that was once obtained at 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Patients having seizures will likely be unresponsive or may have difficulty in comprehending counseling information.. Risks from Concomitant Use with OpioidsInform patients and caregivers that potentially fatal additive effects may occur if SEIZALAM is used with opioids and not to use such drugs concomitantly unless supervised by healthcare provider [see Warnings and Precautions (5.1), Drug Interactions (7.1)]. Abuse, Misuse, and AddictionInform patients that the use of SEIZALAM 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 ReactionsInform patients that use of SEIZALAM more frequently than recommended may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of SEIZALAM may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed 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)]. Concomitant MedicationsAdvise patients to inform their physician about any alcohol consumption and medicine they are now taking, especially blood pressure medication and antibiotics, including drugs they buy without prescription. Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol during benzodiazepine treatment [see Warnings and Precautions (5.6), Drug Interactions (7)]. Impaired Cognitive FunctionAdvise patients not to operate hazardous machinery or motor vehicle until the effects of the drug, such as drowsiness, have subsided [see Warnings and Precautions (5.7)]. PregnancyInstruct patients to inform their physician if they are pregnant or are planning to become pregnant. Several studies have suggested an increased risk of congenital malformations associated with the use of benzodiazepine drugs. Animal studies have demonstrated an effect on early brain development and long-term cognitive effects with exposure to anesthetic and sedation drugs in the third trimester of gestation. Encourage patients to enroll in the North American Antiepileptic Drug Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)].. LactationInstruct patients to inform their physician if they are nursing [see Use in Specific Populations (8.2)].Manufactured by: Hospira, Inc.Lake Forest, IL 60045A Pfizer CompanyDistributed by: Meridian Medical Technologies, Inc.Columbia, MD 21046A Pfizer CompanyLAB-1070-3.0.

OVERDOSAGE SECTION.

10 OVERDOSAGE. SymptomsThe manifestations of midazolam overdosage reported are similar to those observed with other benzodiazepines, including sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma, and untoward effects on vital signs.. TreatmentTreatment of injectable midazolam overdosage is the same as that followed for overdosage with other benzodiazepines. Respiration, pulse rate, and blood pressure should be monitored and general supportive measures should be employed. Attention should be given to the maintenance of patent airway and support of ventilation, including administration of oxygen. An intravenous infusion should be started. Should hypotension develop, treatment may include intravenous fluid therapy, repositioning, judicious use of vasopressors appropriate to the clinical situation, if indicated, and other appropriate countermeasures. There is no information as to whether peritoneal dialysis, forced diuresis, or hemodialysis are of any value in the treatment of midazolam overdosage.Flumazenil, specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with benzodiazepine is known or suspected. There are anecdotal reports of reversal of adverse hemodynamic responses associated with midazolam following administration of flumazenil to pediatric patients. Prior to the administration of flumazenil, necessary measures should be instituted to secure the airway, assure adequate ventilation, and establish adequate intravenous access. The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk patients. The prescriber should be aware of risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users. The administration of flumazenil in cases of benzodiazepine overdose can lead to withdrawal and adverse reactions, including increased seizures. Its use in patients with epilepsy is typically not recommended.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of midazolam were evaluated in single dose-escalation trial in healthy subjects; following IM injection of midazolam at doses ranging from fixed total amounts of mg to 30 mg (one half to three times the recommended dose) or body weight based dose of 0.10 mg/kg to 0.49 mg/kg, the overall median time to maximum plasma concentration (Tmax) was observed at approximately 0.5 hours after administration. The rate and extent of systemic exposure, as assessed by maximum plasma concentration (Cmax) and area under the plasma drug concentration-time curve from time to infinity (AUC0-), tended to increase proportionally with increasing dose from mg to 30 mg.. AbsorptionFollowing IM administration of single 10 mg midazolam dose to healthy subjects, midazolam was absorbed with median Tmax (range) of 0.5 (0.25 to 0.5) hours; midazolam mean (+-SD) Cmax and AUC0- were 113.9 (+-30.9) ng/mL and 402.7 (+-97.0) nghr/mL, respectively.. DistributionThe mean (+-SD) apparent volume of distribution (Vz/F) of midazolam following single IM dose of 10 mg midazolam was 2117 (+-845.1) mL/kg in healthy subjects.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)]. In adults, midazolam is approximately 97% bound to plasma protein, principally albumin. The 1-hydroxy metabolite is approximately 89% bound to plasma protein.. EliminationElimination of the parent drug takes place via hepatic metabolism of midazolam to hydroxylated metabolites that are conjugated and excreted in the urine.. MetabolismIn vitro studies with human liver microsomes indicate that the biotransformation of midazolam is mediated by the cytochrome P450-3A4 (CYP3A4). This enzyme is present in gastrointestinal tract mucosa, as well as in the liver. The 1-hydroxy-midazolam (also termed alpha-hydroxymidazolam) metabolite comprises 60% to 70% of the biotransformation products of midazolam, while 4-hydroxy-midazolam constitutes 5% or less. Small amounts of dihydroxy derivative have also been detected, but not quantified. 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. 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.. ExcretionFollowing IM administration of 10 mg midazolam, mean (+-SD) elimination half-life and apparent total body clearance (CL/F) of midazolam were 4.2 (+-1.87) hours and 367.3 (+-73.5) mL/hr/kg, respectively.The principal urinary excretion product is 1-hydroxy-midazolam in the form of 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 single IV dose is less than 0.5%. Following single IV infusion in healthy volunteers, 45% to 57% of the dose was excreted in the urine as the 1-hydroxymethyl midazolam conjugate.. Specific PopulationsChanges 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 (ARF) appear to have longer elimination half-life for midazolam [see Use in Specific Populations (8.6)]. In other groups, the relationship between prolonged half-life and duration of effect has not been established.. ObesityIn study comparing normal (n=20) and obese patients (n=20), the mean half-life was greater in the obese group (5.9 versus 2.3 hours). This was due to an increase of approximately 50% in the volume of distribution (Vd) corrected for total body weight. The clearance was not significantly different between groups.. Geriatric PatientsIn three parallel-group studies, the pharmacokinetics of midazolam administered IV or IM were compared in young (mean age 29 years, n=52) and healthy elderly subjects (mean age 73 years, n=53). Plasma half-life was approximately 2-fold higher in the elderly. The mean Vd based on total body weight increased consistently between 15% and 100% in the elderly. The mean CL (total clearance) decreased approximately 25% in the elderly in two studies, and was similar to that of the younger patients in the other [see Use in Specific Populations (8.5)].. Male and Female PatientsNo meaningful differences in midazolam exposures (Cmax and AUC) were observed between male and female adults after IM administration.. Patients with Congestive Heart FailureIn patients suffering from congestive heart failure, 2-fold increase in the elimination half-life, 25% decrease in the plasma clearance, and 40% increase in the volume of distribution of midazolam were observed.. Patients with Renal ImpairmentPatients 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 were compared between intensive care unit (ICU) patients who developed acute renal failure (ARF) and control group of subjects with normal renal function. Midazolam was administered as an IV infusion (5 to 15 mg/hour). Midazolam clearance was reduced (1.9 versus 2.8 mL/min/kg), and the half-life was prolonged (7.6 hours versus 13 hours) in the ARF patients. The renal clearance of the 1-hydroxy-midazolam glucuronide was prolonged in the ARF group (4 versus 136 mL/min), and the half-life was prolonged (12 hours versus >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 study of chronic renal failure patients (n=15) receiving single IV dose of midazolam, there was 2-fold increase in the clearance and volume of distribution, but the half-life remained unchanged. Metabolite levels were not studied.. Patients with Hepatic ImpairmentMidazolam pharmacokinetics were studied after single IV dose (0.075 mg/kg) was administered to patients with biopsy-proven alcoholic cirrhosis and control patients. The mean half-life of midazolam increased 2.5-fold in the patients with cirrhosis. Clearance was reduced by 50% and 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. The clinical significance of these findings is unknown.. Drug Interaction Studies. CYP3A4 InhibitorsDrugs that inhibit the activity of CYP3A4 may inhibit midazolam clearance and elevate midazolam concentrations [see Drug Interactions (7.3)].The effect of single oral doses of 800 mg cimetidine and 300 mg ranitidine on steady-state concentrations oral midazolam was examined in 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 placebo-controlled study, erythromycin administered as 500 mg dose, three times day, for week (n=6), reduced the clearance of midazolam following single 0.5 mg/kg IV dose. The half-life was approximately doubled.The effects of diltiazem (60 mg three times day) and verapamil (80 mg three times day) on the pharmacokinetics and pharmacodynamics of midazolam were investigated in three-way crossover study (n=9). The half-life of midazolam increased from to hours when midazolam was taken in conjunction with verapamil or diltiazem. No interaction was observed in healthy subjects between midazolam and nifedipine.In placebo-controlled study, where saquinavir or placebo was administered orally as 1200 mg dose three times day for days (n=12), 56% reduction in the clearance of midazolam following single 0.05 mg/kg IV dose was observed. The half-life was approximately doubled.. The effect of single oral doses of 800 mg cimetidine and 300 mg ranitidine on steady-state concentrations oral midazolam was examined in 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 placebo-controlled study, erythromycin administered as 500 mg dose, three times day, for week (n=6), reduced the clearance of midazolam following single 0.5 mg/kg IV dose. The half-life was approximately doubled.. The effects of diltiazem (60 mg three times day) and verapamil (80 mg three times day) on the pharmacokinetics and pharmacodynamics of midazolam were investigated in three-way crossover study (n=9). The half-life of midazolam increased from to hours when midazolam was taken in conjunction with verapamil or diltiazem. No interaction was observed in healthy subjects between midazolam and nifedipine.. In placebo-controlled study, where saquinavir or placebo was administered orally as 1200 mg dose three times day for days (n=12), 56% reduction in the clearance of midazolam following single 0.05 mg/kg IV dose was observed. The half-life was approximately doubled.. CYP3A4 InducersDrugs that induce the activity of CYP3A4 may increase midazolam clearance and decrease midazolam concentrations.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as SEIZALAM, during pregnancy. Encourage women who are taking SEIZALAM during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.. Risk SummaryThere are no adequate and well-controlled studies of SEIZALAM in pregnant women. Available data suggest that the class of benzodiazepines is not associated with marked increases in risk for congenital anomalies. Although some early epidemiological studies suggested relationship between benzodiazepine use in pregnancy and congenital anomalies such as cleft lip and or palate, these studies had considerable limitations. More recently completed studies of benzodiazepine use in pregnancy have not consistently documented elevated risks for specific congenital anomalies. There is insufficient evidence to assess the effect of benzodiazepine pregnancy exposure on neurodevelopment.There are clinical considerations regarding exposure to benzodiazepines during the second and third trimester of pregnancy or immediately prior to or during childbirth. These risks include decreased fetal movement and/or fetal heart rate variability, floppy infant syndrome, dependence, and withdrawal (see Clinical Considerations and Human Data). Administration of midazolam to rats and rabbits during the period of organogenesis or to rats during late pregnancy and throughout lactation at doses greater than those used clinically did not result in 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. SEIZALAM should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Advise pregnant woman and women of childbearing age of the potential risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.. Clinical Considerations. Fetal/Neonatal Adverse ReactionsInfants born to mothers who have taken benzodiazepines during the later stages of pregnancy can develop dependence, and subsequently withdrawal, during the postnatal period. Clinical manifestations of withdrawal or neonatal abstinence syndrome may include hypertonia, hyperreflexia, hypoventilation, irritability, tremors, diarrhea, and vomiting. These complications can appear shortly after delivery to weeks after birth, and persist from hours to several months, depending on the degree of dependence and the pharmacokinetic profile of the benzodiazepine. Symptoms may be mild and transient or severe. Standard management for neonatal withdrawal syndrome has not yet been defined. Observe newborns who are exposed to SEIZALAM in utero during the later stages of pregnancy for symptoms of withdrawal and manage accordingly.. Labor and DeliveryAdministration of benzodiazepines immediately prior to or during childbirth can result in floppy infant syndrome, which is characterized by lethargy, hypothermia, hypotonia, respiratory depression, and difficulty feeding. Floppy infant syndrome occurs mainly within the first hours after birth and may last up to 14 days. Observe exposed newborns for these symptoms and manage accordingly.. Data. Human Data. Congenital AnomaliesAlthough there are no adequate and well controlled studies of SEIZALAM in pregnant women, there is information about benzodiazepines as class. Dolovich et al. published meta-analysis of 23 studies that examined the effects of benzodiazepine exposure during the first trimester of pregnancy. Eleven of the 23 studies included in the meta-analysis considered the use of chlordiazepoxide and diazepam and not other benzodiazepines. The authors considered case-control and cohort studies separately. The data from the cohort studies did not suggest an increased risk for major malformations (OR 0.90; 95% CI 0.61--1.35) or for oral cleft (OR 1.19; 95% CI 0.34--4.15). The data from the case-control studies suggested an association between benzodiazepines and major malformations (OR 3.01, 95% CI 1.32--6.84) and oral cleft (OR 1.79; 95% CI 1.13--2.82). The limitations of this meta-analysis included the small number of reports included in the analysis, and that most cases for analyses of both oral cleft and major malformations came from only three studies. follow up to that meta-analysis included new cohort studies that examined risk for major malformations and one study that considered cardiac malformations. The authors found no new studies with an outcome of oral clefts. After the addition of the new studies, the odds ratio for major malformations with first trimester exposure to benzodiazepines was 1.07 (95% CI 0.91--1.25).. Neonatal Withdrawal and Floppy Infant SyndromeNeonatal withdrawal syndrome and symptoms suggestive of floppy infant syndrome associated with administration of benzodiazepines during the later stages of pregnancy and peripartum period have been reported. Findings in published scientific literature suggest that the major neonatal side effects of benzodiazepines include sedation and dependence with withdrawal signs. Data from observational studies suggest that fetal exposure to benzodiazepines is associated with the neonatal adverse events of hypotonia, respiratory problems, hypoventilation, low Apgar score, and neonatal withdrawal syndrome.. Animal DataWhen midazolam (0, 0.2, 1, or 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 times the recommended human dose (RHD) of 10 mg based on body surface area (mg/m2).When midazolam (0, 0.2, 0.6, and 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 times the RHD on mg/m2 basis.When midazolam (0, 0.2, 1, or 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 times the RHD on mg/m2 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 period of brain development that takes place during the third trimester of pregnancy in humans.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm. (8.1). 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as SEIZALAM, during pregnancy. Encourage women who are taking SEIZALAM during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.. Risk SummaryThere are no adequate and well-controlled studies of SEIZALAM in pregnant women. Available data suggest that the class of benzodiazepines is not associated with marked increases in risk for congenital anomalies. Although some early epidemiological studies suggested relationship between benzodiazepine use in pregnancy and congenital anomalies such as cleft lip and or palate, these studies had considerable limitations. More recently completed studies of benzodiazepine use in pregnancy have not consistently documented elevated risks for specific congenital anomalies. There is insufficient evidence to assess the effect of benzodiazepine pregnancy exposure on neurodevelopment.There are clinical considerations regarding exposure to benzodiazepines during the second and third trimester of pregnancy or immediately prior to or during childbirth. These risks include decreased fetal movement and/or fetal heart rate variability, floppy infant syndrome, dependence, and withdrawal (see Clinical Considerations and Human Data). Administration of midazolam to rats and rabbits during the period of organogenesis or to rats during late pregnancy and throughout lactation at doses greater than those used clinically did not result in 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. SEIZALAM should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Advise pregnant woman and women of childbearing age of the potential risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.. Clinical Considerations. Fetal/Neonatal Adverse ReactionsInfants born to mothers who have taken benzodiazepines during the later stages of pregnancy can develop dependence, and subsequently withdrawal, during the postnatal period. Clinical manifestations of withdrawal or neonatal abstinence syndrome may include hypertonia, hyperreflexia, hypoventilation, irritability, tremors, diarrhea, and vomiting. These complications can appear shortly after delivery to weeks after birth, and persist from hours to several months, depending on the degree of dependence and the pharmacokinetic profile of the benzodiazepine. Symptoms may be mild and transient or severe. Standard management for neonatal withdrawal syndrome has not yet been defined. Observe newborns who are exposed to SEIZALAM in utero during the later stages of pregnancy for symptoms of withdrawal and manage accordingly.. Labor and DeliveryAdministration of benzodiazepines immediately prior to or during childbirth can result in floppy infant syndrome, which is characterized by lethargy, hypothermia, hypotonia, respiratory depression, and difficulty feeding. Floppy infant syndrome occurs mainly within the first hours after birth and may last up to 14 days. Observe exposed newborns for these symptoms and manage accordingly.. Data. Human Data. Congenital AnomaliesAlthough there are no adequate and well controlled studies of SEIZALAM in pregnant women, there is information about benzodiazepines as class. Dolovich et al. published meta-analysis of 23 studies that examined the effects of benzodiazepine exposure during the first trimester of pregnancy. Eleven of the 23 studies included in the meta-analysis considered the use of chlordiazepoxide and diazepam and not other benzodiazepines. The authors considered case-control and cohort studies separately. The data from the cohort studies did not suggest an increased risk for major malformations (OR 0.90; 95% CI 0.61--1.35) or for oral cleft (OR 1.19; 95% CI 0.34--4.15). The data from the case-control studies suggested an association between benzodiazepines and major malformations (OR 3.01, 95% CI 1.32--6.84) and oral cleft (OR 1.79; 95% CI 1.13--2.82). The limitations of this meta-analysis included the small number of reports included in the analysis, and that most cases for analyses of both oral cleft and major malformations came from only three studies. follow up to that meta-analysis included new cohort studies that examined risk for major malformations and one study that considered cardiac malformations. The authors found no new studies with an outcome of oral clefts. After the addition of the new studies, the odds ratio for major malformations with first trimester exposure to benzodiazepines was 1.07 (95% CI 0.91--1.25).. Neonatal Withdrawal and Floppy Infant SyndromeNeonatal withdrawal syndrome and symptoms suggestive of floppy infant syndrome associated with administration of benzodiazepines during the later stages of pregnancy and peripartum period have been reported. Findings in published scientific literature suggest that the major neonatal side effects of benzodiazepines include sedation and dependence with withdrawal signs. Data from observational studies suggest that fetal exposure to benzodiazepines is associated with the neonatal adverse events of hypotonia, respiratory problems, hypoventilation, low Apgar score, and neonatal withdrawal syndrome.. Animal DataWhen midazolam (0, 0.2, 1, or 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 times the recommended human dose (RHD) of 10 mg based on body surface area (mg/m2).When midazolam (0, 0.2, 0.6, and 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 times the RHD on mg/m2 basis.When midazolam (0, 0.2, 1, or 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 times the RHD on mg/m2 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 period of brain development that takes place during the third trimester of pregnancy in humans.. 8.2 Lactation. Risk SummaryMidazolam is excreted in human milk. Studies assessing the effects of midazolam in breastfed children or on milk production/excretion have not been performed. Postmarketing experience suggests that breastfed infants of mothers taking benzodiazepines, such as SEIZALAM, may have effects of lethargy, somnolence and poor sucking. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for midazolam and any potential adverse effects on the breastfed child from midazolam or from the underlying maternal condition.. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established. Benzodiazepines are not recognized as treatment for status epilepticus in neonates and should not be used in this population.SEIZALAM is not approved for use in neonates or infants. Serious adverse reactions including fatal reactions and the gasping syndrome occurred in premature neonates and low-birth-weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth-weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (SEIZALAM contains 10 mg of benzyl alcohol per mL) [see Warnings and Precautions (5.9)].. 8.5 Geriatric Use. Of the total number of patients from the intent-to-treat (ITT) population in the clinical trial of SEIZALAM, 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.. 8.6 Renal Impairment. Patients with renal impairment may have slower elimination of midazolam and its metabolites, which may result in prolonged drug exposure [see Clinical Pharmacology (12.3)].. 8.7 Congestive Heart Failure. Patients with congestive heart failure eliminate midazolam more slowly, which may result in prolonged drug exposure [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Risks of Cardiorespiratory Adverse Reactions: 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 SEIZALAM must have the skills necessary to manage serious cardiorespiratory adverse reactions, including skills in airway management.(5.6)Impaired Cognitive Function: Because of partial or complete impairment of recall, patients should not operate hazardous machinery or motor vehicle until drug effects have subsided. (5.7). Risks of Cardiorespiratory Adverse Reactions: 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 SEIZALAM must have the skills necessary to manage serious cardiorespiratory adverse reactions, including skills in airway management.(5.6). Impaired Cognitive Function: Because of partial or complete impairment of recall, patients should not operate hazardous machinery or motor vehicle until drug effects have subsided. (5.7). 5.1 Risks from Concomitant Use with Opioids. Concomitant use of benzodiazepines, including SEIZALAM, and opioids may result in profound sedation, respiratory depression, coma, and death. If decision is made to use midazolam concomitantly with opioids, monitor patients closely for respiratory depression and sedation [see Drug Interactions (7.1)]. Practitioners administering SEIZALAM must have the skills necessary to manage serious cardiorespiratory adverse reactions, including skills in airway management.. 5.2 Abuse, Misuse, and Addiction. The use of benzodiazepines, including SEIZALAM, 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 SEIZALAM and throughout treatment, assess each patients risk for abuse, misuse, and addiction. Use of SEIZALAM, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of SEIZALAM 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 substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.. 5.3 Dependence and Withdrawal Reactions After Use of SEIZALAM More Frequently Than Recommended. For patients using SEIZALAM more frequently than recommended, to reduce the risk of withdrawal reactions, use gradual taper to discontinue SEIZALAM (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 ReactionsThe continued use of benzodiazepines may lead to clinically significant physical dependence. Although SEIZALAM 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 SEIZALAM, 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 SyndromeIn some cases, benzodiazepine users have developed protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Drug Abuse and Dependence (9.3)].. 5.4 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 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. SEIZALAM should be administered with caution to patients in shock or coma with depression of vital signs.Practitioners administering SEIZALAM must have the skills necessary to manage serious cardiorespiratory adverse reactions, including skills in airway management.. 5.5 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 SEIZALAM in patients with status epilepticus [see Adverse Reactions (6.1)]. 5.6 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. SEIZALAM 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 state of general anesthesia where the patient may require external support of vital functions. Practitioners administering SEIZALAM 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).. 5.7 Impaired Cognitive Function. Midazolam is associated with 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 motor vehicle until the effects of the drug, such as drowsiness, have subsided, and as their medical condition permits.. 5.8 Glaucoma. Benzodiazepines, including SEIZALAM, can increase intraocular pressure in patients with glaucoma. Measurements of intraocular pressure in patients without eye disease show 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 SEIZALAM. SEIZALAM is not recommended in patients with narrow-angle glaucoma.. 5.9 Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative. SEIZALAM is not approved for use in neonates or infants. Serious and fatal adverse reactions including gasping syndrome can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs, including SEIZALAM. The gasping syndrome is characterized by CNS depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (SEIZALAM contains 10 mg of benzyl alcohol per mL) [see Use in Specific Populations (8.4)].

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Adverse Reactions in the Controlled Study of Intramuscular Midazolam in Patients with Status EpilepticusIn double-blind, randomized, active-controlled clinical study, 448 patients were assigned to receive intramuscular (IM) midazolam via an autoinjector, and 445 were assigned to receive intravenous (IV) lorazepam. Approximately 45% of patients were female, and the mean age was 43 years. Patients were administered treatment by healthcare professional (e.g., paramedic) prior to arrival at hospital.Table lists the adverse reactions occurring in 2% or more of the IM midazolam-treated patients and at rate greater than the IV lorazepam-treated patients.Table Adverse Reactions in 2% or More of IM Midazolam-Treated Patients and More Frequent than in IV Lorazepam-Treated Patients in Out of Hospital Treatment of Status EpilepticusAdverse ReactionIM MidazolamN=448(%)IV LorazepamN=445(%)Upper airway obstruction53Agitation43Pyrexia43Mental status changes32Postictal state32Acute renal failure21. Adverse Reactions in Other Midazolam StudiesFluctuations in vital signs were the most frequently seen findings following parenteral administration of midazolam in adults for uses other than that for which SEIZALAM is indicated, and included decreased tidal volume and/or respiratory rate decrease [11% of patients following intramuscular administration], as well as variations in blood pressure and pulse rate. The majority of serious adverse effects, particularly those associated with oxygenation and ventilation, have been reported when midazolam was administered with other medications capable of depressing the CNS. The incidence of such events was higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube (e.g., upper endoscopy and dental procedures).The following additional adverse reactions were reported after intramuscular administration in adults: Headache (1.3%), and local effects at the IM injection site including pain (3.7%), induration (0.5%), redness (0.5%), and muscle stiffness (0.3%).