Midazolam In 0.8% Sodium Chloride

Prescription

Brand names: MIDAZOLAM IN 0.8% SODIUM CHLORIDE

Dosage Form

Injection

Route

INTRAVENOUS

Manufacturer

B. Braun Medical Inc.

About This Medication

11 DESCRIPTION Midazolam in 0.8% Sodium Chloride Injection is a benzodiazepine available as a sterile, preservative-free, nonpyrogenic solution of midazolam and sodium chloride in water for injection for intravenous use. Each single-dose bag of Midazolam in Sodium Chloride Injection contains either 50 mg/50 mL (1 mg/mL) or 100 mg/100 mL (1 mg/mL) of midazolam and 8 mg/mL of sodium chloride in water for injection. Midazolam in 0.8% Sodium Chloride Injection may contain hydrochloric acid and/or sodium hydroxide for pH adjustment. The pH is 3.0 – 4.0. Midazolam is a white to light yellow crystalline compound, insoluble in water, freely soluble in ethanol, soluble in methanol. Chemically, midazolam is 8-chloro-6-(2-fluorophenyl)-1-methyl-4 H -imidazo[1,5-a] [1,4]benzodiazepine. Midazolam has the empirical formula C 18 H 13 ClFN 3 , a calculated molecular weight of 325.8 and the following structural formula: Structural Formula

Active Ingredients

Ingredient	Strength
Midazolam	-

Indications & Usage

1 INDICATIONS AND USAGE Midazolam in Sodium Chloride Injection is indicated: Continuous intravenous infusion for sedation of intubated and mechanically ventilated adult, pediatric, and neonatal patients as a component of anesthesia or during treatment in a critical care setting. Midazolam in Sodium Chloride Injection is a benzodiazepine indicated for: • Continuous intravenous infusion for sedation of intubated and mechanically ventilated adult, pediatric, and neonatal patients as a component of anesthesia or during treatment in a critical care setting.

How It Works

12.1 Mechanism of Action Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant.

Dosage & Administration

2 DOSAGE AND ADMINISTRATION • For intravenous injection only. Avoid intra-arterial injection or extravasation. ( 2.1 ) • Individualize dosing and titrate to desired clinical response, taking into account patient age, clinical status, and concomitant use of other CNS depressants. ( 2.1 ) • See Full Prescribing Information for complete dosage and administration information. ( 2 ) 2.1 Important Dosage and Administration Instructions Midazolam in Sodium Chloride Injection should only be administered intravenously. Avoid intra-arterial injection or extravasation [see Warnings and Precautions (5.7) ]. Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer Midazolam in Sodium Chloride Injection. Administering personnel must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, including the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation. Supplemental oxygen, resuscitative drugs, and age- and size-appropriate equipment for bag/valve/mask assisted ventilation must be immediately available during administration of Midazolam in Sodium Chloride Injection. A benzodiazepine reversal agent should be immediately available. Continuously monitor vital signs during sedation and through the recovery period [see Warnings and Precautions (5.1) ]. Midazolam must never be used without individualization of dosage particularly when used with other medications capable of producing central nervous system depression [ Warnings and Precautions (5.2) ]. Midazolam in Sodium Chloride Injection can cause respiratory depression. It is a potent sedative agent that requires slow administration and individualization of dosage. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/ or arrest. Continuously monitor patients for early signs of hypoventilation, airway obstruction, and apnea using capnography, pulse oximetry, and clinical assessment [see Warnings and Precautions (5.3) ]. Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric patients [see Warnings and Precautions (5.4) ]. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. If solution is discolored or particulate matter is present, do not use. Once the bag has been penetrated, limit the infusion duration to 48 hours maximum. 2.2 General Dosing Information Individualize dosing and titrate to desired clinical response, taking into account patient age, clinical status, and concomitant use of other CNS depressants. Titrate to effect with multiple small doses while continuously monitoring respiratory and cardiac function (i.e., pulse oximetry). To minimize the potential for oversedation, allow adequate time between doses to achieve peak central nervous system effect (3 to 5 minutes). Adults and Pediatrics Sedation guidelines recommend a careful presedation history to determine how a patient's underlying medical conditions or concomitant medications might affect their response to sedation/ analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting. Pediatrics Pediatric patients generally require higher dosages of midazolam (mg/kg) than adults. For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure. Elderly and Debilitated Patients Intravenous doses of midazolam should be decreased for elderly and for debilitated patients [see Warnings and Precautions (5.6) ]. These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia [see Warnings and Precautions (5.8) ]. Monitoring Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes. This is especially true in pediatric patients. Continuously monitor vital signs during sedation and through the recovery period [see Warnings and Precautions (5.1) ]. 2.3 Dosing Recommendations Table 1 provides dosing recommendations for adult, pediatric, and neonatal patients. Table 1. Dosing Recommendations for Continuous Intravenous Infusion in Adult, Pediatric, and Neonatal Patients ADULT PATIENTS If a loading dose is necessary to rapidly initiate sedation, 0.01 mg/kg to 0.05 mg/kg (approximately 0.5 mg to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 mg/kg/hr to 0.10 mg/kg/hr (1 mg/hr to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients. Use the lowest recommended doses in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids. Individual response to midazolam is variable. Titrate the infusion rate to the desired level of sedation, taking into account the patient's age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation. Assess sedation at regular intervals and adjust the midazolam infusion rate. Finding the minimum effective infusion rate decreases the potential accumulation of midazolam and provides for the most rapid recovery once the infusion is terminated. PEDIATRIC PATIENTS UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients. In obese pediatric patients, calculate the dose based on ideal body weight. Titrate the dose to the desired level of sedation. Assess for desired level of sedation and vital signs at regular intervals. PRETERM AND TERM NEONATAL PATIENTS Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, initiate continuous intravenous infusions of Midazolam in Sodium Chloride Injection at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates >32 weeks. Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. Frequently assess the rate of infusion, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly. When sedating preterm and former preterm neonates WHOSE TRACHEA WAS NOT INTUBATED, monitor respiratory parameters due to an increased risk of apnea. 2.4 Safe Discontinuation of Midazolam in Sodium Chloride Injection After Long-Term Use If Midazolam in Sodium Chloride Injection is administered long-term (for several days to weeks), do not abruptly discontinue. Gradually taper the dosage in physically-dependent patients using a tapering schedule that is individualized to the patient. (see Warnings and Precautions (5.5) ).

Side Effects Overview

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections: Cardiorespiratory Adverse Reactions [see Warnings and Precautions (5.3) ] Paradoxical Behavior [see Warnings and Precautions (5.4) ] Dependence and Withdrawal [see Warnings and Precautions (5.5) ] Impaired Cognitive Function [see Warnings and Precautions (5.8) ] Hypotension and Seizure in Preterm Infants and Neonates [see Warnings and Precautions (5.9) ] Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.10) , Use in Specific Populations (8.1) ] Pediatric Neurotoxicity [see Warnings and Precautions (5.11) ] The following adverse reactions have been identified from literature or postmarketing reports of midazolam. Because some of these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Fluctuations in vital signs were the most frequently seen findings following parenteral administration of midazolam in adults and included decreased tidal volume and/or respiratory rate decrease (23.3% of patients following intravenous administration) and apnea (15.4% of patients following intravenous administration), as well as variations in blood pressure and pulse rate. The majority of serious adverse reactions, particularly those associated with oxygenation and ventilation, have been reported when midazolam is administered with other medications capable of depressing the central nervous system. The incidence of such events is higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube, (e.g., upper endoscopy and dental procedures). Adults Table 2: Additional Adverse Reactions Reported Subsequent to Intravenous Administration as a Single Sedative/anxiolytic/amnestic Agent in Adult Patients: hiccoughs (3.9%) Local effects at the intravenous site nausea (2.8%) tenderness (5.6%) vomiting (2.6%) pain during injection (5.0%) coughing (1.3%) redness (2.6%) "oversedation" (1.6%) induration (1.7%) headache (1.5%) phlebitis (0.4%) drowsiness (1.2%) Pediatric Patients The following adverse events related to the use of intravenous midazolam in pediatric patients were reported in the medical literature: desaturation 4.6%, apnea 2.8%, hypotension 2.7%, paradoxical reactions 2.0%, hiccough 1.2%, seizure-like activity 1.1% and nystagmus 1.1%. The majority of airway-related events occurred in patients receiving other CNS depressing medications and in patients where midazolam was not used as a single sedating agent. Neonates There have been reports of hypotensive episodes and seizures following the administration of midazolam to neonates, [see Warnings and Precautions (5.9) ]. Other Adverse Reactions Occurring at an Incidence of <1.0% Following Intravenous Injection as a Single Sedative/Anxiolytic/Amnesia Agent Respiratory : Laryngospasm, bronchospasm, dyspnea, hyperventilation, wheezing, shallow respirations, airway obstruction, tachypnea Cardiovascular : Bigeminy, premature ventricular contractions, vasovagal episode, bradycardia, tachycardia, nodal rhythm Gastrointestinal : Acid taste, excessive salivation, retching CNS/Neuromuscular : Retrograde amnesia, euphoria, hallucination, confusion, argumentativeness, nervousness, anxiety, grogginess, restlessness, emergence delirium or agitation, prolonged emergence from anesthesia, dreaming during emergence, sleep disturbance, insomnia, nightmares, athetoid movements, seizure-like activity, ataxia, dizziness, dysphoria, slurred speech, dysphonia, paresthesia Special Senses : Blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic movements of eyelids, visual disturbance, difficulty focusing eyes, ears blocked, loss of balance, light-headedness Integumentary : Hive-like elevation at injection site, swelling or feeling of burning, warmth or coldness at injection site Hypersensitivity : Allergic reactions including anaphylactic reactions, hives, rash, pruritus Miscellaneous : Yawning, lethargy, chills, weakness, toothache, faint feeling, hematoma The most common adverse reactions (≥15%) were decreased tidal volume, decreased respiratory rate, and apnea. To report SUSPECTED ADVERSE REACTIONS, contact B. Braun Medical Inc. at 1-833-425-1464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Warnings & Precautions

5 WARNINGS AND PRECAUTIONS Cardiorespiratory Adverse Reactions : Serious cardiorespiratory adverse reactions have occurred, sometimes resulting in death or permanent neurologic injury. ( 5.3 ) Paradoxical Behavior : Agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. ( 5.4 ) Dependence and Withdrawal with Long-Term Use : Use for several days to weeks may lead to physical dependence to midazolam. Do not abruptly discontinue midazolam. Gradually taper the dosage using a tapering schedule that is individualized to the patient. ( 5.5 ) Debilitation and Comorbid Considerations : Higher risk adult and pediatric surgical patients, elderly patients and debilitated adult and pediatric patients require lower dosages, whether or not concomitant sedating medications have been administered. ( 5.6 ) Risk of Intra-Arterial Injection : There have been limited reports of intra- arterial injection of midazolam. Adverse events have included local reactions, as well as isolated reports of seizure activity in which no clear causal relationship was established. ( 5.7 ) Impaired Cognitive Function : Because of partial or complete impairment of recall, patients should not operate hazardous machinery or a motor vehicle until drug effects have subsided. ( 5.8 ) Hypotension and Seizure in Preterm Infants and Neonates : Avoid rapid injection in the neonatal population. ( 5.9 ) Neonatal Sedation and Withdrawal Syndrome : Receiving Midazolam in Sodium Chloride Injection during pregnancy can result in neonatal sedation and/or neonatal withdrawal. ( 5.10 , 8.1 ) Pediatric Neurotoxicity : In developing animals, exposures greater than 3 hours cause neurotoxicity. Weigh benefits against potential risks when considering elective procedures in children under 3 years old. ( 5.11 ) 5.1 Personnel and Equipment for Monitoring and Resuscitation Prior to the intravenous administration of midazolam in any dose, ensure the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/ valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation. Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer Midazolam in Sodium Chloride Injection. Administering personnel must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, including the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation. Continuously monitor patients for early signs of hypoventilation, airway obstruction, or apnea, with means readily available (e.g., pulse oximetry). Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately. A benzodiazepine reversal agent (i.e., flumazenil) should be immediately available during administration of Midazolam in Sodium Chloride Injection. Continuously monitor vital signs during the recovery period. Because intravenous midazolam can depress respiration [see Clinical Pharmacology (12) ] , especially when used concomitantly with opioid agonists and other sedatives [see Dosage and Administration (2) ] , it should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway, and supporting ventilation. 5.2 Risks from Concomitant Use with Opioids, Other Sedative Hypnotics, or Other Central Nervous System Depressants Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Monitor patients for respiratory depression and sedation [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ]. Titrate the dose of Midazolam in Sodium Chloride Injection when administered with opioid analgesics and sedative-hypnotics to the desired clinical response. Continuously monitor sedated patients for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation. These cardiorespiratory effects may be more likely to occur in patients with obstructive sleep apnea, the elderly, and ASA-PS III or IV patients. Concomitant use of barbiturates, alcohol, or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect. Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation. 5.3 Risk 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 adult or pediatric patients with hemodynamic instability. Hypotension occurred more frequently in the sedation studies in patients premedicated with an opioid. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. When used for sedation/anxiolysis/amnesia, midazolam should always be titrated slowly in adult or pediatric patients. Adverse hemodynamic events have been reported in pediatric patients with cardiovascular instability; rapid intravenous administration should also be avoided in this population. Continuously monitor patients for early signs of hypoventilation, airway obstruction, and apnea using capnography, pulse oximetry, and clinical assessment [see Dosage and Administration (2.2) ]. 5.4 Risk of Paradoxical Behavior Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. These reactions may be due to inadequate or excessive dosing or improper administration of midazolam; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions. Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric patients. 5.5 Risk of Dependence and Withdrawal with Long-Term Use of Midazolam in Sodium Chloride Injection The continued use of benzodiazepines for several days to weeks may lead to clinically significant physical dependence. If used for long-term use (i.e., for several days to weeks), abrupt discontinuation or rapid dosage reduction of midazolam, or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use. After extended therapy, do not abruptly discontinue Midazolam in Sodium Chloride Injection. When discontinuing midazolam in a physically-dependent patient, gradually taper the dosage using a tapering schedule that is individualized to the patient [see Dosage and Administration (2.3) , Dependence (9.3) ]. 5.6 Debilitation and Comorbid Considerations Higher risk adult and pediatric surgical patients, elderly patients and debilitated adult and pediatric patients require lower dosages, whether or not concomitant sedating medications have been administered. Adult or pediatric patients with COPD are unusually sensitive to the respiratory depressant effect of midazolam. Pediatric and adult patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction. Adult and pediatric patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly [see Clinical Pharmacology (12.3) ]. Because elderly patients frequently have inefficient function of one or more organ systems and because dosage requirements have been shown to decrease with age, reduced initial dosage of midazolam is recommended, and the possibility of profound and/or prolonged effect should be considered. Do not administer Midazolam in Sodium Chloride Injection to adult or pediatric patients in shock or coma, or in acute alcohol intoxication with depression of vital signs. Particular care should be exercised in the use of intravenous midazolam in adult or pediatric patients with uncompensated acute illnesses, such as severe fluid or electrolyte disturbances. 5.7 Risk of Intra-Arterial Injection There have been limited reports of intra-arterial injection of midazolam. Adverse events have included local reactions, as well as isolated reports of seizure activity in which no clear causal relationship was established. Precautions against unintended intra-arterial injection should be taken. Extravasation should also be avoided. The safety and efficacy of Midazolam in Sodium Chloride Injection following nonintravenous routes of administration have not been established. Midazolam in Sodium Chloride Injection should only be administered intravenously. 5.8 Impaired Cognitive Function Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours. The decision as to when patients who have received injectable midazolam, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized. Gross tests of recovery from the effects of midazolam [see Clinical Pharmacology (12.3) ] cannot be relied upon to predict reaction time under stress. It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer. For pediatric patients, particular care should be taken to assure safe ambulation. 5.9 Risk of Hypotension and Seizure in Preterm Infants and Neonates Rapid injection should be avoided in the neonatal population. Midazolam administered rapidly as an intravenous injection (i.e., less than 2 minutes) has been associated with severe hypotension in neonates, particularly when the patient has also received fentanyl. Likewise, severe hypotension has been observed in neonates receiving a continuous infusion of midazolam who then receive a rapid intravenous injection of fentanyl. Seizures have been reported in several neonates following rapid intravenous administration. The neonate also has reduced and/or immature organ function and is also vulnerable to profound and/or prolonged respiratory effects of midazolam. 5.10 Neonatal Sedation and Withdrawal Syndrome Receiving Midazolam in Sodium Chloride Injection late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremor, inconsolable crying, and feeding difficulties) in the neonate. Monitor neonates exposed to Midazolam in Sodium Chloride Injection during pregnancy or labor for signs of sedation and manage these neonates accordingly [see Use in Specific Populations (8.1) ]. 5.11 Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see Nonclinical Pharmacology (13.2) ]. Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness. Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks. 5.12 Risk of Increased Intraocular Pressure in Patients with Glaucoma Benzodiazepines, including Midazolam in Sodium Chloride Injection, can increase intraocular pressure in patients with glaucoma. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam. Midazolam in Sodium Chloride Injection may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. Patients with open-angle glaucoma may need to have their ophthalmologic status evaluated following treatment with Midazolam in Sodium Chloride Injection. Midazolam in Sodium Chloride Injection is contraindicated in patients with narrow-angle glaucoma.

Contraindications

4 CONTRAINDICATIONS Midazolam in Sodium Chloride Injection is contraindicated in patients with: Known hypersensitivity to midazolam Acute narrow-angle glaucoma Midazolam in Sodium Chloride Injection is contraindicated in patients with: • known hypersensitivity to midazolam. (4) • acute narrow-angle glaucoma.

Pharmacokinetics

12.3 Pharmacokinetics Midazolam's activity is primarily due to the parent drug. Elimination of the parent drug takes place via hepatic metabolism of midazolam to hydroxylated metabolites that are conjugated and excreted in the urine. Six single-dose pharmacokinetic studies involving healthy adults yield pharmacokinetic parameters for midazolam in the following ranges: volume of distribution (Vd), 1.0 to 3.1 L/kg; elimination half-life, 1.8 to 6.4 hours (mean approximately 3 hours); total clearance (Cl), 0.25 to 0.54 L/hr/kg. In a parallel group study, there was no difference in the clearance, in subjects administered 0.15 mg/kg (n=4) and 0.30 mg/kg (n=4) intravenous doses indicating linear kinetics. The clearance was successively reduced by approximately 30% at doses of 0.45 mg/kg (n=4) and 0.6 mg/kg (n=5) indicating non-linear kinetics in this dose range. Absorption Following intramuscular administration, C max for midazolam and its 1-hydroxy metabolite were approximately one-half of those achieved after intravenous injection. Distribution The volume of distribution (Vd) determined from six single-dose pharmacokinetic studies involving healthy adults ranged from 1.0 to 3.1 L/kg. Female gender, old age, and obesity are associated with increased values of midazolam Vd. In humans, midazolam has been shown to cross the placenta and enter into fetal circulation and has been detected in human milk and CSF (see Clinical Pharmacology, Special Populations). In adults and pediatric patients older than 1 year, midazolam is approximately 97% bound to plasma protein, principally albumin and that for 1-hydroxy metabolite is about 89%. Elimination Metabolism In vitro studies with human liver microsomes indicate that the biotransformation of midazolam is mediated by cytochrome P450-3A4. This cytochrome also appears to be present in gastrointestinal tract mucosa as well as liver. Sixty to seventy percent of the biotransformation products is 1-hydroxy-midazolam (also termed alpha-hydroxy-midazolam) while 4- hydroxy-midazolam constitutes 5% or less. Small amounts of a dihydroxy derivative have also been detected but not quantified. The principal urinary excretion products are glucuronide conjugates of the hydroxylated derivatives. Drugs that inhibit the activity of cytochrome P450-3A4 may inhibit midazolam clearance and elevate steady-state midazolam concentrations. Studies of the intravenous administration of 1-hydroxy-midazolam in humans suggest that 1-hydroxy-midazolam is at least as potent as the parent compound and may contribute to the net pharmacologic activity of midazolam. In vitro studies have demonstrated that the affinities of 1- and 4-hydroxy-midazolam for the benzodiazepine receptor are approximately 20% and 7%, respectively, relative to midazolam. Excretion Clearance of midazolam is reduced in association with old age, congestive heart failure, liver disease (cirrhosis) or conditions which diminish cardiac output and hepatic blood flow. The principal urinary excretion product is 1-hydroxy-midazolam in the form of a glucuronide conjugate; smaller amounts of the glucuronide conjugates of 4-hydroxy- and dihydroxy-midazolam are detected as well. The amount of midazolam excreted unchanged in the urine after a single intravenous dose is less than 0.5% (n=5). Following a single intravenous infusion in 5 healthy volunteers, 45% to 57% of the dose was excreted in the urine as 1-hydroxymethyl midazolam conjugate. Pharmacokinetics-Continuous Infusion The pharmacokinetic profile of midazolam following continuous infusion, based on 282 adult subjects, has been shown to be similar to that following single-dose administration for subjects of comparable age, gender, body habitus and health status. However, midazolam can accumulate in peripheral tissues with continuous infusion. The effects of accumulation are greater after long-term infusions than after short-term infusions. The effects of accumulation can be reduced by maintaining the lowest midazolam infusion rate that produces satisfactory sedation. Infrequent hypotensive episodes have occurred during continuous infusion; however, neither the time to onset nor the duration of the episode appeared to be related to plasma concentrations of midazolam or alpha-hydroxy-midazolam. Further, there does not appear to be an increased chance of occurrence of a hypotensive episode with increased loading doses. Patients with renal impairment may have longer elimination half-lives for midazolam [see Clinical Pharmacology (12.3) ]. Specific Populations Changes in the pharmacokinetic profile of midazolam due to drug interactions, physiological variables, etc., may result in changes in the plasma concentration-time profile and pharmacological response to midazolam in these patients. For example, patients with acute renal failure appear to have a longer elimination half-life for midazolam and may experience delayed recovery [see Clinical Pharmacology (12.3) ]. In other groups, the relationship between prolonged half-life and duration of effect has not been established. Age: Pediatrics and Neonates In pediatric patients aged 1 year and older, the pharmacokinetic properties following a single dose of midazolam reported in 10 separate studies of midazolam are similar to those in adults. Weight-normalized clearance is similar or higher (0.19 to 0.80 L/hr/kg) than in adults and the terminal elimination half-life (0.78 to 3.3 hours) is similar to or shorter than in adults. The pharmacokinetic properties during and following continuous intravenous infusion in pediatric patients in the operating room as an adjunct to general anesthesia and in the intensive care environment are similar to those in adults. In seriously ill neonates, however, the terminal elimination half-life of midazolam is substantially prolonged (6.5 to 12.0 hours) and the clearance reduced (0.07 to 0.12 L/hr/kg) compared to healthy adults or other groups of pediatric patients. It cannot be determined if these differences are due to age, immature organ function or metabolic pathways, underlying illness or debility. Age: Geriatric In three parallel group studies, the pharmacokinetics of midazolam administered intravenous or intramuscular were compared in young (mean age 29, n=52) and healthy elderly subjects (mean age 73, n=53). Plasma half-life was approximately two-fold higher in the elderly. The mean Vd based on total body weight increased consistently between 15% to 100% in the elderly. The mean Cl decreased approximately 25% in the elderly in two studies and was similar to that of the younger patients in the other. Obese In a study comparing normals (n=20) and obese patients (n=20) the mean half-life was greater in the obese group (5.9 vs 2.3 hrs). This was due to an increase of approximately 50% in the Vd corrected for total body weight. The clearance was not significantly different between groups. Congestive Heart Failure In patients suffering from congestive heart failure, there appeared to be a two-fold increase in the elimination half-life, a 25% decrease in the plasma clearance and a 40% increase in the volume of distribution of midazolam. Hepatic Impairment Midazolam pharmacokinetics were studied after an intravenous single dose (0.075 mg/kg) was administered to 7 patients with biopsy proven alcoholic cirrhosis and 8 control patients. The mean half-life of midazolam increased 2.5-fold in the alcoholic patients. Clearance was reduced by 50% and the Vd increased by 20%. In another study in 21 male patients with cirrhosis, without ascites and with normal kidney function as determined by creatinine clearance, no changes in the pharmacokinetics of midazolam or 1-hydroxy-midazolam were observed when compared to healthy individuals. Renal Impairment Patients with renal impairment may have longer elimination half-lives for midazolam and its metabolites which may result in slower recovery. Midazolam and 1-hydroxy-midazolam pharmacokinetics in 6 ICU patients who developed acute renal failure (ARF) were compared with a normal renal function control group. Midazolam was administered as an infusion (5 to 15 mg/hours). Midazolam clearance was reduced (1.9 vs 2.8 mL/min/kg) and the half-life was prolonged (7.6 vs 13 hours) in the ARF patients. The renal clearance of the 1-hydroxy-midazolam glucuronide was prolonged in the ARF group (4 vs 136 mL/min) and the half-life was prolonged (12 vs >25 hours). Plasma levels accumulated in all ARF patients to about ten times that of the parent drug. The relationship between accumulating metabolite levels and prolonged sedation is unclear. In a study of chronic renal failure patients (n=15) receiving a single intravenous dose, there was a two-fold increase in the clearance and volume of distribution but the half-life remained unchanged. Metabolite levels were not studied.

Frequently Asked Questions

1 INDICATIONS AND USAGE Midazolam in Sodium Chloride Injection is indicated: Continuous intravenous infusion for sedation of intubated and mechanically ventilated adult, pediatric, and neonatal patients as a component of anesthesia or during treatment in a critical care setting. Midazolam in Sodium Chloride Injection is a benzodiazepine indicated for: • Continuous intravenous infusion for sedation of intubated and mechanically ventilated adult, pediatric, and neonatal patients as a component of anesthesia or during treatment in a critical care setting.

2 DOSAGE AND ADMINISTRATION • For intravenous injection only. Avoid intra-arterial injection or extravasation. ( 2.1 ) • Individualize dosing and titrate to desired clinical response, taking into account patient age, clinical status, and concomitant use of other CNS depressants. ( 2.1 ) • See Full Prescribing Information for complete dosage and administration information. ( 2 ) 2.1 Important Dosage and Administration Instructions Midazolam in Sodium Chloride Injection should only be administered intravenously. Avoid intra-arterial injection or extravasation [see Warnings …

5 WARNINGS AND PRECAUTIONS Cardiorespiratory Adverse Reactions : Serious cardiorespiratory adverse reactions have occurred, sometimes resulting in death or permanent neurologic injury. ( 5.3 ) Paradoxical Behavior : Agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. ( 5.4 ) Dependence and Withdrawal with Long-Term Use : Use for several days to weeks may lead to physical dependence to midazolam. Do not abruptly discontinue midazolam. Gradually taper the …

4 CONTRAINDICATIONS Midazolam in Sodium Chloride Injection is contraindicated in patients with: Known hypersensitivity to midazolam Acute narrow-angle glaucoma Midazolam in Sodium Chloride Injection is contraindicated in patients with: • known hypersensitivity to midazolam. (4) • acute narrow-angle glaucoma.

Midazolam In 0.8% Sodium Chloride is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

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References & Data Sources

• DailyMed — Midazolam In 0.8% Sodium Chloride drug label (National Library of Medicine)
• openFDA — Midazolam In 0.8% Sodium Chloride label data (U.S. Food & Drug Administration)
• RxNorm — RXCUI 2541170 (NLM Normalized Drug Names)
• NDC Directory — Midazolam In 0.8% Sodium Chloride (FDA National Drug Code)

Medical Disclaimer

The information on this page is intended for educational purposes only and should not be used as a substitute for professional medical advice, diagnosis, or treatment.

Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition or medication.

Data sources: DailyMed (NLM), openFDA, MFDS