MIDAZOLAM HCL

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer undiluted on an empty stomach (presedation fasting). Do not mix with any water or juice prior to administration.
-Measure dosage using a calibrated oral syringe.
-Midazolam syrup is not intended for chronic administration.
-Resuscitative medications and size-appropriate equipment for bag/valve/mask ventilation and intubation must be readily available.
Extemporaneous Compounding-Oral
Extemporaneous Oral Solution (2.5 mg/mL)
-Combine the 5 mg/mL injection with a flavored, dye-free syrup (e.g., Syrpalta) in a 1:1 ratio.
-Storage: The resulting solution is stable for 56 days at 7, 20, or 40 degrees C when stored in an amber glass bottle.



Injectable Administration
-Only practitioners trained in maintaining a patent airway should administer midazolam; have age- and size-appropriate resuscitative drugs and equipment readily available.
-Administer parenteral midazolam to patients receiving extracorporeal membrane oxygenation (ECMO) outside of the circuit if possible; the drug is substantially adsorbed by circuit components.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
IV Push
-May dilute with 5% Dextrose Injection or 0.9% Sodium Chloride Injection if desired to facilitate administration over appropriate time period (i.e., at least 2 minutes).
-The 1 mg/mL formulation is recommended to facilitate slower injection.
-Inject IV slowly over at least 2 minutes at intervals of at least 2 minutes.
-Do not administer by rapid IV injection, especially in neonatal patients; severe hypotension and seizures have been reported in neonates who received midazolam by rapid IV administration.

Continuous IV Infusion
-May dilute in 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringer's Injection. Do not further dilute the premix bag.
-ASHP Recommended Standard Concentrations for Pediatric Continuous Infusions: 0.03 mg/mL, 1 mg/mL, or 5 mg/mL.
-Storage: Solutions diluted with 5% Dextrose Injection or 0.9% Sodium Chloride Injection (final concentration 0.5 mg/mL) are stable for 24 hours; solutions prepared with Lactated Ringer's Injection are stable at room temperature for 4 hours.

Intramuscular Administration
-Inject deeply into a large muscle mass (e.g., anterolateral thigh or deltoid [children and adolescents only]).



Rectal Administration
NOTE: Midazolam is not approved by the FDA for rectal administration.
-Studies have utilized the 5 mg/mL solution for injection, administered at a concentration of 1 to 5 mg/mL via a rectally inserted lubricated catheter or tube. -In one study, the original 5 mg/mL solution was diluted with saline to a concentration of 2 mg/mL unless the volume of the dose exceeded 10 mL, in which case the solution was administered undiluted (5 mg/mL).

-Hold the buttock cheeks closed for 5 minutes after administration to avoid loss of the drug.


Other Administration Route(s)
Intranasal Administration
Nayzilam
-For patients at increased risk of respiratory depression, consider administration under healthcare professional supervision prior to treatment; this may be performed in the absence of a seizure episode.
-Do not test or prime before use; there is only 1 dose of midazolam in the nasal spray unit. Do not open the blister package until ready to use.
-Hold the nasal spray unit with a thumb on the plunger and middle and index fingers on each side of the nozzle.
-Place the tip of the nozzle into 1 nostril until fingers on either side of the nozzle touch the bottom of the nose.
-Press the plunger firmly to deliver the dose using 1 motion. The patient does not need to breathe deeply.
-If a second dose is needed, use a new nasal spray unit in the other nostril.
-Storage: Each nasal spray unit is for single use only. Throw away the unit and blister packaging after use.

Solution for injection
NOTE: This dosage form is not approved by the FDA for intranasal administration.
-Intranasal midazolam may be administered via drop installation with a needleless syringe or spray with a mucosal atomizer device. Use of the mucosal atomizer device improves absorption.
-To reduce nasal burning and bitter taste, premedicate with intranasal lidocaine spray (10 mg per puff in the nares) and give an oral drop of cherry syrup afterward. Nasal burning may last 30 seconds.
-Clear the nasal passages prior to administration (e.g., suction or have the patient blow their nose).
-Place the patient's head at 45 degrees.
-Using the 5 mg/mL solution for injection, administer half of the total dose to each nare. Do not use more than 0.5 to 1 mL of medication per nostril. If a higher dose is required, apply it in 2 separate doses a few minutes apart to allow for adequate absorption of the first dose.-For administration with a mucosal atomizer device, compress the device quickly.
-For administration with a needleless syringe, apply the calculated dose to the nares over 15 seconds.

-The patient should remain in a semi-reclined position for several minutes after administration.

Buccal Administration
NOTE: Midazolam is not approved by the FDA for buccal administration.
-The intravenous or oral solution may be given buccally.
-Apply the calculated dose to buccal cavity between the gum and the cheek using an oral syringe.
-Massage the cheek gently after administration.

Respiratory depression and related adverse reactions are among the most concerning of midazolam use; all patients must be carefully monitored for changes in respiratory status. Serious cardiorespiratory reactions, such as cardiac arrest or respiratory arrest, have occurred after midazolam administration, sometimes resulting in permanent neurologic injury and death. Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately. Oral midazolam administered for pediatric sedation at recommended doses resulted in adverse respiratory reactions in approximately 8% of patients during clinical trials (n = 397). Such adverse reactions included hypoxia (2%), laryngospasm (2%), rhonchi (1%), cough, respiratory depression (1%), airway obstruction (1%), upper airway congestion (1%), and shallow respirations; apnea, hypercarbia, oxygen desaturation, stridor, and sneezing/rhinorrhea occurred at an incidence less than 1%. Higher incidences of oxygen desaturation (4.6%), as well as apnea (2.8%) and hiccups (1.2%) have been reported in association with parenteral midazolam in the medical literature. Laryngospasm, bronchospasm, dyspnea, hyperventilation, wheezing, shallow respirations (hypoventilation), airway obstruction, tachypnea, and yawning have also been reported in less than 1% of pediatric and adult patients after administration of IV midazolam, primarily as a single agent. Respiratory complications are more likely to occur with the concomitant use of other CNS depressants, in pediatric patients younger than 6 months of age, in those with limited pulmonary reserve, or in patients without an endotracheal tube undergoing upper airway (e.g., endoscopy, dental) procedures. Of note, local irritation after intranasal administration of midazolam commonly results in less serious respiratory reactions such as brief coughing, sneezing, throat irritation (3%), and rhinorrhea (3%). Although respiratory depression was observed during intranasal midazolam trials, cardiorespiratory arrest was not reported. Decreases in peripheral oxygen saturation were generally transitory; only 2 of 292 patients (1 with a history of sleep apnea and 1 with intercurrent seizure) required supplemental oxygen.

In the medical literature, hypotension has been reported in 2.7% of pediatric patients after IV administration. The hypotensive effects of midazolam are more common in neonates, critically ill patients with hemodynamic instability, and in those receiving concurrent medications that may lower blood pressure (e.g., opioids). Severe hypotension has been reported after concomitant use of midazolam and fentanyl in neonates, particularly when either agent was administered as a rapid injection. Midazolam should not be administered by rapid injection in any population. Infrequently, hypotensive episodes have occurred during continuous IV infusion; however, neither the onset nor duration appears to be related to plasma concentrations of the drug or its metabolite. Interventional treatments for hypotension have been necessary in rare instances. Other cardiac effects that have been reported with the use of midazolam in less than 1% of pediatric or adult patients include bigeminy, premature ventricular contractions (PVCs), vasovagal episode, bradycardia, sinus tachycardia, and nodal rhythm. Very rarely cardiopulmonary arrest has occurred. All patients receiving midazolam should be monitored carefully for cardiac and/or respiratory adverse effects. Premature and low birth weight neonates, as well as any pediatric patient receiving high doses of IV midazolam may be at particular risk for toxicities associated with benzyl alcohol, a preservative found in some parenteral solutions. In large amounts, benzyl alcohol may cause toxicity presenting as gasping respirations, acidosis, hypotension, bradycardia, and cardiovascular collapse.

Tolerance to midazolam may develop after use more frequently than recommended or for a prolonged period of time. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of benzodiazepines may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines. Do not use intranasal midazolam to treat more than 1 episode of acute repetitive convulsions every 3 days and for no more than 5 episodes per month, as chronic daily use may promote tolerance and increase the frequency and/or severity of tonic-clonic convulsions.

Anterograde amnesia can occur after administration of therapeutic doses of benzodiazepines, such as midazolam. Amnesia and memory impairment are common pharmacologic effects and are often clinically desirable with midazolam use, particularly during critical care sedation, during the perioperative period, or prior to or during certain medical procedures. The risk for developing anterograde amnesia increases at higher doses and with concurrent ingestion of alcohol. Retrograde amnesia and related confusion are not common and have been reported as adverse reactions in less than 1% of pediatric and adult patients.

Sedation is clearly an intended effect of midazolam use. In relation, drowsiness (1.2% adults), grogginess (less than 1%), dizziness (less than 1%), vertigo (less than 1%), and slurred speech (less than 1%) may occur with IV or oral use. Drowsiness (10%) was also the most common adverse reaction reported during intranasal midazolam clinical trials. To minimize the potential for oversedation or prolonged sedation, allow adequate time (e.g., 3 to 5 minutes for IV midazolam) between IV midazolam and/or concomitant sedative doses and assess sedation before subsequent drug administration.

Disinhibition and paradoxical stimulation can occur with benzodiazepine use and is more common in children compared to adults. In clinical trials, paradoxical reactions were reported in 2% of pediatric patients after IV midazolam administration. Agitation, combativeness, hyperactivity, and involuntary movements (tremor, tonic/clonic activity) have been reported in both pediatric and adult patients. Related symptoms such as dysphoria, excitability, anxiety, aggression, restlessness, nervousness, hallucinations, mood swings (emotional lability), adverse behavior, and emergence delirium or agitation were reported in less than 1% of patients receiving midazolam. Other symptoms of paradoxical stimulation may include irritability, psychosis, delirium, hostility, rage, talkativeness, euphoria, mania, sleep disturbances, nightmares, insomnia, and hyperreflexia. Premature neonates appear to be at particular risk for myoclonic reactions (myoclonia). Pediatric patients receiving preoperative sedation with midazolam may experience an increase in the occurrence of nightmares during the week after the procedure; the mechanism for this temporary behavior change is unknown. In general, psychiatric reactions appear to be more common in patients with psychiatric disorders, particularly those with histories of anger and aggression. Although it is possible that some paradoxical reactions may be the result of cerebral hypoxia or expression of underlying symptomatology of the patient, a direct causal relationship between the use of benzodiazepines and impulse control impairment or aggressive behavior has not been established. Nevertheless, careful evaluation is recommended prior to proceeding with midazolam treatment if signs of paradoxical stimulation occur. Administration of flumazenil may reverse central nervous system stimulation.

Seizures have been reported in several neonates after rapid IV administration of midazolam, particularly with the concomitant use of fentanyl. Do not administer midazolam by rapid injection. Premature neonates appear to be at particular risk for paradoxical myoclonic reactions. Other psychomotor effects including seizure-like activity (1.1%), nystagmus (1.1%), athetoid movements (less than 1%), and ataxia (less than 1%) have been associated with IV midazolam use in pediatric patients.

Centrally mediated effects such as headache (1.5% adults), paresthesias (less than 1%), and dysphonia (less than 1%) have been associated with parenteral midazolam use. Headache (4%) and dysarthria (2%) were among the most common adverse reactions reported during intranasal midazolam clinical trials. In addition, sleep disturbances including dreaming during emergence, insomnia, and nightmares have rarely occurred with IV midazolam use. Pediatric patients receiving preoperative sedation with midazolam may experience an increase in the occurrence of nightmares during the week after the procedure. The mechanism for this temporary behavior change is unknown.

Nausea (4% or less) and vomiting (8% or less) have been reported with oral midazolam use. In general, other gastrointestinal effects are rare; hypersalivation, gagging, and drooling have been reported with oral use while hypersalivation, dysgeusia (acid taste), and retching have been reported with IV administration. Abnormal taste/dysgeusia (2%) has been reported with intranasal midazolam during clinical trials. Bitter taste has been frequently reported in children receiving the injectable formulation of midazolam intranasally for procedural sedation. In these cases, a drop of oral cherry syrup after midazolam administration may help alleviate bad taste.

Prolonged use of benzodiazepines can produce physiological dependence with or without psychological dependence. The risk of psychological dependence increases in those with a history of alcohol or substance abuse. 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, including respiratory depression, overdose, and death. Caution is advised when considering the use of benzodiazepines in patients with a known or suspected history of substance abuse. To discourage abuse, prescribe the smallest appropriate quantity of the benzodiazepine and provide proper disposal instructions for unused drug. Avoid or minimize concomitant use of CNS depressants or other medications associated with addiction or abuse. Clinically significant physiological dependence may occur with continued use of benzodiazepines. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of benzodiazepines after continued use may precipitate acute withdrawal reactions, which can be life-threatening. Midazolam dependence in pediatric patients is more likely to occur in the setting of prolonged infusions in critically ill patients. The optimal weaning schedule has not been determined; however, patients who receive prolonged infusions should be gradually weaned from the drug to avoid withdrawal. Withdrawal symptoms may range from mild dysphoria and insomnia to a major withdrawal syndrome including abdominal and muscle cramps, vomiting, sweating, tremors, and seizures. Withdrawal symptoms in infants may include abdominal distention and tachycardia. In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Use a gradual dosage taper to lower the risk of withdrawal reactions when reducing the dose or discontinuing therapy.

Increased lacrimation was reported in 2% of patients during intranasal midazolam clinical trials. Other special senses adverse reactions including blurred vision, diplopia, strabismus, pinpoint pupils, cyclic movements of the eyelids, visual impairment, difficulty focusing eyes, ears blocked, loss of balance, and light-headedness have been reported with the use of IV or oral midazolam in less than 1% of patients.

Hypersensitivity reactions including anaphylactoid reactions, urticaria, rash, and pruritus have been rarely observed in pediatric and adult patients after administration of IV midazolam as a single agent.

Miscellaneous adverse reactions such as lethargy, chills, weakness, dental pain (toothache), feeling faint, and hematoma have been observed in less than 1% of pediatric and adult patients after IV administration of midazolam as a single agent.

An injection site reaction, such as erythema and pain, has been reported after parenteral administration of midazolam. Specifically, IV administration has been associated with a hive-like elevation, swelling or feeling of burning, and warmth or coldness at the injection site in less than 1% of pediatric and adult patients during clinical trials. Tenderness (5.6%), pain during injection (5%), erythema (2.6%), induration (1.7%), and phlebitis (0.4%) have also been reported in adult patients. Local reactions associated with intramuscular (IM) administration in adults have included pain (3.7%), induration (0.5%), erythema (0.5%), and muscle stiffness (0.3%). Limited reports of intraarterial administration have resulted in local reactions. Avoid both intraarterial administration and extravasation.

Local effects including nasal irritation and discomfort (9%), throat irritation (3%), rhinorrhea (3%), and abnormal taste (2%) were reported during clinical trials for intranasal midazolam. The intravenous formulation of midazolam is acidic (pH = 3.3) and, when used intranasally, may result in nasal irritation and burning, as well as bitter taste in up to 66% of patients. Although these effects are transient, patients and their caregivers should be forewarned prior to administration. Pretreatment with intranasal lidocaine spray (10 mg per puff in the nares) or an oral drop of cherry syrup after midazolam administration may help alleviate discomfort and bad taste. Brief coughing, sneezing, or crying may also occur immediately after administration. Cough (20%) and rhinorrhea (18%) were the most frequent reactions reported in a pilot study of injectable midazolam give intranasally for pediatric procedural sedation (n = 58; age range: 1 to 40 months).

Benzodiazepines cross the placenta and may produce sedation, hypotonia, lethargy, and neonatal respiratory depression at birth. Monitor neonates exposed during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Neonatal withdrawal or a neonatal abstinence syndrome has also been reported following the ingestion of therapeutic doses of benzodiazepines during the last weeks of pregnancy. Clinical manifestations of neonatal withdrawal may include hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties. These complications can appear shortly after delivery to 3 weeks after birth and persist from hours to several months, depending on the degree of dependence and pharmacokinetic profile of the benzodiazepine. Observe neonates who are exposed to benzodiazepines in utero during the later stages of pregnancy for symptoms of withdrawal and manage appropriately. Benzodiazepines should be withdrawn cautiously and slowly, using a very gradual dosage-tapering schedule.

When used for short-term sedation during endotracheal intubation, midazolam does not protect against the characteristic rise in intracranial pressure, heart rate, and/or blood pressure associated with intubation under light general anesthesia.

Midazolam is contraindicated in any patient with a known or suspected hypersensitivity to midazolam or any component of the formulation. For example, some of the oral syrup formulations such as those that contain artificial cherry flavor or cherry-burgundy flavor are contraindicated in patients allergic to cherries. Patients with a benzodiazepine hypersensitivity to other benzodiazepines may experience a cross-sensitivity to midazolam. Some midazolam injectable products contain benzyl alcohol as a preservative; these products are contraindicated for intrathecal administration or epidural administration. Limited reports of seizure activity and local reactions have been associated with intraarterial administration, but a clear causal effect cannot be made. Avoid unintended intraarterial injection and local extravasation.

Use midazolam with caution in patients with a history of autism, bipolar disorder, or psychosis. Paradoxical reactions (e.g., agitation, mania) to benzodiazepines are more common in patients with psychiatric and/or personality disorders, particularly in those with a history of anger and aggression. Paradoxical stimulation and disinhibition are both more common in children compared to adults. Though they must be used with caution in this population, longer-acting benzodiazepines (lorazepam, clonazepam, diazepam) are commonly used in clinical practice for the acute management of psychosis and mania, as well as in the treatment of extrapyramidal symptoms associated with antipsychotics. Preexisting depression may emerge or worsen with the use of benzodiazepines. Although use of midazolam is limited to closely monitored inpatient use or intermittent outpatient seizure rescue, it may be prudent to closely monitor patients with a history of depression or suicidal ideation for worsening symptoms during periods of consciousness due to an increased risk of suicidal ideation and behavior in patients receiving antiepileptic drugs (AEDs). Inform patients, caregivers, and families of the increased risk of suicidal thoughts and behaviors and advise them to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. AEDs should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. Suicidal ideation or behavior has occurred as early as 1 week after AED initiation and may occur any time during treatment. A pooled analysis of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (at least 5 years of age) was conducted. There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving AEDs had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2 to 2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor.

Parenteral and oral administration of midazolam requires an experienced clinician trained in the use of resuscitative equipment and skilled in airway management. Use of these dosage forms also requires a specialized care setting that can provide continuous monitoring of respiratory and cardiac functioning; oral midazolam should not be administered at home or outside the care setting in which procedures will be performed. Midazolam has been associated with respiratory depression and respiratory arrest, especially when given via intravenous administration for procedural sedation. Death or hypoxic encephalopathy has resulted in some instances where these symptoms were not recognized or properly treated. Individualize the midazolam dose based on the patient's age, weight, indication, concomitant medications, and disease history. High risk surgical and debilitated patients, patients undergoing upper airway procedures (i.e., endoscopy), and those with hemodynamic compromise may need lower dosages of midazolam with close monitoring. Many of these patients may be vulnerable to hypoventilation or reduced elimination of midazolam. Prior to administration of oral or parenteral dosage forms, ensure the immediate availability of oxygen, resuscitative drugs, and age- and size-appropriate ventilation and intubation equipment. Monitor patients for early signs of respiratory insufficiency, respiratory depression, hypoventilation, airway obstruction, or apnea (i.e., via pulse oximetry), which may lead to hypoxia and/or cardiac arrest. Have flumazenil available for immediate use. For deeply sedated patients receiving midazolam for procedural sedation, a dedicated individual, other than the person performing the procedure, should monitor the patient. When used for sedation/anxiolysis/amnesia, administer IV midazolam over at least 2 minutes and wait an additional 2 minutes to assess sedation before administering an additional dose. For patients who are prescribed intranasal midazolam for seizure rescue and are at increased risk for respiratory depression, consider administration under medical supervision, in the absence of a seizure episode, prior to treatment. Counsel patients and caregivers on appropriate use at home. Continuous monitoring of respiratory and cardiac function is recommended in patients with status epilepticus after treatment with midazolam until the patient is stabilized.

Avoid rapid IV administration of midazolam (less than 2 minutes) in neonates due to the risk of severe hypotension, hypoventilation, and/or seizures, particularly if the neonate has received fentanyl. The same precaution applies to rapid injections of fentanyl while the neonate is receiving midazolam continuous infusions. Premature neonates have significantly slower clearance of midazolam compared to other populations; use extreme caution with dosage titration in this population. Some midazolam injectable products contain benzyl alcohol as a preservative; use preservative free products in neonates whenever possible. Although dose ranges for preterm and term newborns are well below that which would lead to benzyl alcohol toxicity, the clinician should be aware of the toxic potential, especially if other drugs containing benzyl alcohol are administered. Excessive amounts of the preservative benzyl alcohol in newborns have been associated with hypotension, metabolic acidosis, and kernicterus. A "gasping syndrome" characterized by central nervous system depression, metabolic acidosis, and gasping respirations has been associated with benzyl alcohol dosages more than 99 mg/kg/day in neonates. However, the minimum amount of benzyl alcohol at which toxicity may occur is unknown and premature and low-birth-weight neonates may be more likely to develop toxicity. Repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in neonates, infants, and children younger than 3 years, including in utero exposure during the third trimester, may have negative effects on brain development. Consider the benefits of appropriate anesthesia in young children against the potential risks, especially for procedures that may last more than 3 hours or if multiple procedures are required during the first 3 years of life. It may be appropriate to delay certain procedures if doing so will not jeopardize the health of the child. No specific anesthetic or sedation drug has been shown to be safer than another. Human studies suggest that a single short exposure to a general anesthetic in young pediatric patients is unlikely to have negative effects on behavior and learning; however, further research is needed to fully characterize how anesthetic exposure affects brain development. In utero exposure to benzodiazepines during the later stages of pregnancy may result in decreased fetal movement and/or heart rate variability, sedation (hypotonia, lethargy, neonatal respiratory depression), neonatal abstinence syndrome (NAS), floppy infant syndrome (FIS), or other withdrawal symptoms during the postnatal period. Monitor the neonate for hypotonia and withdrawal symptoms, including hyperreflexia, irritability, restlessness, tremors, inconsolable crying, or feeding difficulties and manage accordingly. The incidence, time to onset, and duration of NAS or FIS symptoms is multi-factorial (e.g., duration of use, drug lipophilicity, placental disposition, degree of accumulation in neonatal tissues). FIS typically occurs after chronic fetal exposure to long-acting benzodiazepines, or when benzodiazepines are administered shortly before delivery, resulting in newborn toxicity of variable severity and duration. FIS primarily occurs within the first few hours after labor and may last for up to 14 days.

Do not use intranasal midazolam to treat more than 1 episode of acute repetitive convulsions every 3 days and for no more than 5 episodes per month. Chronic daily use may promote tolerance and increase the frequency and/or severity of tonic-clonic convulsions. Patients receiving continuous infusion of midazolam in critical care settings over an extended period of time, may experience symptoms of withdrawal after abrupt discontinuation. Abrupt discontinuation or rapid dosage reduction of benzodiazepines after continued use may precipitate acute withdrawal reactions, which can be life-threatening. The risks of physiological dependence and withdrawal increase with longer treatment duration and higher daily dose. Benzodiazepine dependence can occur after administration of therapeutic doses for as few as 1 to 2 weeks and withdrawal symptoms may be seen after the discontinuation of therapy. To reduce the risk of acute withdrawal reactions, use a gradual taper to reduce the dosage or to discontinue benzodiazepines. No standard benzodiazepine tapering schedule is suitable for all patients; therefore, create a patient-specific plan to gradually reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently, decrease the dosage more slowly. Benzodiazepine withdrawal also can be more intense if the benzodiazepine involved possesses a relatively short duration of action such as midazolam. Patients with a history of a seizure disorder should not be withdrawn abruptly from benzodiazepines due to the risk of precipitating seizures; status epilepticus has also been reported. Clinicians should be aware that the use of flumazenil may increase the risk of seizures, particularly in long-term users of benzodiazepines.

Particular caution is required in determining the interval needed after outpatient procedures or surgery or an acute seizure before it is safe for any patient to participate in ambulation or activities requiring coordination and concentration (e.g., riding a bicycle, operating a motor vehicle or hazardous machinery). Although recommendations specific to pediatric patients are not available, it is recommended that no patient operates hazardous machinery or drives a motor vehicle until their medical condition permits and the central nervous system depressant effects have subsided or until 1 full day after surgery, whichever is longer.

As with other benzodiazepines, midazolam should be used with extreme caution in patients with pulmonary disease and in patients with respiratory insufficiency resulting from chronic lung disease (CLD), status asthmaticus, abnormal airway anatomy, obstructive sleep apnea, cyanotic congenital heart disease, or pulmonary hypertension. Additionally, avoid coadministration with other CNS depressants, especially opioids, unless no other alternatives are available as coadministration significantly increases the risk for profound sedation, respiratory depression, low blood pressure, coma, and death. Reserve concomitant prescribing of benzodiazepines and opioids for use in patients for whom alternative treatment options are inadequate. If concomitant use is necessary, use the lowest effective dosage for minimum duration, follow patients closely for signs and symptoms of respiratory depression and sedation, and advise both patients and caregivers about the risks. Hypoventilation, airway obstruction, and apnea are more likely to occur when midazolam is administered to patients with decreased pulmonary reserve, significant CNS depression, or ethanol intoxication. Cardiorespiratory effects may be more likely in ASA-PS III or IV patients. Hypercarbia and hypoxia after premedication with oral midazolam may pose a risk to patients with congenital heart disease and pulmonary hypertension. Carefully monitor respiratory status and oxygen saturation in at risk patients. For patients who are prescribed intranasal midazolam for seizure rescue and are at increased risk for respiratory depression, consider administration under medical supervision, in the absence of a seizure episode, prior to treatment. Counsel patients and caregivers on appropriate use at home.

Midazolam can cause significant hypotension and should not be administered to patients in shock or coma that is not medically-induced. Use with caution in patients with cardiac disease, depressed vital signs, and/or uncompensated acute illnesses, such as severe electrolyte imbalance, hypovolemia, and dehydration. If hypotension develops, consider countermeasures including intravenous fluid therapy, repositioning, and judicious use of vasopressors. Hypotension may be more pronounced when midazolam is administered with an opioid; when given together, use smaller initial doses of both the opioid and midazolam and titrate the dosages in small increments. In addition, use midazolam with extreme caution in patients with poor ventricular function and elevated ventricular end-diastolic pressure, as it can compromise cardiac output and coronary perfusion.

Midazolam is metabolized in the liver; use with caution in patients with hepatic disease or hepatic encephalopathy. Similarly, the half-life and volume of distribution are increased in patients with congestive heart failure or obesity. FDA-approved labeling recommends dosing oral and parenteral midazolam based on ideal body weight in obese patients. Although the half-life is not significantly prolonged in patients with chronic renal failure, the peak concentrations of midazolam can be higher. The half-life of midazolam and its metabolites may be prolonged in patients with acute renal failure or renal impairment, and these patients can experience more rapid induction of and prolonged recovery from anesthesia.

Midazolam is contraindicated in patients with acute closed-angle glaucoma. Benzodiazepines can increase intraocular pressure in patients with glaucoma. Midazolam may be used in patients with open-angle glaucoma who are receiving appropriate treatment; these patients may need to have their ophthalmologic status evaluated after midazolam treatment. Measurements of intraocular pressure in patients without eye disease show a moderate lowering after induction with midazolam; patients with glaucoma have not been studied.

Use midazolam with caution in patients with a history of alcoholism or substance abuse due to the potential for psychological dependence. The use of benzodiazepines exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Assess patients for risks of addiction, abuse, or misuse before drug initiation, and monitor patients who receive benzodiazepines routinely for development of these behaviors or conditions. A potential risk of abuse should not preclude appropriate treatment in any patient, but requires more intensive counseling and monitoring. To discourage abuse, the smallest appropriate quantity of the benzodiazepine should be prescribed, and proper disposal instructions for unused drug should be given to patients. Avoid or minimize concomitant use of CNS depressants or other medications associated with addiction or abuse. 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, including respiratory depression, overdose, and death. Advise patients to seek immediate medical attention if they experience symptoms such as trouble breathing. Available data suggest the benzodiazepine dependence potential of midazolam is at least equivalent to that of diazepam. No statistically significant or clinically relevant differences in subjective positive effects (e.g., Drug Liking, Overall Drug Liking, Take Drug Again, and High) were reported in a comparative assessment of intranasal and oral midazolam in adult patients with a history of benzodiazepine recreational use; however, subjective positive effects on all these measures were significantly greater for intranasal midazolam when compared to placebo confirming that intranasal midazolam has abuse potential.

Description: Midazolam is a short-acting benzodiazepine used for sedation, anxiolysis, and amnesia. Parenteral and intranasal formulations are used for the acute treatment of seizures; the parenteral formulation has also been administered buccally for this indication. Systematic review of over 700 young patients has suggested midazolam, by any route, is superior to diazepam (RR = 1.52; 95% CI = 1.27 to 1.82) for seizure cessation. For seizure control, nonparenteral midazolam is comparable to intravenous diazepam (RR = 0.79; 95% CI = 0.19 to 3.36) and buccal midazolam is superior to rectal diazepam (RR = 1.54; 95% CI = 1.29 to 1.85). Evidence-based guidelines specifically recommend intramuscular midazolam as an initial therapy choice for convulsive status epilepticus, noting intranasal or buccal midazolam are reasonable alternative choices in the prehospital setting or where parenteral therapy is not available. Oral midazolam is useful in reducing anxiety and inducing sedation in children who might otherwise require intravenous sedation or general anesthesia to perform a medical or dental procedure; intranasal administration has also been used for this indication. FDA-approved labeling contains a black-box warning that describes the risk of profound sedation, respiratory depression, coma, and death with the concomitant use of opioids. Intravenous midazolam is FDA-approved in pediatric patients as young as neonates; oral midazolam is approved in pediatric patients as young as 6 months of age; intranasal midazolam is approved in patients 12 years and older.

General dosing information
-Midazolam dosage must be individualized and carefully titrated to desired effect. Individual response may vary with age, physical status, underlying disease state, and concomitant medications.-If used in combination with an opioid or other central nervous system depressant for non-seizure indications, the dose of both drugs should be reduced; it is recommended to reduce the initial midazolam dose by approximately 30% to 50% and carefully titrate to clinical effect.
-Begin with lower doses and titrate carefully in patients with hemodynamic and/or cardiorespiratory compromise.
-Allow 3 to 5 minutes in between intravenous doses to minimize the potential for oversedation.

-Calculate midazolam doses based on ideal body weight for obese patients.

For procedural sedation and amnesia induction and to control preoperative anxiety:
Oral dosage:
Infants, Children, and Adolescents 6 months to 16 years: 0.25 to 0.5 mg/kg PO as single dose 30 to 45 minutes before the procedure; may give additional dose once after 20 to 30 minutes if necessary (Max cumulative dose: 20 mg).
Intravenous dosage:
Infants younger than 6 months: Limited information is available; it is not clear at what age infants shift from neonatal to pediatric physiology in terms of handling and responding to midazolam. Doses of 0.05 mg/kg/dose IV have been used in neonates and infants older than 6 months; therefore, starting with a dose smaller than that and titrating to effect would be a reasonable approach. Infants younger than 6 months are particularly vulnerable to airway obstruction and hypoventilation; therefore, titration with small increments to clinical effect and careful monitoring are essential. Midazolam should be administered as an inducing agent only by those trained in anesthesia.
Infants and Children 6 months to 5 years: 0.05 to 0.1 mg/kg/dose (Max: 2 mg) IV; may repeat once in 2 to 3 minutes if needed. Max cumulative dose: 0.6 mg/kg or 6 mg, whichever is less.
Children 6 to 12 years: 0.025 to 0.1 mg/kg/dose (Max: 2 mg) IV; may repeat once in 2 to 3 minutes if needed. Max cumulative dose: 0.6 mg/kg or 6 mg, whichever is less.
Adolescents: 0.05 to 0.1 mg/kg/dose IV or a flat dose of 1 to 2.5 mg; may repeat once in 2 to 3 minutes if needed. Max cumulative dose: 10 mg.
Intramuscular dosage:
Infants, Children, and Adolescents: 0.1 to 0.2 mg/kg/dose (Max: 10 mg/dose) IM 30 to 60 minutes before the procedure; doses up to 0.5 mg/kg IM have been used in more anxious patients.
Intranasal dosage*:
Neonates: Limited data are available; 0.2 mg/kg intranasally as a single dose has been used.
Infants, Children, and Adolescents: 0.2 to 0.5 mg/kg (Max: 10 mg) intranasally once. Average time to effective sedation is 7 to 15 minutes (range: 3 to 40 minutes). In studies using doses of 0.4 to 0.5 mg/kg, average time to sedation recovery was 30 to 50 minutes (range: 12 to 153 minutes); mean duration of sedation was 23 minutes (range: 10 to 50 minutes). Premedicating with intranasal lidocaine spray may reduce nasal irritation.
Rectal dosage*:
Infants, Children, and Adolescents: 0.25 to 0.5 mg/kg PR once. Doses up to 1 mg/kg/dose PR have been used in infants and young children (age range: 6 months to 5 years) but may be associated with a higher incidence of agitation.

For sedation maintenance in mechanically-ventilated patients:
Continuous Intravenous Infusion dosage:
Premature Neonates 32 weeks and younger: 0.015 to 0.06 mg/kg/hour continuous IV infusion. May run the infusion more rapidly for the first several hours to obtain therapeutic response. Adjust dose as needed to administer the lowest possible effective dose. Midazolam infusions are not currently recommended for preterm neonates because of the increased incidence of adverse neurological events.
Neonates older than 32 weeks: 0.015 to 0.06 mg/kg/hour continuous IV infusion. May run the infusion more rapidly for the first several hours to obtain therapeutic response. Adjust dose as needed to administer the lowest possible effective dose.
Infants, Children, and Adolescents: 0.05 to 0.2 mg/kg/dose IV loading dose, then 0.06 to 0.12 mg/kg/hour continuous IV infusion, initially. Adjust dose by 25% increments as needed to achieve target sedation score. Rates may be titrated to a range of 0.024 to 0.36 mg/kg/hour.

For the treatment of status epilepticus*:
Intramuscular dosage:
Infants, Children, and Adolescents weighing 13 to 40 kg: 0.2 mg/kg/dose (Max: 5 mg/dose) IM as a single dose. Midazolam is the drug of choice for IM administration of emergent initial therapy.
Children and Adolescents weighing more than 40 kg: 0.2 mg/kg/dose (Max: 10 mg/dose) IM as a single dose. Midazolam is the drug of choice for IM administration of emergent initial therapy.
Intranasal dosage:
Infants, Children, and Adolescents: 0.2 mg/kg/dose (Max: 10 mg/dose) intranasally as a single dose; divide the dose between nares. Intranasal midazolam is a reasonable initial therapy alternative when parenteral therapy is not available.
Buccal dosage:
Infants 3 to 11 months: 0.3 to 0.5 mg/kg/dose (Max: 2.5 mg/dose) buccally as a single dose. Buccal midazolam is a reasonable initial therapy alternative when parenteral therapy is not available.
Children 1 to 4 years: 0.3 to 0.5 mg/kg/dose (Max: 5 mg/dose) buccally as a single dose. Buccal midazolam is a reasonable initial therapy alternative when parenteral therapy is not available.
Children 5 to 9 years: 0.3 to 0.5 mg/kg/dose (Max: 7.5 to 10 mg/dose) buccally as a single dose. Buccal midazolam is a reasonable initial therapy alternative when parenteral therapy is not available.
Children and Adolescents 10 to 17 years: 0.3 to 0.5 mg/kg/dose (Max: 10 mg/dose) buccally as a single dose. Buccal midazolam is a reasonable initial therapy alternative when parenteral therapy is not available.
Intravenous dosage:
Neonates: 0.15 mg/kg/dose IV bolus, followed by 0.06 mg/kg/hour (1 mcg/kg/minute) continuous IV infusion was used in 13 term neonates with seizures refractory to phenobarbital or phenytoin. The infusion rate was increased by 0.03 to 0.06 mg/kg/hour (0.5 to 1 mcg/kg/minute) every 2 minutes until seizures were controlled or a maximum rate of 1.1 mg/kg/hour (18 mcg/kg/minute) was reached.
Infants, Children, and Adolescents: 0.2 mg/kg/dose (Max: 10 mg/dose) IV bolus, followed by 0.05 to 2 mg/kg/hour (0.8 to 33 mcg/kg/minute). Titrate by 0.05 to 0.1 mg/kg/hour (0.8 to 1.6 mcg/kg/minute) every 3 to 4 hours to clinical response; may give additional 0.1 to 0.2 mg/kg/dose IV bolus for breakthrough seizures. Other benzodiazepines (e.g., lorazepam) are preferred intravenous agents.

For sedation during rapid-sequence intubation (RSI)*:
Intravenous dosage:
Neonates: 0.05 to 0.1 mg/kg/dose IV. Midazolam has a slower onset than other agents used for RSI. Allow 1 to 2 minutes for effect prior to administering paralytic agents.
Infants, Children, and Adolescents: 0.1 to 0.4 mg/kg/dose (Max: 10 mg/dose) IV. Midazolam has a slower onset than other agents used for RSI. Allow 1 to 2 minutes for effect prior to administering paralytic agents.

For the treatment of intermittent, stereotypic, acute repetitive seizures (i.e., seizure clusters) that are distinct from a patient's usual seizure pattern:
Intranasal dosage (Nayzilam):
Children and Adolescents 12 to 17 years: 5 mg (1 spray) in 1 nostril. May administer additional 5 mg (1 spray) in the opposite nostril after 10 minutes if no response to the initial dose. Do not give a second dose if the person has trouble breathing or if there is excessive sedation uncharacteristic of the person during a seizure cluster episode. Max: 2 doses/single episode. Do not treat more than 1 episode every 3 days or more than 5 episodes/month.

For the treatment of acute agitation* in the prehospital or emergency department setting:
Oral dosage:
Children and Adolescents: 0.1 mg/kg/dose (Max: 2 mg) PO every 30 to 60 minutes as needed.
Intravenous or Intramuscular dosage:
Children and Adolescents: 0.1 mg/kg/dose (Max: 2 mg) IV/IM every 30 to 60 minutes as needed.

Maximum Dosage Limits:
-Neonates
Specific maximum dosage information is not available; the dose required is dependent on route of administration, indication, and clinical response.
-Infants
1 to 5 months: Specific maximum dosage information is not available; the dose required is dependent on route of administration, indication, and clinical response.
6 to 11 months: 1 mg/kg PO total dose for procedural sedation; a total dose up to 0.6 mg/kg IV may be necessary for amnesia induction; specific maximum dosage information for other routes or indications is not available; the dose required is dependent on route of administration, indication, and clinical response.
-Children
1 to 11 years: 1 mg/kg (Max: 20 mg) PO total dose for procedural sedation; a total dose up to 0.6 mg/kg (Max: 6 mg) IV may be necessary for amnesia induction; specific maximum dosage information for other routes or indications is not available; the dose required is dependent on route of administration, indication, and clinical response.
12 years: 1 mg/kg (Max: 20 mg) PO total dose for procedural sedation; a total dose up to 0.6 mg/kg (Max: 6 mg) IV may be necessary for amnesia induction; 1 spray (5 mg)/dose intranasal up to 2 doses/episode for acute repetitive seizures; specific maximum dosage information for other routes or indications is not available; the dose required is dependent on route of administration, indication, and clinical response.
-Adolescents
1 mg/kg (Max: 20 mg) PO total dose for procedural sedation; a total dose up to 10 mg IV may be necessary for amnesia induction; 1 spray (5 mg)/dose intranasal up to 2 doses/episode for acute repetitive seizures; specific maximum dosage information for other routes or indications is not available; the dose required is dependent on route of administration, indication, and clinical response.

Patients with Hepatic Impairment Dosing
Dosage should be modified depending on clinical response and degree of hepatic impairment, but no quantitative recommendations are available.

Patients with Renal Impairment Dosing
Dosage adjustment may be necessary in patients with renal impairment as the half-life of midazolam and its active metabolite are prolonged. The following initial dosage adjustments have been recommended for pediatric patients :
GFR 30 mL/minute/1.73m2 or more: No dosage adjustment necessary.
GFR 10 to 29 mL/minute/1.73m2: Reduce usual dose by 25%.
GFR less than 10 mL/minute/1.73m2: Reduce usual dose by 50%.

Intermittent Hemodialysis and Peritoneal Dialysis
Reduce the initial dose by 50% then titrate to desired clinical effect.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Benzodiazepines act at the level of the limbic, thalamic, and hypothalamic regions of the central nervous system (CNS) and can produce any level of CNS depression required including sedation, hypnosis, skeletal muscle relaxation, and anticonvulsant activity. Benzodiazepines exert their effects through enhancement of the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex. GABA is an inhibitory neurotransmitter that exerts its effects at specific receptor subtypes designated GABA-A and GABA-B. GABA-A is the primary receptor subtype in the CNS and is thought to be involved in the actions of anxiolytics and sedatives.

Specific benzodiazepine receptor subtypes are thought to be coupled to GABA-A receptors. Three types of BNZ receptors are located in the CNS and other tissues; the BNZ1 receptors are located in the cerebellum and cerebral cortex, the BNZ2 receptors in the cerebral cortex and spinal cord, and the BNZ3 receptors in peripheral tissues. Activation of the BNZ1 receptor is thought to mediate sleep while the BNZ2 receptor affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. Benzodiazepines bind nonspecifically to BNZ1 and BNZ2 which ultimately enhances the effects of GABA. Midazolam has twice the affinity for benzodiazepine receptors than diazepam does. Unlike barbiturates which augment GABA responses by increasing the length of time that chloride channels are open, benzodiazepines enhance the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.

The antianxiety action of benzodiazepines may be a result of their ability to block cortical and limbic arousal after stimulation of the reticular pathways while muscle relaxation properties are mediated by inhibiting both mono- and polysynaptic pathways. Benzodiazepines can also depress muscle and motor nerve function directly. Animal studies of the anticonvulsant actions suggest that benzodiazepines augment presynaptic inhibition of neurons, thereby limiting the spread of electrical activity, although they do not actually inhibit the abnormally discharging focus.

Pharmacokinetics: Midazolam is approved for oral, parenteral, and intranasal administration, and is administered via buccal and rectal routes off-label. Midazolam is widely distributed and crosses the blood-brain barrier. Midazolam is approximately 97% protein-bound, primarily to albumin. Extensive hydroxylation occurs in the liver. The primary metabolite is alpha-hydroxymidazolam (also termed 1-hydroxymidazolam), which is equipotent to midazolam. Up to 80% of midazolam is recovered in the urine as alpha-hydroxymidazolam glucuronide. Roughly 4% of the dose is metabolized to 4-hydroxymidazolam and 1,4-dihydroxylmidazolam; these minor metabolites have less pharmacologic activity than midazolam and are conjugated by the liver with subsequent renal excretion. Less than 0.03% of a dose is excreted unchanged in the urine. In healthy adults, the mean Vd is 1 to 3.1 L/kg and the half-life is approximately 2 to 6 hours (mean: approximately 3 hours). The Vd in non-neonatal pediatric patients is similar to or slightly larger than that of adults, and the half-life is similar to or shorter than that of adults. Clearance is reduced in patients with significant liver disease and conditions that reduce cardiac output and hepatic blood flow.

Affected cytochrome P450 isoenzymes: CYP3A4
Midazolam is metabolized by the hepatic isozyme CYP3A4. Inhibitors of this pathway can potentiate the clinical effects of midazolam. Interactions of this type are most pronounced with oral midazolam. However, the pharmacokinetics of IV midazolam may also be affected to a lesser extent.


-Route-Specific Pharmacokinetics
Oral Route
After oral administration, midazolam is rapidly absorbed and undergoes extensive first pass metabolism. Oral midazolam's bioavailability is roughly 36% and is independent of age or weight. Onset of anxiolytic and sedative effects occur approximately 10 to 30 minutes after oral administration, with the degree of sedation dependent on the dose administered and the presence or absence of other medications. Duration of effect is approximately 40 to 70 minutes. Food does not appear to affect the extent of absorption, but the indications for oral midazolam often preclude feeding. In clinical studies, a relationship between plasma concentrations of midazolam and its active metabolite and sedation scores was seen after administration of a single oral dose to pediatric patients; patients with higher sedation scores had significantly higher plasma concentrations. No such trend was seen between plasma concentrations and anxiolysis scores.

Intravenous Route
The onset of effect occurs approximately 1.5 to 5 minutes after intravenous administration in pediatric patients; time of onset is affected by the dose administered and the presence or absence of other narcotic medications. Duration of effect is approximately 30 to 45 minutes after a single dose. While the pharmacokinetic profile of midazolam via continuous IV infusion is similar to that after single doses, midazolam can accumulate in peripheral tissues during continuous infusion. Accumulation is greater with long-term infusions compared to short infusions. Therefore, despite midazolam's relatively short half-life compared to some other benzodiazepines, time to awakening after a long-term infusion may be delayed as a result of drug accumulation in tissues. Using the lowest effective infusion rate helps minimize accumulation.

Intramuscular Route
After intramuscular administration, the absorption of midazolam is rapid, with a mean bioavailability greater than 90%. Onset of action after IM administration is 5 minutes, and maximum effect is seen in 15 to 30 minutes.

Other Route(s)
Intranasal Route
The absorption of midazolam from the highly vascularized nasal mucosa is rapid. Sedation and psychomotor impairment generally begin within 10 minutes. Peak effects are seen within 30 minutes to 2 hours post dose. Pharmacodynamic effects generally return to near baseline by 4 hours post dose. Bioavailability is 44% to 55%, which is higher than by the oral route (36%). A mean Cmax and AUC of 54.7 ng/mL and 126.2 ng/mL x hour were attained in a median of 17.3 minutes (range: 7.8 to 28.2 minutes) after a single 5 mg dose in healthy adults. When compared to the intravenous route (n = 6), mean plasma concentrations of midazolam 0.2 mg/kg after intranasal administration (n = 6) were lower within the first 2 hours, but similar in the subsequent 3 hours after administration in 12 healthy children (mean age: 2.5 years; range: 1.75 to 4 years) scheduled for minor surgery. In children receiving intranasal midazolam, a mean Cmax of 104 mcg/L was obtained in 12 minutes. Half-life (2.2 hours) and mean residence time (2.7 hours; AUCt/AUC) in the intranasal arm were similar to those in the intravenous arm (t1/2 = 2.4 hours; MRT = 2.7 hours). However, apparent Vd was larger in the intranasal group (4.12 L/kg vs. 2.37 L/kg IV) and plasma clearance was faster (24 mL/kg/minute vs. 13 mL/kg/minute IV).

Buccal Route
Onset of effect occurs approximately 20 to 30 minutes after buccal administration of the IV formulation of midazolam. Duration of effect is approximately 40 to 70 minutes.

Rectal Route
Onset of effect occurs approximately 10 to 30 minutes after rectal administration of the IV formulation of midazolam. Duration of effect is approximately 60 to 90 minutes.


-Special Populations
Pediatrics
Neonates
Neonates have significantly longer half-lives and slower clearance than other populations. The mean elimination half-life and clearance of IV midazolam in 15 premature and term neonates (gestational age: 29 to 41 weeks; postnatal age: 1 to 5 days) was 12 hours and 1.7 mL/kg/minute, respectively. The elimination half-life was correlated with gestational age, with the more premature neonates having longer half-lives. FDA-approved labeling reports a prolonged half-life in seriously ill neonates of 6.5 to 12 hours.

Infants, Children, and Adolescents
The mean elimination half-life of midazolam after a single oral dose ranged from 2.2 to 6.8 hours in pediatric patients 6 months to 15 years. The elimination half-life and clearance of midazolam after a single IV dose in pediatric patients older than 1 year of age were 0.78 to 3.3 hours and 2.8 to 13 mL/kg/minute, respectively.

Hepatic Impairment
The Cmax and bioavailability were 43% and 100% higher, respectively, after administration of oral midazolam to adult patients with cirrhosis. The half-life and Vd of midazolam may be increased and clearance decreased in patients with hepatic impairment. The mean half-life increased 2.5-fold, the Vd was increased by 20%, and the clearance was decreased by 50% in adult patients with alcoholic cirrhosis after single IV doses of midazolam compared to controls. However, the pharmacokinetics of midazolam were unchanged in another study of patients with cirrhosis.

Renal Impairment
The half-life of midazolam and its metabolites may be longer in patients with renal impairment, which may prolong exposure. Midazolam clearance was decreased (1.9 vs. 2.8 mL/kg/minute) and half-life was prolonged (13 vs. 7.6 hours) in adult patients with acute renal failure receiving a continuous IV infusion of midazolam compared to controls during clinical trials. Renal clearance and half-life of the alpha-hydroxymidazolam glucuronide were prolonged (4 vs. 136 mL/minute and 12 vs. 25 hours or more, respectively). Plasma concentrations accumulated in patients with acute renal failure to about 10 times that of the parent drug. In patients with chronic renal failure, there was a 2-fold increase in the clearance and Vd of midazolam but the half-life remained unchanged after a single IV dose. Intranasal midazolam pharmacokinetics are expected to be similar in patients with mild renal impairment when compared to those with normal renal function; studies did not include adequate numbers of patients with moderate to severe impairment for analysis.

Obesity
Mean half-life of parenteral midazolam is greater in obese patients (5.9 hours) compared to normal weight patients (2.3 hours), due to an increase of approximately 50% in the Vd corrected for total body weight. Clearance is not significantly different.

Other
Congestive Heart Failure
A 2-fold increase in elimination half-life, a 25% decrease in plasma clearance, and a 40% increase in Vd of midazolam were observed in patients suffering from congestive heart failure.