" Citing a lack of cardiovascular benefit, the FDA is taking the unusual step of withdrawing approvals it had previously given for use of niacin and fenofibric acid with statins to treat high cholesterol.
The decision affects niac"...
Midazolam Injection (midazolam) is indicated -
- intramuscularly or intravenously for preoperative sedation/anxiolysis/amnesia;
- intravenously as an agent for sedation/anxiolysis/amnesia prior to or during diagnostic, therapeutic or endoscopic procedures, such as bronchoscopy, gastroscopy, cystoscopy, coronary angiography and cardiac catheterization, oncology procedures, radiologic procedures, suture of lacerations and other procedures either alone or in combination with other CNS depressants;
- intravenously for induction of general anesthesia, before administration of other anesthetic agents. With the use of narcotic premedication, induction of anesthesia can be attained within a relatively narrow dose range and in a short period of time. Intravenous midazolam can also be used as a component of intravenous supplementation of nitrous oxide and oxygen (balanced anesthesia);
- continuous intravenous infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in a critical care setting.
Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours. (see CLINICAL PHARMACOLOGY.)
DOSAGE AND ADMINISTRATION
Midazolam is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam to be 3 to 4 times as potent per mg as diazepam. BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM INJECTION (midazolam) IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid or intravenous administration may result in respiratory depression, airway obstruction and/or arrest. The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see BOXED WARNING and WARNINGS).
Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam. (see WARNINGS).
Midazolam should only be administered IM or IV (see WARNINGS).
Care should be taken to avoid intra-arterial injection or extravasation. (see WARNINGS).
Midazolam Injection (midazolam) may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer's solution for up to 4 hours. Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.
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. Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants. Continuous monitoring of respiratory and cardiac function is required (ie, pulse oximetry).
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.
Titration to effect with multiple small doses is essential for safe administration. It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation. Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration. This is an important consideration for all patients who receive intravenous midazolam.
Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).
Pediatrics: For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.
Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.
USUAL ADULT DOSE
| For preoperative sedation /anxiolysis/amnesia (induction
of sleepiness or drowsiness and relief of apprehension and to impair memory of perioperative events).
For intramuscular use, midazolam should be injected deep in a large muscle mass.
| The recommended premedication dose of midazolam for good risk (ASA Physical
Status I & II) adult patients below the age of 60 years is 0.07 to 0.08
mg/kg IM (approximately 5 mg IM) administered up to 1 hour before surgery.
The dose must be individualized and reduced when IMindent midazolam is administered to patients with chronic obstructive pulmonary disease, other higher risk surgical patients, patients 60 or more years of age, and patients who have received concomitant narcotics or other CNS depressants (see ADVERSE REACTIONS). In a study of patients 60 years or older, who did not receive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05 mg/kg) of midazolam produced adequate sedation during the preoperative period. The dose of 1 mg IM midazolam may suffice for some older patients if the anticipated intensity and duration of sedation is less critical. As with any potential respiratory depressant, these patients require observation for signs of cardiorespiratory depression after receiving IM midazolam.
Onset is within 15 minutes, peaking at 30 to 60 minutes. It can be administered concomitantly with atropine sulfate or scopolamine hydrochloride and reduced doses of narcotics.
Sedation/anxiolysis/amnesia for procedures (see INDICATIONS): Narcotic premedication results in less variability in patient response and a reduction in dosage of midazolam. For peroral procedures, the use of an appropriate topical anesthetic is recommended. For bronchoscopic procedures, the use of narcotic premedication is recommended.
Midazolam 1 mg/mL formulation is recommended for sedation/anxiolysis/amnesia for procedures to facilitate slower injection. Both the 1 mg/mL and the 5 mg/mL formulations may be diluted with 0.9% sodium chloride or 5% dextrose in water.
When used for sedation /anxiolysis/amnesia for a procedure, dosage
must be individualized and titrated. Midazolam should always be titrated
slowly; administer over at least 2 minutes and allow an additional 2
or more minutes to fully evaluate the sedative effect. Individual response
will vary with age, physical status and concomitant medications, but
may also vary independent of these factors. (see WARNINGS
concerning cardiac/respiratory arrest/airway obstruction/ hypoventilation).
| Induction of Anesthesia:
For induction of general anesthesia, before administration of other anesthetic agents.
Injectable midazolam can also be used during maintenance of anesthesia, for surgical procedures, as a component of balanced anesthesia. Effective narcotic premedication is especially recommended in such cases.
| Individual response to the drug is variable, particularly when a narcotic
premedication is not used. The dosage should be titrated to the desired
effect according to the patient's age and clinical status.
When midazolam is used before other intravenous agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.
In the absence of premedication, an average adult under the age of 55 years will usually require an initial dose of 0.3 to 0.35 mg/kg for induction, administered over 20 to 30 seconds and allowing 2 minutes for effect. If needed to complete induction, increments of approximately 25% of the patient's initial dose may be used; induction may instead be completed with inhalational anesthetics. In resistant cases, up to 0.6 mg/kg total dose may be used for induction, but such larger doses may prolong recovery.Unpremedicated patients over the age of 55 years usually require less midazolam for induction; an initial dose of 0.3 mg/kg is recommended. Unpremedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.2 to 0.25 mg/kg will usually suffice; in some cases, as little as 0.15 mg/kg may suffice.
When the patient has received sedative or narcotic premedication, particularly narcotic premedication, the range of recommended doses is 0.15 to 0.35 mg/kg.
In average adults below the age of 55 years, a dose of 0.25 mg/kg, administered over 20 to 30 seconds and allowing 2 minutes for effect, will usually suffice.
The initial dose of 0.2 mg/kg is recommended for good risk (ASA I & II) surgical patients over the age of 55 years.
In some patients with severe systemic disease or debilitation, as little as 0.15 mg/kg may suffice.
Narcotic premedication frequently used during clinical trials included fentanyl (1.5 to 2 mcg/kg IV, administered 5 minutes before induction), morphine (dosage individualized, up to 0.15 mg/kg IM), and meperidine (dosage individualized, up to 1 mg/kg IM). Sedative premedications were hydroxyzine pamoate (100 mg orally) and sodium secobarbital (200 mg orally). Except for intravenous fentanyl, administered 5 minutes before induction, all other premedications should be administered approximately 1 hour prior to the time anticipated for midazolam induction.
Incremental injections of approximately 25% of the induction dose should be given in response to signs of lightening of anesthesia and repeated as necessary.
|For continuous infusion, midazolam 5 mg/mL formulation is recommended diluted to a concentration of 0.5 mg/mL with 0.9% sodium chloride or 5% dextrose in water.|| Usual Adult Dose:
If a loading dose is necessary to rapidly initiate sedation, 0.01 to 0.05 mg/kg (approximately 0.5 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 to 0.1 mg/kg/hr (1 to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients. The lowest recommended doses should be used in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids.
Individual response to midazolam is variable. The infusion rate should be titrated 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. Assessment of sedation should be performed at regular intervals and the midazolam infusion rate adjusted up or down by 25% to 50% of the initial infusion rate so as to assure adequate titration of sedation level. Larger adjustments or even a small incremental dose may be necessary if rapid changes in the level of sedation are indicated. In addition, the infusion rate should be decreased by 10% to 25% every few hours to find the minimum effective 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. Patients who exhibit agitation, hypertension, or tachycardia in response to noxious stimulation, but who are otherwise adequately sedated, may benefit from concurrent administration of an opioid analgesic. Addition of an opioid will generally reduce the minimum effective midazolam infusion rate.
|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 do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring (see tables below). In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate patient monitoring see BOXED WARNING, WARNINGS, DOSAGE AND ADMINISTRATION, Monitoring. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation.|
OBSERVER'S ASSESSMENT OF ALERTNESS/SEDATION (OAA/S)
|Responsiveness||Speech|| Assessment Categories
|Responds readily to name spoken in normal tone||normal||normal||clear, no ptosis||5 (alert)|
|Lethargic response to name spoken in normal tone||mild slowing or thickening||mild relaxation||glazed or mild ptosis (less than half the eye)||4|
|Responds only after slurring or name is called loudly and/or repeatedly||slurring or prominent slowing||marked relaxation (slack jaw)||glazed and marked ptosis (half the eye or more)||3|
|Responds only after mild prodding or shaking||few recognizable words||-||-||2|
|Does not respond to mild prodding or shaking||-||-||-||1 (deep sleep)|
FREQUENCY OF OBSERVER'S ASSESSMENT OF ALERTNESS/SEDATION COMPOSITE SCORES IN ONE STUDY OF PEDIATRIC PATIENTS UNDERGOING PROCEDURES WITH INTRAVENOUS MIDAZOLAM FOR SEDATION
| Age Range
|1 (deep sleep)||2||3||4||5 (alert)|
|> 2-5||22|| 9
|> 5-12||34|| 1
|> 12-17||18||0|| 4
For sedation/anxiolysis/amnesia prior to anesthesia or for procedures, intramuscular midazolam can be used to sedate pediatric patients to facilitate less traumatic insertion of an intravenous catheter for titration of additional medication.
| Usual Pediatric Dose (Non-Neonatal)
Sedation after intramuscular midazolam is age and dose dependent: higher doses may result in deeper and more prolonged sedation. Doses of 0.1 to 0.15 mg/kg are usually effective and do not prolong emergence from general anesthesia. For more anxious patients, doses up to 0.5 mg/kg have been used. Although not systematically studied, the total dose usually does not exceed 10 mg. If midazolam is given with an opioid, the initial dose of each must be reduced.
| Intravenously by Intermittent Injection
For sedative/anxiolysis/amnesia prior to and during procedures or prior to anesthesia.
Usual Pediatric Dose (Non-Neonatal)
| Continuous Intravenous Infusion
For sedation/anxiolysis/amnesia in critical care settings.
| Usual Pediatric Dose (Non-Neonatal)
To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect IN PATIENTS WHOSE TRACHEA IS INTUBATED. (Midazolam should not be administered as a rapid intravenous dose.) This loading dose may be followed by a continuous intravenous infusion to maintain the effect. An infusion of midazolam has been used in patients whose trachea was intubated but who were allowed to breathe spontaneously. Assisted ventilation is recommended for pediatric patients who are receiving other central nervous system depressant medications such as opioids. Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect. Frequent assessment at regular intervals using standard pain/sedation scales is recommended. Drug elimination may be delayed in patients receiving erythromycin and/or other P450 3A4 enzyme inhibitors (see PRECAUTIONS: DRUG INTERACTIONS) and in patients with liver dysfunction, low cardiac output (especially those requiring inotropic support), and in neonates. Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when midazolam is rapidly administered.When initiating an infusion with midazolam in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments and the patient monitored for hemodynamic instability (eg, hypotension). These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.
| Continuous Intravenous Infusion
For sedation in critical care settings.
| Usual Neonatal Dose
Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous infusions of midazolam should be initiated 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. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation. This is particularly important because of the potential for adverse effects related to metabolism of the benzyl alcohol (see WARNINGS: Usage In Preterm Infants and Neonates). 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. Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients whose trachea is not intubated.
|Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.|
Package configurations for Midazolam Hydrochloride Injection containing midazolam hydrochloride equivalent to 5 mg midazolam/mL:
1 mL vials - unit pack of 10
2 mL vials - unit pack of 10
5 mL vials - unit pack of 10
10 mL vials - unit pack of 10
Package configurations for Midazolam Hydrochloride Injection containing midazolam hydrochloride equivalent to 1 mg midazolam/mL:
2 mL vials - unit pack of 10
5 mL vials - unit pack of 10
10 mL vials - unit pack of 10
Case packs containing 20 unit packs are also available for each vial size.
Store at controlled room temperature 15 to 30°C (59-86°F). [see USP]
Mfg by: Novex Pharma, Richmond Hill, Ontario Canada, L4C 5H2, Mfg for: Apotex Corp. Weston, FL 33326, Revised: August 2000. FDA Rev date: 11/20/2002This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 1/4/2008
Additional Midazolam Injection Information
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