Drug Facts
Composition & Profile
Identifiers & Packaging
HOW SUPPLIED: Midazolam Injection, USP (Preservative-free) is supplied as follows: NDC Midazolam Injection, USP (Preservative-free) (1 mg per mL) Package Factor 82449-203-02 2 mg per 2 mL Single-Dose Vial 10 vials per carton 82449-204-02 5 mg per 5 mL Single-Dose Vial 10 vials per carton NDC Midazolam Injection, USP (Preservative-free) (5 mg per mL) Package Factor 82449-205-02 5 mg per 1 mL Single-Dose Vial 10 vials per carton 82449-206-02 10 mg per 2 mL Single-Dose Vial 10 vials per carton Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Discard unused portion.; Package/Label Display Panel NDC 82449-203-02 Midazolam Injection, USP CIV 2 mg per 2 mL* (1 mg per mL*) For Intravenous or Intramuscular Use Sterile Preservative Free Discard unused portion 10 x 2 mL Single-Dose Vials NDC 82449-203-01 Midazolam Injection, USP CIV 2 mg per 2 mL* (1 mg per mL*) Sterile, Nonpyrogenic For Intravenous or Intramuscular Use Preservative Free 2 mL Single-Dose Vial 2 mL Carton 2 mL Vial; Package/Label Display Panel NDC 82449-205-02 Midazolam Injection, USP CIV 5 mg per mL* For Intravenous or Intramuscular Use Sterile Preservative Free Discard unused portion 10 x 1 mL Single-Dose Vials NDC 82449-205-01 Midazolam Injection, USP CIV 5 mg per mL* Sterile, Nonpyrogenic For Intravenous or Intramuscular Use Preservative Free 1 mL Single-Dose Vial 1 mL Carton 1 mL Vial; Package/Label Display Panel NDC 82449-204-02 Midazolam Injection, USP CIV 5 mg per 5mL* (1 mg per mL) For Intravenous or Intramuscular Use Sterile Preservative Free Discard unused portion 10 x 5 mL Single-Dose Vials NDC 82449-204-02 Midazolam Injection, USP CIV 5 mg per mL* (1mg per mL) Sterile, Nonpyrogenic For Intravenous or Intramuscular Use Preservative Free 1 mL Single-Dose Vial 5 mL Carton 5 mL Vial; Package/Label Display Panel NDC 82449-206-02 Midazolam Injection, USP CIV 10 mg per 2 mL*(5 mg per mL) For Intravenous or Intramuscular Use Sterile Preservative Free Discard unused portion 10 x 2 mL Single-Dose Vials NDC 82449-206-01 Midazolam Injection, USP CIV 10 mg per 2 mL*(5 mg per mL) Sterile, Nonpyrogenic For Intravenous or Intramuscular Use Preservative Free 1 mL Single-Dose Vial 10 mg per 2 mL Carton 10 mg per 2 mL Vial
- HOW SUPPLIED: Midazolam Injection, USP (Preservative-free) is supplied as follows: NDC Midazolam Injection, USP (Preservative-free) (1 mg per mL) Package Factor 82449-203-02 2 mg per 2 mL Single-Dose Vial 10 vials per carton 82449-204-02 5 mg per 5 mL Single-Dose Vial 10 vials per carton NDC Midazolam Injection, USP (Preservative-free) (5 mg per mL) Package Factor 82449-205-02 5 mg per 1 mL Single-Dose Vial 10 vials per carton 82449-206-02 10 mg per 2 mL Single-Dose Vial 10 vials per carton Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Discard unused portion.
- Package/Label Display Panel NDC 82449-203-02 Midazolam Injection, USP CIV 2 mg per 2 mL* (1 mg per mL*) For Intravenous or Intramuscular Use Sterile Preservative Free Discard unused portion 10 x 2 mL Single-Dose Vials NDC 82449-203-01 Midazolam Injection, USP CIV 2 mg per 2 mL* (1 mg per mL*) Sterile, Nonpyrogenic For Intravenous or Intramuscular Use Preservative Free 2 mL Single-Dose Vial 2 mL Carton 2 mL Vial
- Package/Label Display Panel NDC 82449-205-02 Midazolam Injection, USP CIV 5 mg per mL* For Intravenous or Intramuscular Use Sterile Preservative Free Discard unused portion 10 x 1 mL Single-Dose Vials NDC 82449-205-01 Midazolam Injection, USP CIV 5 mg per mL* Sterile, Nonpyrogenic For Intravenous or Intramuscular Use Preservative Free 1 mL Single-Dose Vial 1 mL Carton 1 mL Vial
- Package/Label Display Panel NDC 82449-204-02 Midazolam Injection, USP CIV 5 mg per 5mL* (1 mg per mL) For Intravenous or Intramuscular Use Sterile Preservative Free Discard unused portion 10 x 5 mL Single-Dose Vials NDC 82449-204-02 Midazolam Injection, USP CIV 5 mg per mL* (1mg per mL) Sterile, Nonpyrogenic For Intravenous or Intramuscular Use Preservative Free 1 mL Single-Dose Vial 5 mL Carton 5 mL Vial
- Package/Label Display Panel NDC 82449-206-02 Midazolam Injection, USP CIV 10 mg per 2 mL*(5 mg per mL) For Intravenous or Intramuscular Use Sterile Preservative Free Discard unused portion 10 x 2 mL Single-Dose Vials NDC 82449-206-01 Midazolam Injection, USP CIV 10 mg per 2 mL*(5 mg per mL) Sterile, Nonpyrogenic For Intravenous or Intramuscular Use Preservative Free 1 mL Single-Dose Vial 10 mg per 2 mL Carton 10 mg per 2 mL Vial
Overview
Midazolam Injection, USP is a water-soluble benzodiazepine available as a sterile, nonpyrogenic parenteral dosage form for intravenous or intramuscular injection. Each mL contains midazolam hydrochloride,USP equivalent to 1 mg or 5 mg midazolam compounded with 0.8% sodium chloride; the pH is adjusted to approximately 3 (2.5 to 3.5) and is adjusted with sodium hydroxide and, if necessary, hydrochloric acid. Midazolam is a white to light yellow crystalline compound, insoluble in water. The hydrochloride salt of midazolam, which is formed in situ , is soluble in aqueous solutions. Chemically, midazolam HCl,USP is 8-chloro-6-(2-fluorophenyl)-1-methyl- 4H -imidazo[1,5-a][1,4]benzodiazepine hydrochloride. Midazolam hydrochloride,USP has the empirical formula C 18 H 13 ClFN 3 •HCl, a calculated molecular weight of 362.25 and the following structural formula: Under the acidic conditions required to solubilize midazolam in the product, midazolam is present as an equilibrium mixture (shown below) of the closed ring form shown above and an open-ring structure formed by the acid-catalyzed ring opening of the 4,5-double bond of the diazepine ring. The amount of open-ring form is dependent upon the pH of the solution. At the specified pH of the product, the solution may contain up to about 25% of the open-ring compound. At the physiologic conditions under which the product is absorbed (pH of 5 to 8) into the systemic circulation, any open-ring form present reverts to the physiologically active, lipophilic, closed-ring form (midazolam) and is absorbed as such. The following chart plots the percentage of midazolam present as the open-ring form as a function of pH in aqueous solutions. As indicated in the graph, the amount of open-ring compound present in solution is sensitive to changes in pH over the pH range specified for the product: 3.0 to 4.0 for the 1 mg/mL concentration and 3.0 to 3.6 for the 5 mg/mL concentration. Above pH 5, at least 99% of the mixture is present in the closed-ring form. structural formula midazolam pH Dependence
Indications & Usage
Midazolam hydrochloride injection 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, 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.
Dosage & Administration
Midazolam hydrochloride injection is a potent sedative agent that requires slow administration and individualization of dosage. Clinical experience has shown midazolam hydrochloride 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 HYDROCHLORIDE INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS. Excessive single doses or rapid 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, involuntarymovements, hyperactivity and combativeness have been reported in adult and pediatric patients. Should such reactions occur, caution should be exercised before continuing administration of midazolam hydrochloride (see WARNINGS ). Midazolam hydrochloride injection should only be administered IM or IV (see WARNINGS ). Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS ). Midazolam Hydrochloride Injection 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. 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 maymove 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.
Warnings & Precautions
WARNINGS: Personnel and Equipment for Monitoring and Resuscitation Prior to the intravenous administration of midazolam in any dose, 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 should be ensured. Patients should be continuously monitored 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. The immediate availability of specific reversal agents (flumazenil) is highly recommended. Vital signs should continue to be monitored during the recovery period. Because intravenous midazolam can depress respiration (see CLINICAL PHARMACOLOGY ), especially when used concomitantly with opioid agonists and other sedatives (see DOSAGE AND ADMINISTRATION ), 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. 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 (see DOSAGE AND ADMINISTRATION for complete information). Risks From Concomitant Use With Opioids Concomitant use of benzodiazepines, including midazolam, and opioids may result in profound sedation, respiratory depression, coma, and death. If a decision is made to use midazolam concomitantly with opioids, monitor patients closely for respiratory depression and sedation (see PRECAUTIONS/Drug Interactions ). Risk of Respiratory Adverse Events Serious cardiorespiratory adverse events 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 a narcotic. Individualization of Dosage Midazolam must never be used without individualization of dosage particularly when used with other medications capable of producing central nervous system depression. See DOSAGE AND ADMINISTRATION for complete information. Other Adverse Events 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 hydrochloride; 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 hydrochloride and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric patients. Concomitant Use of Central Nervous System Depressants Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation, or apnea and may contribute to profound and/or prolonged drug effect. Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation. 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 hydrochloride. 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 ). 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 hydrochloride is recommended, and the possibility of profound and/or prolonged effect should be considered. Injectable midazolam should not be administered 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. Risk of Intra-arterial Injection There have been limited reports of intra-arterial injection of midazolam hydrochloride. 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 following nonintravenous and nonintramuscular routes of administration have not been established. Midazolam hydrochloride should only be administered intramuscularly or intravenously. Return to Full 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 ) 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 1 full day after anesthesia and surgery, whichever is longer. For pediatric patients, particular care should be taken to assure safe ambulation. Neonatal Sedation and Withdrawal Syndrome Use of Midazolam Injection, USP late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate (see PRECAUTIONS: Pregnancy). Monitor neonates exposed to Midazolam Injection, USP during pregnancy or labor for signs of sedation and monitor neonates exposed to Midazolam Injection, USP during pregnancy for signs of withdrawal; manage these neonates accordingly. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications (including midazolam hydrochloride) containing this preservative must take into account the total amount of benzyl alcohol administered. The recommended dosage range of midazolam hydrochloride for preterm and term infants includes amounts of benzyl alcohol well below that associated with toxicity; however, the amount of benzyl alcohol at which toxicitymay occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the dailymetabolic load of benzyl alcohol from these combined sources (see WARNINGS and PRECAUTIONS - Pediatric Use). 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 PRECAUTIONS / Pregnancy and Pediatric Use and ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY ). 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.
Boxed Warning
WARNINGS Personnel and Equipment for Monitoring and Resuscitation Adults and Pediatrics: Intravenous midazolam hydrochloride has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. In some cases, where this was not recognized promptly and treated effectively, death or hypoxic encephalopathy has resulted. Intravenous midazolam hydrochloride should be used only in hospital or ambulatory care settings, including physicians’ and dental offices, that provide for continuous monitoring of respiratory and cardiac function, e.g., pulse oximetry. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured (see WARNINGS ). For deeply sedated pediatric patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure. Risks From Concomitant Use With Opioids Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Monitor patients for respiratory depression and sedation (see WARNINGS, PRECAUTIONS/Drug Interactions ). Individualization of Dosage Midazolam hydrochloride must never be used without individualization of dosage. The initial intravenous dose for sedation in adult patients may be as little as 1 mg, but should not exceed 2.5 mg in a normal healthy adult. Lower doses are necessary for older (over 60 years) or debilitated patients and in patients receiving concomitant narcotics or other central nervous system (CNS) depressants. The initial dose and all subsequent doses 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. The use of the 1 mg/mL formulation or dilution of the 1 mg/mL or 5 mg/mL formulation is recommended to facilitate slower injection. Doses of sedative medications in pediatric patients must be calculated on a mg/kg basis, and initial doses and all subsequent doses should always be titrated slowly. The initial pediatric dose of midazolam for sedation/anxiolysis/amnesia is age, procedure, and route dependent (see DOSAGE AND ADMINISTRATION for complete dosing information). Neonates : Midazolam hydrochloride should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid IV administration, particularly with concomitant use of fentanyl (see DOSAGE AND ADMINISTRATION for complete information).
Contraindications
: Injectable midazolam hydrochloride is contraindicated in patients with a known hypersensitivity to the drug. Benzodiazepines are contraindicated in patients with acute narrow- angle glaucoma. Benzodiazepines may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam hydrochloride; patients with glaucoma have not been studied.
Adverse Reactions
See WARNINGS concerning serious cardiorespiratory events and possible paradoxical reactions. 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 IV and 10.8% of patients following IM administration) and apnea (15.4% of patients following IV administration), as well as variations in blood pressure and pulse rate. The majority of serious adverse effects, particularly those associated with oxygenation and ventilation, have been reported when midazolam hydrochloride 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 The following additional adverse reactions were reported after intramuscular administration: headache (1.3%) Local effects at IM Injection site pain (3.7%) induration (0.5%) redness (0.5%) muscle stiffness (0.3%) Administration of intramuscular midazolam hydrochloride to elderly and/or higher risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially narcotics (see DOSAGE AND ADMINISTRATION ). The following additional adverse reactions were reported subsequent to intravenous administration as a single sedative/anxiolytic/amnestic agent in adult patients: hiccoughs (3.9%) nausea (2.8%) vomiting (2.6%) coughing (1.3%) “oversedation” (1.6%) headache (1.5%) drowsiness (1.2%) Local effects at the IV site tenderness (5.6%) pain during injection (5.0%) redness (2.6%) induration (1.7%) phlebitis (0.4%) Pediatric Patients The following adverse events related to the use of IV midazolam hydrochloride 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 For information concerning hypotensive episodes and seizures following the administration of midazolam hydrochloride to neonates (see Boxed WARNING , CONTRAINDICATIONS , WARNINGS and PRECAUTIONS ). Other adverse experiences, observed mainly following IV injection as a single sedative/anxiolytic/amnesia agent and occurring at an incidence of 1.0% in adult and pediatric patients, are as follows: 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 anaphylactoid reactions, hives, rash, pruritus Miscellaneous: Yawning, lethargy, chills, weakness, toothache, faint feeling, hematoma
Drug Interactions
Effect of Concomitant Use of Benzodiazepines and Opioids The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABA A sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Monitor patients closely for respiratory depression and sedation. Other CNS Depressants The sedative effect of intravenous midazolam is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly opioids (e.g., morphine, meperidine and fentanyl) and also secobarbital and droperidol. Consequently, the dosage of midazolam should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response (see DOSAGE AND ADMINISTRATION ). Other Drug Interactions Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the P450 3A4 enzyme system such as cimetidine (not ranitidine), erythromycin, diltiazem, verapamil, ketoconazole and itraconazole. These drug interactions may result in prolonged sedation due to a decrease in plasma clearance of midazolam. The effect of single oral doses of 800 mg cimetidine and 300 mg ranitidine on steady-state concentrations of oral midazolam was examined in a randomized crossover study (n=8). Cimetidine increased the mean midazolam steady-state concentration from 57 to 71 ng/mL. Ranitidine increased the mean steady-state concentration to 62 ng/mL. No change in choice reaction time or sedation index was detected after dosing with the H2 receptor antagonists. In a placebo-controlled study, erythromycin administered as a 500 mg dose, three times a day, for 1 week (n=6), reduced the clearance of midazolam following a single 0.5 mg/kg IV dose. The half-life was approximately doubled. Caution is advised when midazolam is administered to patients receiving erythromycin since this may result in a decrease in the plasma clearance of midazolam. The effects of diltiazem (60 mg three times a day) and verapamil (80 mg three times a day) on the pharmacokinetics and pharmacodynamics of oral midazolam were investigated in a three-way crossover study (n=9). The half-life of midazolam increased from 5 to 7 hours when midazolam was taken in conjunction with verapamil or diltiazem. No interaction was observed in healthy subjects between midazolam and nifedipine. In a placebo-controlled study where saquinavir or placebo was administered orally as a 1200 mg dose, three times a day, for 5 days (n=12), a 56% reduction in the clearance of midazolam following a single 0.05 mg/kg IV dose was observed. The half-life was approximately doubled. A moderate reduction in induction dosage requirements of thiopental (about 15%) has been noted following use of intramuscular midazolam hydrochloride for premedication in adults. The intravenous administration of midazolam hydrochloride decreases the minimum alveolar concentration (MAC) of halothane required for general anesthesia. This decrease correlates with the dose of midazolam hydrochloride administered; no similar studies have been carried out in pediatric patients but there is no scientific reason to expect that pediatric patients would respond differently than adults. Although the possibility of minor interactive effects has not been fully studied, midazolam and pancuronium have been used together in patients without noting clinically significant changes in dosage, onset or duration in adults. Midazolam hydrochloride does not protect against the characteristic circulatory changes noted after administration of succinylcholine or pancuronium and does not protect against the increased intracranial pressure noted following administration of succinylcholine. Midazolam does not cause a clinically significant change in dosage, onset or duration of a single intubating dose of succinylcholine; no similar studies have been carried out in pediatric patients but there is no scientific reason to expect that pediatric patients would respond differently than adults. No significant adverse interactions with commonly used premedications or drugs used during anesthesia and surgery (including atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, d-tubocurarine, succinylcholine and other nondepolarizing muscle relaxants) or topical local anesthetics (including lidocaine, dyclonine HCl and Cetacaine) have been observed in adults or pediatric patients. In neonates, however, severe hypotension has been reported with concomitant administration of fentanyl. This effect has been observed in neonates on an infusion of midazolam who received a rapid injection of fentanyl and in patients on an infusion of fentanyl who have received a rapid injection of midazolam.
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