WARNING Adult and Pediatrics Intravenous midazolam 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 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, i.e., 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 . For deeply sedated pediatric patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure. Neonates Midazolam 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.

Composition:

Each 5ml Solution contains 11.1mg Midazolam hydrochloride (equivalent to 10mg Midazolam base).

      Mechanism of action:

Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant The effects of midazolam on the CNS are dependent on the dose administered, the route of administration, and the presence or absence of other medications. Onset time of sedative effects after IM administration in adults is 15 minutes with peak sedation occurring 30 to 60 minutes following injection. Sedation in adult and pediatric patients is achieved within 3 to 5 minutes after intravenous (IV) injection.

Sixty to seventy percent of the biotransformation products is 1-hydroxy-midazolam (also termed alpha-hydroxy- midazolam) while 4-hydroxy-midazolam constitutes 5% or less.

Clearance of midazolam is reduced in association with old age, congestive heart failure, liver disease (cirrhosis) or conditions which diminish cardiac output and hepatic blood flow. The principal urinary excretion product is 1-hydroxy-midazolam in the form of a glucuronide conjugate. The amount of midazolam excreted unchanged in the urine after a single IV dose is less than 0.5% (n=5). However, midazolam can accumulate in peripheral tissues with continuous infusion.

Patients with renal impairment may have longer elimination half-lives for midazolam .

The mean Vd based on total body weight increased consistently between 15% to 100% in the elderly. In patients suffering from congestive heart failure, there appeared to be a two-fold increase in the elimination half-life, a 25% decrease in the plasma clearance and a 40% increase in the volume of distribution of midazolam.

Pharmacokenitic Properities: 

Absorption: The absolute bioavailability of the intramuscular route was greater than 90%.

Following IM administration, Cmax for midazolam and its 1-hydroxy metabolite were approximately one-half of those achieved after intravenous injection.

Distribution:

In humans, midazolam has been shown to cross the placenta and enter into fetal circulation and has been detected in human milk and CSF (see Special Populations).

In adults and pediatric patients older than 1 year, midazolam is approximately 97% bound to plasma protein, principally albumin.

Metabolism:

In vitro studies with human liver microsomes indicate that the biotransformation of midazolam is mediated by cytochrome P450 3A4. Drugs that inhibit the activity of cytochrome P450 3A4 may inhibit midazolam clearance and elevate steady-state midazolam concentrations.

Excretion: Clearance of midazolam is reduced in association with old age, congestive heart failure, liver disease (cirrhosis) or conditions which diminish cardiac output and hepatic blood flow.

The principal urinary excretion product is 1-hydroxy-midazolam in the form of a glucuronide conjugate; smaller amounts of the glucuronide conjugates of 4-hydroxy- and dihydroxymidazolam are detected as well. The amount of midazolam excreted unchanged in the urine after a single IV dose is less than 0.5% (n=5). Following a single IV infusion in 5 healthy

volunteers, 45% to 57% of the dose was excreted in the urine as 1-hydroxymethyl midazolam conjugate.

Indications:

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.

 Contraindications:

•  Midazolam 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.

• Midazolam is not intended for intrathecal or epidural administration due to the presence of the preservative benzyl alcohol in the dosage form.

Dosage and administration: 

Standard dosage:

Indication	Adults <60 years	Adults ≥ 60 years / debilitated or chronically ill	Children
Conscious sedation	IV Initial dose: 2-2.5mg Titration doses: 1mg Total dose : 3.5-7.5mg	IV Initial dose : 0.5-1mg Titration doses : 0.5- 1mg Total dose : <3.5mg	IV in patients 6 months-5 years Initial dose: 0.05-0.1mg/kg Total dose: <6mg IV in patients 6-12 years Initial dose: 0.025-0.05mg/kg Total dose: <10mg IM 1-15 years 0.05-0.15mg/kg
Anaesthesia premedication	IV 1-2mg repeated IM 0.07-0.1mg/kg	IV Initial dose: 0.5mg. Slow uptitration as needed. IM 0.025-0.05mg/kg	IM 1-15 years 0.08-0.2mg/kg
Anaesthesia induction	IV 0.15-0.2mg/kg (0.3-0.35 without premedication)	IV 0.05-0.15 mg/kg (0.15-0.3 without premedication)
Sedative component in combined anaesthesia	IV intermittent doses of 0.03-0.1mg/kg or continuous infusion of 0.03-0.1mg/kg/h	IV lower doses than recommended for adults <60 years
Sedation in ICU	IV Loading dose: 0.03-0.3mg/kg in increments of 1-2.5mg Maintenance dose: 0.03-0.2mg/kg/h	IV in neonates <32 weeks gestational age : 0.03mg/kg/h IV in neonates >32 weeks and children up to 6 months: 0.06mg/kg/h IV in patients >6 months of age: Loading dose: 0.05-0.2mg/kg Maintenance dose: 0.06- 0.12mg/kg/h

 

Method of administration

CONSCIOUS SEDATION DOSAGE:

For conscious sedation prior to diagnostic or surgical intervention, midazolam is administered IV The dose must be individualised and titrated, and should not be administered by rapid or single bolus injection. The onset of sedation may vary individually depending on the physical status of the patient and the detailed circumstances of dosing (e.g. speed of administration, amount of dose). If necessary, subsequent doses may be administered according to the individual need. The onset of action is about 2 minutes after the injection. Maximum effect is obtained in about 5 to 10 minutes.

Adults:

• The IV injection of midazolam should be given slowly at a rate of approximately 1mg in 30 seconds.
• In adults below the age of 60 the initial dose is 2 to 2.5mg given 5 to 10 minutes before the beginning of the procedure. Further doses of 1mg may be given as necessary. Mean total doses have been found to range from 3.5 to 7.5mg. A total dose greater than 5mg is usually not necessary.
• In adults over 60 years of age, debilitated or chronically ill patients, the initial dose must be reduced to 0.5-1.0mg and given 5-10 minutes before the beginning of the procedure. Further doses of 0.5 to 1mg may be given as necessary. Since in these patients the peak effect may be reached less rapidly, additional midazolam should be titrated very slowly and carefully. A total dose greater than 3.5mg is usually not necessary.

Paediatric population:

IV administration: midazolam should be titrated slowly to the desired clinical effect. The initial dose of midazolam should be administered over 2 to 3 minutes. One must wait an additional 2 to 5 minutes to fully evaluate the sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with small increments until the appropriate level of sedation is achieved. Infants and young children less than 5 years of age may require substantially higher doses (mg/kg) than older children and adolescents.

• Paediatric patients less than 6 months of age: paediatric patients less than 6 month of age are particularly vulnerable to airway obstruction and hypoventilation. For this reason, the use in conscious sedation in children less than 6 months of age is not recommended.

• Paediatric patients 6 months to 5 years of age: initial dose 0.05 to 0.1mg/kg. A total dose up to 0.6mg/kg may be necessary to reach the desired endpoint, but the total dose should not exceed 6mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

• Paediatric patients 6 to 12 years of age: initial dose 0.025 to 0.05mg/kg. A total dose of up to 0.4mg/kg to a maximum of 10mg may be necessary. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

• Paediatric patients 12 to 16 years of age: should be dosed as adults.

IM administration: the doses used range between 0.05 and 0.15mg/kg. A total dose greater than 10.0mg is usually not necessary. This route should only be used in exceptional cases. Rectal administration should be preferred as IM injection is painful.

• In children less than 15kg of body weight, midazolam solutions with concentrations higher than 1mg/ml are not recommended. Higher concentrations should be diluted to 1mg/ml.

Anaesthesia Dosage:

Premedication:

Premedication with midazolam given shortly before a procedure produces sedation (induction of sleepiness or drowsiness and relief of apprehension) and preoperative impairment of memory. Midazolam can also be administered in combination with anticholinergics. For this indication midazolam should be administered IV or IM, deep into a large muscle mass 20 to 60 minutes before induction of anaesthesia), or preferably via the rectal route in children (see below). Close and continuous monitoring of the patients after administration of premedication is mandatory as interindividual sensitivity varies and symptoms of overdose may occur.

Adults :

• For preoperative sedation and to impair memory of preoperative events, the recommended dose for adults of ASA Physical Status I & II and below 60 years is 1-2mg IV repeated as needed, or 0.07 to 0.1mg/kg administered IM The dose must be reduced and individualised when midazolam is administered to adults over 60 years of age, debilitated, or chronically ill patients.
• The recommended initial IV dose is 0.5mg and should be slowly uptitrated as needed. A dose of 0.025 to 0.05mg/kg administered IM is recommended. In case of concomitant administration of narcotics the midazolam dose should be reduced. The usual dose is 2 to 3mg.

Paediatric population :

Neonates and children up to 6 months of age:

The use in children less than 6 months of age is not recommended as available data are limited.

Children over 6 months of age:

IM administration: As IM injection is painful, this route should only be used in exceptional cases. Rectal administration should be preferred. However, a dose range from 0.08 to 0.2mg/kg of midazolam administered IM has been shown to be effective and safe.

• In children between ages 1 and 15 years, proportionally higher doses are required than in adults in relation to body- weight.
• In children less than 15kg of body weight, midazolam solutions with concentrations higher than 1mg/ml are not recommended. Higher concentrations should be diluted to 1mg/ml.

Induction:

Adults :

If midazolam is used for induction of anaesthesia before other anaesthetic agents have been administered, the individual response is variable. The dose should be titrated to the desired effect according to the patient's age and clinical status. When midazolam is used before or in combination with other IV or inhalation agents for induction of anaesthesia, the initial dose of each agent should be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents. The desired level of anaesthesia is reached by stepwise titration. The IV induction dose of midazolam should be given slowly in increments. Each increment of not more than 5mg should be injected over 20 to 30 seconds allowing 2 minutes between successive increments.

• In premedicated adults below the age of 60 years, an IV dose of 0.15 to 0.2mg/kg will usually suffice. In non-premedicated adults below the age of 60 the dose may be higher (0.3 to 0.35mg/kg IV). 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 anaesthetics. In resistant cases, a total dose of up to 0.6mg/kg may be used for induction, but such larger doses may prolong recovery.

• In premedicated adults over 60 years of age, debilitated or chronically ill patients, the dose should be significantly reduced, e.g., down to 0.05-0.15mg/kg administered IV over 20- 30 seconds and allowing 2 minutes for effect. Non-premedicated adults over 60 years of age usually require more midazolam for induction; an initial dose of 0.15 to 0.3mg/kg is recommended. Non-premedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.15 to 0.25mg/kg will usually suffice.

Sedative component in combined anaesthesia:

Adults :

• Midazolam can be given as a sedative component in combined anaesthesia by either further intermittent small IV doses (range between 0.03 and 0.1mg/kg) or continuous infusion of IV midazolam (range between 0.03 and 0.1mg/kg/h) typically in combination with analgesics. The dose and the intervals between doses vary according to the patient's individual reaction.
•  In adults over 60 years of age, debilitated or chronically ill patients, lower maintenance doses will be required.

Sedation in intensive care units:

The desired level of sedation is reached by stepwise titration of midazolam followed by either continuous infusion or intermittent bolus, according to the clinical need, physical status, age and concomitant medication.

Adults :

- IV loading dose: 0.03 to 0.3 mg/kg should be given slowly in increments. Each increment of 1 to 2.5 mg should be injected over 20 to 30 seconds allowing 2 minutes between successive increments. In hypovolaemic, vasoconstricted, or hypothermic patients the loading dose should be reduced or omitted. When midazolam is given with potent analgesics, the latter should be administered first so that the sedative effects of midazolam can be safely titrated on top of any sedation caused by the analgesic.

- IV maintenance dose: doses can range from 0.03 to 0.2 mg/kg/h. In hypovolaemic, vasoconstricted, or hypothermic patients the maintenance dose should be reduced. The level of sedation should be assessed regularly. With long-term sedation, tolerance may develop and the dose may have to be increased.

Paediatric population :

Neonates and children up to 6 months of age:

• Midazolam should be given as a continuous IV infusion, starting at 0.03 mg/kg/h (0.5 µg/kg/min) in neonates with a gestational age <32 weeks, or 0.06 mg/kg/h (1 µg/kg/min) in neonates with a gestational age >32 weeks and children up to 6 months.
• Intravenous loading doses are not recommended in premature infants, neonates and children up to 6 months, 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.
• Careful monitoring of respiratory rate and oxygen saturation is required.

Children over 6 months of age:

• In intubated and ventilated paediatric patients, a loading dose of 0.05 to 0.2 mg/kg IV should be administered slowly over at least 2 to 3 minutes to establish the desired clinical effect. Midazolam should not be administered as a rapid intravenous dose. The loading dose is followed by a continuous IV infusion at 0.06 to 0.12 mg/kg/h (1 to 2 µg/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 IV doses of midazolam can be administered to increase or maintain the desired effect.
• When initiating an infusion with midazolam in haemodynamically compromised patients, the usual loading dose should be titrated in small increments and the patient monitored for haemodynamic instability, e.g., hypotension. These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.
• In premature infants, neonates and children less than 15kg of body weight, midazolam solutions with concentrations higher than 1mg/ml are not recommended. Higher concentrations should be diluted to 1mg/ml.

Renal Impairment

In patients with severe renal impairment (creatinine clearance below 30 ml/min) midazolam may be accompanied by more pronounced and prolonged sedation possibly including clinically relevant respiratory and cardiovascular depression. Midazolam should therefore be dosed carefully in this patient population and titrated for the desired effect.

In patients with renal failure (creatinine clearance <10ml/min) the pharmacokinetics of unbound midazolam following a single IV dose is similar to that reported in healthy volunteers. However, after prolonged infusion in intensive care unit (ICU) patients, the mean duration of the sedative effect in the renal failure population was considerably increased.

Hepatic Impairment

Hepatic impairment reduces the clearance of IV midazolam with a subsequent increase in terminal half-life.

Therefore the clinical effects in patients with hepatic impairment may be stronger and prolonged. The required dose of midazolam may have to be reduced and proper monitoring of vital signs should be established.

Overdose:

The manifestations of midazolam overdosage reported are similar to those observed with other benzodiazepines, including sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma and untoward effects on vital signs.

Treatment of Overdosage:

Respiration, pulse rate and blood pressure should be monitored and general supportive measures should be employed. Attention should be given to the maintenance of a patent airway and support of ventilation, including administration of oxygen. An intravenous infusion should be started. Should hypotension develop, treatment may include intravenous fluid therapy,  judicious use of vasopressors appropriate to the clinical situation and other appropriate countermeasures.

Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines.

Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, assure adequate ventilation, and establish adequate intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for re -sedation, respiratory depression and other residual benzodiazepine effects for an appropriate period after treatment.

Side effects:

• The majority of serious adverse effects, particularly those associated with oxygenation and ventilation, have been reported when midazolam is administered with other medications capable of depressing the central nervous system. The incidence of such events is higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube (eg. upper endoscopy and dental procedures).
• The following additional adverse reactions were reported after intramuscular administration: Headache, Local effects at IM Injection site: pain ,induration ,redness, muscle stiffness.
• The following additional adverse reactions were reported subsequent to intravenous administration as a single sedative/anxiolytic/amnestic agent in adult patients: hiccoughs, nausea, vomiting , coughing, "oversedation" , headache, drowsiness, Local effects at the IV site: tenderness, pain during injection, redness, induration, phlebitis.
• The following adverse events related to the use of IV midazolam in pediatric patients were reported in the medical literature: oxygen desaturation, apnea, hypotension, paradoxical reactions , hiccough, seizure-like activity and nystagmus.

Special warnings and precautions:  

1. Midazolam must never be used without individualization of dosage particularly when used with other medications capable of producing central nervous system depression.

2. 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.

3. Vital signs should continue to be monitored during the recovery period.

4.  When used for sedation/anxiolysis/amnesia, midazolam should always be titrated slowly in adult or pediatric patients.

5. Higher risk adult and pediatric surgical patients, elderly patients and debilitated  patients require lower dosages, whether or not concomitant sedating medications have been administered.

6. Adult or pediatric patients with COPD are unusually sensitive to the respiratory depressant effect of midazolam.

7. Midazolam should not be administered to patients in shock or coma, or in acute alcohol intoxication with depression of vital signs.

8. Particular care should be exercised in the use of midazolam in patients with uncompensated acute illnesses, such as severe fluid or electrolyte disturbances.

9. Must take into account the total amount of benzyl alcohol administered when administration of high dosages of medications (including midazolam) containing this preservative.

10. It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer. For pediatric patients, particular care should be taken to assure safe ambulation.

11. Adverse hemodynamic events have been reported in pediatric patients with cardiovascular instability; rapid intravenous administration should also be avoided in this population.

12. 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. 13. 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.

14. Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. These reactions may be due to inadequate or excessive dosing or improper

administration of midazolam; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions. Should such reactions occur.

15. 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.

Usage in Pregnancy: Teratogenic Effects: Pregnancy Category D

An increased risk of congenital malformations associated with the use of benzodiazepine drugs (diazepam and chlordiazepoxide) has been suggested in several studies. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus.

Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines.

If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus.

Usage In Preterm Infants and Neonates:

Rapid injection should be avoided in the neonatal population.

Because midazolam is transferred transplacentally and because other benzodiazepines given in the last weeks of pregnancy have resulted in neonatal CNS depression, midazolam is not recommended for obstetrical use.

The recommended dosage range of midazolam for preterm and term infants includes amounts of benzyl alcohol well below that associated with toxicity.

Nursing Mothers:

Midazolam is excreted in human milk. Caution should be exercised when MIDAZOLAM is administered to a nursing woman.

Pediatric Use:

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 closer monitoring. In obese pediatric patients, the dose should be calculated based on ideal body weight.

Geriatric Use

Because geriatric patients may have altered drug distribution and diminished hepatic and/or renal function, reduced doses of midazolam are recommended.

Tolerance :

Some loss of efficacy has been reported when midazolam was used as long- term sedation in intensive care units (ICU).

Dependence:

When midazolam is used in long-term sedation in ICU, it should be borne in mind that physical dependence on midazolam may develop. The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a medical history of alcohol and/or drug abuse (see section 4.8).

Withdrawal symptoms:

During prolonged treatment with midazolam in ICU, physical dependence may develop. Therefore, abrupt termination of the treatment will be accompanied by withdrawal symptoms. The following symptoms may occur: headaches, diarrhoea, muscle pain, extreme anxiety, tension, restlessness, confusion, irritability, sleep disturbances, mood changes, hallucinations and convulsions. In severe cases, the following symptoms may occur: depersonalisation, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact. Since the risk of withdrawal symptoms is greater after abrupt discontinuation of treatment, it is recommended to decrease doses gradually.

Amnesia:

Anterograde amnesia may occur at therapeutic doses (frequently this effect is very desirable in situations such as before and during surgical and diagnostic procedures), the duration of which is directly related to the administered dose, with the risk increasing at higher dosages. Prolonged amnesia can present problems in outpatients, who are scheduled for discharge following intervention. After receiving midazolam parenterally, patients should be discharged from hospital or consulting room only if accompanied by an attendant.

Drug Interactions:           

• The sedative effect of intravenous midazolam is accentuated by any concomitantly administered medication, which depresses the central nervous system, particularly narcotics  (eg, morphine, meperidine and fentanyl) and also secobarbital and droperidol.
• 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 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.
• A moderate reduction in induction dosage requirements of thiopental (about 15%) has been noted following use of intramuscular midazolam for premedication in adults.
• The intravenous administration of midazolam decreases the minimum alveolar concentration  (MAC) of halothane required for general anesthesia. This decrease correlates with the dose of midazolam administered.

Midazolam 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