Midazolam, VERSED®

• VERSED®

• Benzodiazepines (Premedicant-Sedative-Anesthetic Agent )

Midazolam Injection: 5 mg/mL, 15 mg/3 mL, 5 mg/5mL, 50 mg/10 mL.

Adults:

1. As intramuscular premedication prior to surgical or diagnostic procedures.

2. As an intravenous agent for patients requiring sedation/anxiolysis/amnesia prior to and during short endoscopic or short diagnostic procedures and direct-current cardioversion.

3. As an alternative intravenous agent for the induction of anesthesia.

4. Continuous intravenous infusion in intubated, mechanically ventilated patients requiring sedation in the Intensive Care Unit (ICU)

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Pediatrics:

1. As intramuscular premedication prior to surgical or diagnostic procedures.

2. As an intravenous agent for patients requiring sedation/anxiolysis/amnesia prior to and during short endoscopic or short diagnostic procedures and direct-current cardioversion.

3. As an alternative intravenous agent for the induction of anesthesia.

4. Continuous intravenous infusion in intubated, mechanically ventilated patients requiring sedation in the Intensive Care Unit (ICU)

• Mechanism of action: Enhances GABAergi (gamma-Aminobutyric acid) inhibition, Midazolam decreases the cyclic GMP level in the cerebellum.

• Absorption: Intramuscular, Intravenous. Onset of sedative effect: about 15 minutes. Peak sedation occurring: 30-60 minutes following injection. Peak plasma concentration >>> 90 ng/ML (intramuscular)
• Metabolism: predominantly mediated by cytochrome P-450 3A4 (CYP3A4) isozyme in liver.
• Distribution: 97% binds to plasma proteins
• Excretion:Half life: 2-6 hours, 90% Urine, 10% Feces

Midazolam is compatible with:

1. 5% Dextrose Injection and
2. 9% Sodium Chloride Injection.
3. Both the 1 mg/mL and 5 mg/mL formulations may be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection.

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Recommended Adult Dosage:

1. Intramuscular Premedication for preoperative sedation and to impair memory of perioperative events >>> 0.07 to 0.08 mg/kg IM administered 30 to 60 minutes preoperatively >>> Decrease the dose of Midazolam in concomitant use with Opioids.

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2. Intravenous Sedation:

For short endoscopic or short diagnostic procedures and direct current cardioversion >>> Injection 1 mg/mL IV slowly injection! (When used for intravenous sedation, midazolam should not be administered by rapid or single bolus intravenous administration>>> Midazolam can be used alone or concomitantly with opioids!

Patients <55 y/o:

Initial dose: No more than 2 to 2.5 mg

Max dose: 5 mg (Do not exceed 0.1 mg/kg)

 

 

Patients >=55y/o:

Initial dose: No more than 1 to 1.5 mg

Max dose: 3.5 mg (Do not exceed 0.07 mg/kg

 

 

Dosage for Intravenous Induction:

A: Unpremedicated Patients:

Patient < 55 y/o:

Initial dose: 0.3-0.35 mg/kg

Increments: If needed to complete induction, increments of approximately 25%of the initial dose may be used.

 

 

 

Patient >= 55y/o:

Initial dose: 0.3 mg/kg

Increments: If needed to complete induction, increments of approximately 25%of the initial dose may be used.

 

 

Patient with severe systemic disease or debilitation:

Initial dose: 0.2-0.25 mg/kg (In some casesas little as 0.15mg/kg will suffice)

Increments: The need forincrement doses tocomplete inductionmust be evaluated bythe anesthesiologist

 

 

 

B: Premedicated Patients: (Opioids or CNS Depressants)

Patients < 55 y/o:

Initial dose: 0.15-0.35 mg/kg /0.25 mg/kg will usually suffice

Increments: If needed to complete induction, increments of approximately 25% Of the initial dose may be used.

 

 

Patients >=55 y/o:

Initial dose: 0.2 mg/kg

Increment dose: If needed to complete induction, increments of approximately 25% of the initial dose may be used.

 

 

Patient with severe systemic disease or debilitation:

Initial dose: 0.15-0,2 mg/kg in some cases as little as 0.15 mg/kg will suffice

Increments: The need for increment doses to complete induction must be evaluated by the

anesthesiologist

(Method of Administration doses are administered over 20 to 30 seconds, allowing 2 minutes for effect)

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3.  ICU Sedation: For initiation and maintenance of ICU sedation in intubated, mechanically ventilated patients

 

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4. Recommended Pediatric Dosage:

Generally require higher doses of midazolam than do adults.

In obese individuals, the dose should be calculated based on ideal body weight.

 

 

Intramuscularly

Usual Pediatric Dose >>> 0.1-0.15 mg/kg

For more anxious pediatric patients >>> doses up to 0.5 mg/kg

 

 

Intravenously by Intermittent Injection

Usual Pediatric Dose:

6 months-5 years => Initial dose: 0.015-0.1 mg/kg / Total dose: 0.6 mg/kg

6-12 years => Initial dose: 0.025-0.05 mg/kg / Total dose: 0.4 mg/kg

12-17 years => Initial dose and Total dose => As adults

Attention: The initial dose should be administered over 2-3 minutes, wait for an additional 2-3 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.

 

 

Continuous Intravenous Infusion (For Sedation in Critical Care Settings)

Usual Pediatric Dose:

Initial dose: => 0.05 to 0.2 mg/kg over at least2 to 3 minutes

Continuous intravenous infusion dose: 0.001-0.002 mg/kg/min (1-2 mcg/kg/min).

Neonates: Midazolam Intravenous loading doses should not be used in neonates (Preterm and term) => continuous intravenous infusion of Midazolam Injection should be initiated at a rate of 0.0005-0.001 mg/kg/min (0.5-1 mcg/kg/min).

1. Enzyme inhibitor medications >>> Concomitant use of Midazolam with these medications will increase the plasma dose level of Midazolam:

 

• Itraconazol: In case of administering with high dose Midazolam
• Fluconazol: In case of administering with high dose Midazolam
• Erythromycin
• Saquinavir

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2. Enzyme inducer medication: Concomitant use of Midazolam with these medications will increase the plasma dose level of Midazolam:

• Sodium Valporate: May increase the need for Midazolam. Adjust the dose in epileptic patients.

More than 10%:

• Decreased respiratory rate >>> more than 20%
• Apnea

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Less than 10%:

• Drowsiness
• Excessive Sedation
• Dizziness
• Hallucination
• Emesis/Vomiting

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Less than 1%:

• Cardiovascular: Premature ventricular contractions, bigeminy, vasovagal episode, bradycardia, tachycardia, and nodal rhythm.
• Respiratory: Laryngospasm, bronchospasm, dyspnea, shallow respiration, hyperventilation and wheezing.
• CNS/Neuromuscular: Nervousness, restlessness, anxiety, argumentativeness, aggression, insomnia, nightmares; deep sedation, prolonged sedation, oversedation, disorientation, slurred speech, emergence delirium, agitation during emergence, prolonged emergence from anesthesia, dreaming during emergence; dysphoria, euphoria, anterograde amnesia, lightheadedness, feeling faint; tremors, muscle contractions, twitches and abnormal spontaneous muscular activity, tonic/clonic movements, athetoid movements; ataxia.
• Gastrointestinal: Acid taste, excessive salivation and retching.
• Special Senses: Blurred vision, diplopia, nystagmus, visual disturbance, difficulty focusing eyes, pinpoint pupils, cyclic movement of eyelids, ears blocked and loss of balance.
• Dermatological: Erythema, rash, pruritus and hives.

Hypersensitivity: Allergic reactions, including anaphylactic shock.

• Known hypersensitivity to benzodiazepines
• Acute pulmonary insufficiency
• Severe chronic obstructive pulmonary disease (COPD)
• Acute narrow angle glaucoma
• Some medications: Boceprevir, Cobicistat, Itraconazol, Nelfinavir, Ritonavir, Paritaprevir, Ombitasvir, Sodium oxybate, Telaprevir.

Pregnancy: Category D

Lactation: Not recommended in nursing mother

1.  Midazolam Injection must never be used without individualization of dose. The immediate availability of oxygen and other appropriate medication, and the equipment necessary for resuscitation, the maintenance of a patent airway, support of ventilation and cardiac function, should be ensured prior to the use of intravenous midazolam in any dose.

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2. Continuously monitor patients for early signs of hypoventilation or apnea >>> Caution for hypoxia/cardiac arrest. Vital signs should continue to be monitored during the recovery period. Opioid agonists and other sedatives add to the respiratory depression produced by midazolam.

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3. Caution: Midazolam should only be administered intramuscularly or

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4. Concomitant use of barbiturates, alcohol, opioids or other CNS depressants increases the risk of apnea and may contribute to excessive and/or prolonged drug effect.

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5. Midazolam should not be given with an opioid as an intramuscular combination for premedication due to the risk of apnea >>> If opioid premedication is given, Decrease the subsequent dose of midazolam.

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6. Patients MUST NOT engage in hazardous activities requiring complete mental alertness >>> operating machinery / driving a motor vehicle

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7. During bronchoscopies, in patients with high Co2 retention, use of opioid premedication is recommended.

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8. Physical and psychological dependence may occur during benzodiazepine treatment >>> Especially in patients with long-term/ High dose treatment >>> alcoholism, drug abuse or marked psychiatric disorders.

 

• Withdrawal: symptoms may occur from a few hours to over a week after discontinuing treatment >>> tremor, restlessness, insomnia, anxiety, headache and inability to concentrate to sweating, muscular/abdominal spasms and perceptual changes. Do not do abrupt dose reduction! Do it gradually.

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9. Geriatrics and debilitated patients: Decrease Midazolam dose

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10. Pediatrics: pediatric patients generally require higher doses of midazolam than adults

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11. When given immediately before Cæsarean section, midazolam can cause depression of the infant.

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12. Extremely caution in patients with: congestive heart failure, chronic renal failure, severe alcoholic cirrhosis >>> exhibit changes in Midazolam elimination half-life.

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13. hypnotic effect of intravenous midazolam and the risk of apnea is accentuated by premedication, particularly opioids (e.g. morphine, meperidine and fentanyl), secobarbital, and the droperidol-fentanyl

14. Single bolus intravenous administration >>> When used for intravenous sedation, midazolam should not be administered by rapid or single bolus intravenous administration.

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15. Decrease the dose of Midazolam in concomitant use with Opioids.

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16. The onset of effect of midazolam is rapid and its duration of action short.

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17. Overdosage:

Symptoms:

• Sedation, somnolence, confusion, impaired, coordination, diminished reflexes, untoward effects on vital signs, coma and possible cardiorespiratory arrest.

Treatment:

• Continuous monitoring of vital signs including EKG immediately.
• Immediate attention should be given to the maintenance of an adequate airway and support of ventilation.
• Cardiopulmonary resuscitation may be required
• Flumazenil (Benzodiazepine antagonist –Specific antidote) >>> 0.2 mg IV in 13-30 minutes >>> If no response after 30 minutes, add 0.3 mg in 30 seconds one minute later. Maximum total dose: 3 mg/hr (contact your regional Poison Control Centre for more information)