- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- Premedication before induction of anaesthesia
- Induction of anaesthesia:
- As a sedative component in combined anaesthesia.
- Premedication before induction of anaesthesia
Adults <60 years
Adults ≥ 60 years / debilitated or chronically ill
Initial dose: 2-2.5 mg
Titration doses: 1 mg
Total dose : 3.5-7.5 mg
Initial dose : 0.5-1 mg
Titration doses : 0.5-1 mg
Total dose : <3.5 mg
i.v. in patients 6 months-5 years
Initial dose: 0.05-0.1 mg/kg
Total dose: <6 mg
i.v. in patients 6-12 years
Initial dose: 0.025-0.05 mg/kg
Total dose: <10 mg
rectal >6 months
i.m. 1-15 years
1-2 mg repeated
Initial dose: 0.5mg
Slow uptitration as needed
rectal >6 months
i.m. 1-15 years
0.15-0.2 mg/kg (0.3-0.35 without premedication)
0.05-0.15 mg/kg (0.15-0.3 without premedication)
Sedative component in combined anaesthesia
intermittent doses of 0.03-0.1 mg/kg or continuous infusion of 0.03-0.1 mg/kg/h
lower doses than recommended for adults <60 years
Sedation in ICU
Loading dose: 0.03-0.3 mg/kg in increments of 1‑2.5 mg
Maintenance dose: 0.03-0.2 mg/kg/h
i.v. in neonates <32 weeks gestational age
i.v. in neonates>32 weeks and children up to 6 months
i.v. in patients>6 months of age
Loading dose: 0.05-0.2 mg/kg
Maintenance dose: 0.06-0.12 mg/kg/h
AdultsThe i.v. injection of midazolam should be given slowly at a rate of approximately 1 mg in 30 seconds. In adults below the age of 60 the initial dose is 2 to 2.5 mg given 5 to 10 minutes before the beginning of the procedure. Further doses of 1 mg may be given as necessary. Mean total doses have been found to range from 3.5 to 7.5 mg. A total dose greater than 5 mg is usually not necessary. In adults over 60 years of age, debilitated or chronically ill patients, the initial dose must be reduced to 0.5-1.0 mg and given 5-10 minutes before the beginning of the procedure. Further doses of 0.5 to 1 mg 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 3.5 mg is usually not necessary.
ChildrenI.V. 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 0.1 mg/kg. A total dose up to 0.6 mg/kg may be necessary to reach the desired endpoint, but the total dose should not exceed 6 mg. 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 0.05 mg/kg. A total dose of up to 0.4 mg/kg to a maximum of 10 mg 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. Rectal administration: the total dose of midazolam usually ranges from 0.3 to 0.5 mg/kg. Rectal administration of the ampoule/vial solution is performed by means of a plastic applicator fixed on the end of the syringe. If the volume to be administered is too small, water may be added up to a total volume of 10 ml. Total dose should be administered at once and repeated rectal administration avoided. The use in children less than 6 months of age is not recommended, as available data in this population are limited. I.M. administration: the doses used range between 0.05 and 0.15 mg/kg. A total dose greater than 10.0 mg is usually not necessary. This route should only be used in exceptional cases. Rectal administration should be preferred as i.m. injection is painful. In children less than 15 kg of body weight, midazolam solutions with concentrations higher than 1 mg/ml are not recommended. Higher concentrations should be diluted to 1 mg/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 i.v. or i.m., 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.
AdultsFor 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 1-2 mg i.v. repeated as needed, or 0.07 to 0.1 mg/kg administered i.m. 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 i.v. dose is 0.5 mg and should be slowly uptitrated as needed. A dose of 0.025 to 0.05 mg/kg administered i.m. is recommended. In case of concomitant administration of narcotics the midazolam dose should be reduced. The usual dose is 2 to 3 mg.
Paediatric PatientsNeonates 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 ageRectal administration: The total dose of midazolam, usually ranging from 0.3 to 0.5 mg/kg should be administered 15 to 30 minutes before induction of anaesthesia. Rectal administration of the ampoule solution is performed by means of a plastic applicator fixed on the end of the syringe. If the volume to be administered is too small, water may be added up to a total volume of 10 ml. I.M. administration: As i.m. 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 0.2 mg/kg of midazolam administered i.m. 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 15 kg of body weight, midazolam solutions with concentrations higher than 1 mg/ml are not recommended. Higher concentrations should be diluted to 1 mg/ml. INDUCTION
AdultsIf 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 i.v. 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 i.v. induction dose of midazolam should be given slowly in increments. Each increment of not more than 5 mg should be injected over 20 to 30 seconds allowing 2 minutes between successive increments. • In premedicated adults below the age of 60 years, an i. v. dose of 0.15 to 0.2 mg/kg will usually suffice. In non-premedicated adults below the age of 60 the dose may be higher (0.3 to 0.35 mg/kg i.v.). 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 0.6 mg/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- 0.15 mg/kg administered i.v. 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 0.3 mg/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 0.25 mg/kg will usually suffice. SEDATIVE COMPONENT IN COMBINED ANAESTHESIA
AdultsMidazolam can be given as a sedative component in combined anaesthesia by either further intermittent small i.v. doses (range between 0.03 and 0.1 mg/kg) or continuous infusion of i.v. midazolam (range between 0.03 and 0.1 mg/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 (see section 4.5).
AdultsI.V. 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. I.V. 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.
Neonates and children up to 6 months of ageMidazolam should be given as a continuous i.v. 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 i.v. 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 i.v. 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 i.v. 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 15 kg of body weight, midazolam solutions with concentrations higher than 1 mg/ml are not recommended. Higher concentrations should be diluted to 1 mg/ml.
Use in Special Populations
Renal ImpairmentIn patients with renal impairment (creatinine clearance <10ml/min) the pharmacokinetics of unbound midazolam following a single i.v. 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 (shown after prolonged infusion in intensive care unit (ICU) patients) was considerably increased most likely due to accumulation of α-hydroxymidazolam glucuronide.There is no specific data in patients with severe renal impairment (creatinine clearance below 30 ml/min) receiving midazolam for induction of anaesthesia.
Hepatic ImpairmentHepatic impairment reduces the clearance of i.v. midazolam with a subsequent increase in terminal half-life. Therefore the clinical effects may be stronger and prolonged. The required dose of midazolam may be reduced and proper monitoring of vital signs should be established. (see section 4.4).
Paediatric populationSee above and section 4.4.
- patients with chronic respiratory insufficiency
- patients with chronic renal failure, impaired hepatic function or with impaired cardiac function
- paediatric patients specially those with cardiovascular instability.
ToleranceSome loss of efficacy has been reported when midazolam was used as long-term sedation in intensive care units (ICU).
DependenceWhen 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 symptomsDuring 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, muscle pain, anxiety, tension, restlessness, confusion, irritability, rebound insomnia, mood changes, hallucinations and convulsions. Since the risk of withdrawal symptoms is greater after abrupt discontinuation of treatment, it is recommended to decrease doses gradually.
AmnesiaMidazolam causes anterograde amnesia (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. Prolonged amnesia can present problems in outpatients, who are scheduled for discharge following intervention. After receiving midazolam parenterally, patients should be discharged from the hospital or consulting room only if accompanied by an attendant.
Paradoxical reactionsParadoxical reactions such as agitation, involuntary movements (including tonic/clonic convulsions and muscle tremor), hyperactivity, hostility, rage reaction, aggressiveness, paroxysmal excitement and assault, have been reported to occur with midazolam. These reactions may occur with high doses and/or when the injection is given rapidly. The highest incidence to such reactions have been reported among children and the elderly. Altered elimination of midazolam Midazolam elimination may be altered in patients receiving compounds that inhibit or induce CYP3A4 and the dose of midazolam may need to be adjusted accordingly (see section 4.5). Midazolam elimination may also be delayed in patients with liver dysfunction, low cardiac output and in neonates (see section 5.2).
Preterm infants and neonatesDue to an increased risk of apnoea, extreme caution is advised when sedating preterm and former preterm non intubated patients. Careful monitoring of respiratory rate and oxygen saturation is required. Rapid injection should be avoided in the neonatal population. Neonates have reduced and/or immature organ function and are also vulnerable to profound and/or prolonged respiratory effects of midazolam. Adverse haemodynamic events have been reported in paediatric patients with cardiovascular instability; rapid intravenous administration should be avoided in this population.
Paediatric patients less than 6 months:In this population, midazolam is indicated for sedation in ICU only.Paediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation, therefore titration with small increments to clinical effect and careful respiratory rate and oxygen saturation monitoring are essential (see also section 'Preterm infants' above).
Concomitant use of alcohol / CNS depressants:The concomitant use of midazolam with alcohol or/and CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of midazolam possibly including severe sedation or clinically relevant respiratory depression (see section 4.5).
Medical history of alcohol or drug abuse:Midazolam as other benzodiazepines should be avoided in patients with a medical history of alcohol or drug abuse.
Criteria for discharge:After receiving midazolam, patients should be discharged from the hospital or consulting room only when recommended by the treating physician and only if accompanied by an attendant. It is recommended that the patient is accompanied when returning home after discharge.Midazolam 5 mg/ml contains 3.16 mg sodium per ml.This should be taken into consideration for patients on a controlled sodium diet.
≥1/100 to <1/10
≥1/1,000 to <1/100
≥1/10,000 to <1/1,000
Cannot be estimated from the available data
Absorption after i.m. injectionAbsorption of midazolam from the muscle tissue is rapid and complete. Maximum plasma concentrations are reached within 30 minutes. The absolute bioavailability after i.m. injection is over 90%.
Absorption after rectal administrationAfter rectal administration midazolam is absorbed quickly. Maximum plasma concentration is reached in about 30 minutes. The absolute bioavailability is about 50%.
DistributionWhen midazolam is injected i.v., the plasma concentration-time curve shows one or two distinct phases of distribution. The volume of distribution at steady state is 0.7-1.2 l/kg. 96-98 % of midazolam is bound to plasma proteins. The major fraction of plasma protein binding is due to albumin. There is a slow and insignificant passage of midazolam into the cerebrospinal fluid. In humans, midazolam has been shown to cross the placenta slowly and to enter foetal circulation. Small quantities of midazolam are found in human milk.
MetabolismMidazolam is almost entirely eliminated by biotransformation. The fraction of the dose extracted by the liver has been estimated to be 30-60 %. Midazolam is hydroxylated by the cytochrome P4503A4 isozyme and the major urinary and plasma metabolite is alpha-hydroxymidazolam. Plasma concentrations of alpha-hydroxymidazolam are 12% of those of the parent compound. Alpha-hydroxymidazolam is pharmacologically active, but contributes only minimally (about 10%) to the effects of intravenous midazolam.
EliminationIn healthy volunteers, the elimination half-life of midazolam is between 1.5 -2.5 hours. Plasma clearance is in the range of 300-500 ml/min. Midazolam is excreted mainly by renal route (60-80% of the injected dose) and recovered as glucuroconjugated alpha-hydroxymidazolam. Less than 1 % of the dose is recovered in urine as unchanged drug. The elimination half-life of alpha-hydroxy-midazolam is shorter than 1 hour. When midazolam is given by i.v. infusion, its elimination kinetics do not differ from those following bolus injection.
Pharmacokinetics in special populations
ElderlyIn adults over 60 years of age, the elimination half-life may be prolonged up to four times.
ChildrenThe rate of rectal absorption in children is similar to that in adults but the bioavailability is lower (5- 18%).The elimination half-life after i.v. and rectal administration is shorter in children 3-10 years old (1-1.5 hours) as compared with that in adults. The difference is consistent with an increased metabolic clearance in children.
NeonatesIn neonates the elimination half-life is on average 6-12 hours, probably due to liver immaturity and the clearance is reduced (see section 4.4).
ObeseThe mean half-life is greater in obese than in non-obese patients (5.9 vs 2.3 hours). This is due to an increase of approximately 50% in the volume of distribution corrected for total body weight. The clearance is not significantly different in obese and non-obese patients.
Patients with hepatic impairmentThe elimination half-life in cirrhotic patients may be longer and the clearance smaller as compared to those in healthy volunteers (see 4.4 Special warnings and precautions for use).
Patients with renal impairmentThe elimination half-life in patients with chronic renal failure is similar to that in healthy volunteers.
Critically ill patientsThe elimination half-life of midazolam is prolonged up to six times in the critically ill.
Patients with cardiac insufficiencyThe elimination half-life is longer in patients with congestive heart failure compared with that in healthy subjects (see section 4.4).
Shelf-life before first opening3 years.
Shelf-life after first openingMidazolam 1 mg/ml, 2 mg/ml or 5 mg/ml Injection are intended for single use. Unused solution is to be disposed of.
Shelf-life after dilutionChemical and physical in-use stability of the dilutions (see section 6.6) has been demonstrated for 72 hours at 25°C.From the microbiological point of view, the dilutions should be used immediately.If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions.
5 amp. of 1 ml
10 amp. of 1 ml
25 amp. of 1 ml
50 amp. of 1 ml
100 amp. of 1 ml
5 amp. of 2 ml
10 amp. of 2 ml
25 amp. of 2 ml
50 amp. of 2 ml
100 amp. of 2 ml
5 amp. of 3 ml
10 amp. of 3 ml
25 amp. of 3 ml
50 amp. of 3 ml
100 amp. of 3 ml
5 amp. of 5 ml
10 amp. of 5 ml
25 amp. of 5 ml
50 amp. of 5 ml
100 amp. of 5 ml
5 amp. of 10 ml
10 amp. of 10 ml
25 amp. of 10 ml
50 amp. of 10 ml
100 amp. of 10 ml
5 amp. of 18 ml
10 amp. of 18 ml
25 amp. of 18 ml
50 amp. of 18 ml
100 amp. of 18 ml
hameln pharmaceuticals ltd
Nexus, Gloucester Business Park, Gloucester, GL3 4AG
+44 (0)1452 632 732
+44 (0)1452 621 661