Dormicum

Film-coated tablet: Midazolam (Dormicum) 15 mg film-coated tablets are oval, cylindrical, biconvex, grey-blue tablets with "15" engraved on one side and a break-mark on the other side.
Each tablet contains: Midazolam as maleate, EP 15 mg.
Sterile/Radioactive Statement: Not applicable.
Solution for injection: Active ingredient: Midazolam (as midazolam hydrochloride formed in situ).
Midazolam (Dormicum) Ampoules 5 mg/1 mL, 15 mg/3 mL, 5 mg/5 mL.
Sterile/Radioactive Statement: Sterile product.
Excipients/Inactive Ingredients: Film-coated tablet: Anhydrous lactose, microcrystalline cellulose, maize starch, magnesium stearate. [Midazolam (Dormicum) tablets contain anhydrous lactose. For warning related to lactose monohydrate, see General under Precautions.
Solution for injection: Sodium chloride, hydrochloric acid, sodium hydroxide, water for injections.

Therapeutic/Pharmacologic Class of Drug: Pharmacotherapeutic group: Hypnotics and sedatives: benzodiazepine derivatives. ATC code: N05CD08.
Pharmacology: Pharmacodynamics: Mechanism of Action: Midazolam (Dormicum) has a hypnotic and sedative effect characterized by a rapid onset and short duration of action. It also exerts anxiolytic, anticonvulsant and muscle-relaxant effects. Midazolam (Dormicum) impairs psychomotor function after single and/or multiple doses but causes minimal hemodynamic changes.
The central actions of benzodiazepines are mediated through an enhancement of the GABAergic neurotransmission at inhibitory synapses. In the presence of benzodiazepines, the affinity of the GABA receptor for the neurotransmitter is enhanced through positive allosteric modulation resulting in an increased action of released GABA on the postsynaptic transmembrane chloride ion flux.
Solution for injection: Chemically midazolam is a derivative of the imidazobenzodiazepine group. Although the free base is a lipophilic substance with low solubility in water, the basic nitrogen in position 2 of the imidazobenzodiazepine ring system enables the active ingredient of Midazolam (Dormicum) to form water‑soluble salts with acids. This together with rapid metabolic transformation are the reasons for rapid onset and short duration of effects. Because of its low toxicity, midazolam has a wide therapeutic range.
After I.M. or I.V. administration anterograde amnesia of short duration occurs (the patient does not recall events that occurred during the peak of activity of the compound).
Clinical/Efficacy Studies: No text.
Pharmacokinetics: Absorption: Film-coated tablet: Midazolam is absorbed rapidly and completely after oral administration.
Due to the substantial first-pass effect, the absolute bioavailability of oral midazolam ranges 30-70%. Midazolam exhibits linear pharmacokinetics following oral doses of 7.5-20 mg.
After a single administration of a Midazolam (Dormicum) 15 mg tablet, maximum plasma concentrations of 70-120 ng/mL are reached within one hour. Food prolongs the time to peak plasma concentration by around one hour, pointing to a reduced absorption rate of midazolam. The absorption half-life is 5-20 minutes.
Solution for injection: Absorption after I.M. injection: Absorption 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 administration: After rectal administration, midazolam is absorbed quickly. Maximum plasma concentration is reached in about 30 minutes. The absolute bioavailability is about 50%.
Distribution: Film-coated tablet: The tissue distribution of midazolam is very rapid and in most cases a distribution phase is not apparent or is essentially completed within 1-2 hours after oral administration.
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 cerebrospinal fluid. In humans, midazolam has been shown to cross the placenta slowly and to enter fetal circulation. Small quantities of midazolam are found in human milk. Midazolam is not a substrate for drug transporters.
Solution for injection: When midazolam is injected I.V., the plasma concentration‑time curve shows one or two distinct disposition phases. 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 binding protein is 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 fetal circulation. Small quantities of midazolam are found in human milk. Midazolam is not a substrate for drug transporters.
Metabolism: Film-coated tablet: Midazolam is almost entirely eliminated by biotransformation. Midazolam is hydroxylated by Cytochrome P450, CYP3A isozymes. Both isozymes, CYP3A4 and also CYP3A5 are actively involved in the two key pathways for the hepatic oxidative metabolism of midazolam. The metabolism of midazolam after oral administration relies to a comparable extent on intestinal CYP3A and on hepatic CYP3A.
There are two main oxidized metabolites 1'-hydroxymidazolam (also named α-hydroxymidazolam) and 4-hydroxymidazolam. 1'-hydroxymidazolam is the major urinary and plasma metabolite. Plasma concentrations of 1'-hydroxymidazolam may reach 30-50% those of the parent compound. 1'-hydroxymidazolam is pharmacologically active and contributes significantly (about 34%) to the effects of oral midazolam.
Solution for injection: Midazolam is almost entirely eliminated by biotransformation. Midazolam is hydroxylated by the cytochrome P450, CYP3A4 and CYP3A5 isozymes and the major urinary and plasma metabolite is 1'-hydroxymidazolam (also known as α-hydroxymidazolam). Plasma concentrations of 1'-hydroxymidazolam are 12% of those of the parent compound. 1'-hydroxymidazolam is pharmacologically active, but contributes only minimally (about 10%) to the effects of intravenous midazolam.
Elimination: Film-coated tablet: In young healthy volunteers, the elimination half-life of midazolam ranges from 1.5 to 2.5 hours. The elimination half-life of 1'-hydroxymidazolam is shorter than 1 hour; therefore after midazolam administration the concentration of the parent compound and the main metabolite decline in parallel. Less than 1% of the dose is recovered in urine as unchanged drug. 60-80% of the dose is glucuronidated and excreted in the urine in the form of 1'-hydroxymidazolam conjugate. Midazolam is a non-accumulating drug when given once daily. Repeated administrations of midazolam do not induce drug-metabolizing enzymes.
Solution for injection: In young healthy volunteers, the elimination half‑life of midazolam ranges from 1.5 to 2.5 hours. The elimination half-life of the metabolite is shorter than 1 hour; therefore after midazolam administration the concentration of the parent compound and the main metabolite decline in parallel. Plasma clearance of midazolam is in the range of 300‑500 mL/min. Midazolam's metabolites are excreted mainly by the renal route: 60-80% of the dose is excreted in urine as glucuroconjugated 1'-hydroxymidazolam. Less than 1% of the dose is recovered in urine as unchanged drug.
When midazolam is given by I.V. infusion, its elimination kinetics do not differ from those following bolus injection. Repeated administrations of midazolam do not induce drug-metabolizing enzymes.
Pharmacokinetics in Special Populations: Film-coated tablet: Elderly: In elderly male subjects over 60 years of age, the elimination half‑life of midazolam was significantly prolonged by a factor 2.5 as compared with younger male subjects. Total midazolam clearance was significantly reduced in male elderly subjects and the bioavailability of the oral tablet was significantly increased. However, no significant differences were observed in elderly female compared to younger subjects.
Patients with hepatic impairment: The pharmacokinetics of midazolam were significantly modified in patients with chronic liver disease including advanced liver cirrhosis. In particular, as a consequence of a decreased liver clearance, the elimination half-life was prolonged and the absolute bioavailability of oral midazolam was significantly increased in cirrhotic patients compared to control.
Patients with renal impairment: The pharmacokinetics of unbound midazolam are not altered in patients with severe renal impairment.
The pharmacologically mildly active major midazolam metabolite, 1'-hydroxymidazolam glucuronide, which is excreted through the kidney, accumulates in patients with severe renal impairment. This accumulation produces a prolonged sedation. Oral midazolam should therefore be administered carefully and titrated to the desired effect (see Special Dosage Instructions under Dosage & Administration).
Obese patients: In obese patients, the volume of distribution of midazolam is increased. As a consequence, the mean elimination half-life of midazolam is longer in obese than in non-obese patients (5.9 hours vs 2.3 hours). The oral bioavailability of the midazolam tablet was not different in obese patients compared to non-obese patients.
Solution for injection: Elderly: In adults over 60 years of age, the elimination half‑life may be prolonged up to four times. See General and Use in the Elderly under Precautions.
Children: The rate of rectal absorption in children is similar to that in adults but the bioavailability is lower (5-18%). However, the elimination half-life (t_1/2) after I.V. and rectal administration is shorter in children 3-10 years as compared with that in adults (1-1.5 hr). The difference is consistent with an increased metabolic clearance in children. See General and Use in Children under Precautions.
Newborn: In preterm and term newborn infants, the elimination half-life is on average 6-12 hours, probably due to liver immaturity and the clearance is reduced.
Neonates with asphyxia-related hepatic and renal impairment are at risk of generating unexpectedly high serum midazolam concentrations due to a significantly decreased and variable clearance. See General under Precautions.
Obese: The mean half-life is greater in obese than in non-obese patients (8.4 vs 2.7 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 impairment: The clearance in cirrhotic patients may be reduced and the elimination half-life may be longer when compared to those in healthy volunteers. See General under Precautions.
Patients with renal impairment: The pharmacokinetics of unbound midazolam are not altered in patients with severe renal impairment. The pharmacologically mildly active major midazolam metabolite, 1'-hydroxy-midazolam glucuronide, which is excreted through the kidney, accumulates in patients with severe renal impairment. This accumulation produces a prolonged sedation. Midazolam should therefore be administered carefully and titrated to the desired effect. See General and Use in Special populations: Renal impairment under Precautions.
Critically ill patients: The elimination half-life of midazolam is prolonged in the critically ill. See General under Precautions.
Patients with cardiac insufficiency: The elimination half-life is longer in patients with congestive heart failure compared with that in healthy subjects. See General under Precautions.
Toxicology: Preclinical Safety: Solution for injection: There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the monograph.
Carcinogenicity: No text.
Mutagenicity: No text.
Impairment of Fertility: No text.
Teratogenicity: No text.
Other: No text.

Film-coated tablet: Short-term treatment of insomnia.
Benzodiazepines are only indicated when the disorder is severe, disabling or subjecting the individual to extreme distress.
Sedation in premedication before surgical or diagnostic procedures.
Solution for injection: Midazolam (Dormicum) is a short-acting sleep-inducing drug that is indicated as follows: In adults: Conscious sedation before and during diagnostic or therapeutic procedures with or without local anesthesia.
Anesthesia: Premedication before induction of anesthesia; induction of anesthesia; as a sedative component in combined anesthesia.
Sedation in intensive care units.
In pediatrics: Conscious sedation before and during diagnostic or therapeutic procedures with or without local anesthesia.
Anesthesia: Premedication before induction of anesthesia.
Sedation in intensive care units.
For dosage recommendation in specific age range see Table 1 in Dosage & Administration.

Film-coated tablet: Duration of treatment should be as short as possible. Generally, the duration of treatment varies from a few days to a maximum of 2 weeks. The tapering-off process should be tailored to the individual. Treatment with Midazolam (Dormicum) should not be terminated abruptly (see Drug Abuse and Dependence under Precautions).
In certain cases, extension beyond the maximum treatment period may be necessary; if so, it should not take place without re-evaluation of the patient's status. Owing to the rapid onset of action Midazolam (Dormicum) tablets should be taken immediately before going to sleep, and swallowed whole with fluid. Midazolam (Dormicum) can be taken at any time of the day, provided the patient is subsequently assured of at least 7-8 hours undisturbed sleep.
Standard dosage: Dosage range: 7.5-15 mg.
Treatment should be started with the lowest recommended dose. The maximum dose should not be exceeded because of the increased risk of CNS adverse effects possibly including clinically relevant respiratory and cardiovascular depression.
Premedication: In premedication, Midazolam (Dormicum) should be given 30-60 minutes before the procedure.
Special Dosage Instructions: Elderly and/or debilitated patients: In elderly and/or debilitated patients, the recommended dose is 7.5 mg.
Elderly patients showed a larger sedative effect, therefore they may be at increased risk of cardio-respiratory depression as well. Thus, Midazolam (Dormicum) should be used very carefully in elderly patients, and if needed, a lower dose should be considered.
Patients with hepatic impairment: Patients with severe hepatic impairment should not be treated with Midazolam (Dormicum) (see Contraindications). In patients with mild to moderate hepatic impairment, the lowest dose possible should be considered, not exceeding 7.5 mg (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
Patients with renal impairment: In patients with severe renal impairment, Midazolam (Dormicum) may be accompanied by more pronounced and prolonged sedation, possibly including clinically relevant respiratory and cardiovascular depression. Midazolam (Dormicum) should therefore be dosed carefully in this patient population and titrated for the desired effect.
The lowest dose should be considered, not exceeding 7.5 mg (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
Solution for injection: Midazolam is a potent sedative agent that requires slow administration and individualization of dosage.
The dose should be individualized and titration is strongly recommended to safely obtain the desired state of sedation according to the clinical need, physical status, age and concomitant medication.
In adults over 60 years of age, critically ill patients, high-risk patients and pediatric patients, the dose should be determined with caution and risk factors related to each patient should be taken into account.
The drug takes effect in about 2 minutes after intravenous injection. Maximum effect is obtained in about 5 to 10 minutes.
Standard dosages are provided in the table as follows. Additional details are given in the text following the table. (See Table 1.)

Click on icon to see table/diagram/image

Conscious sedation: For basal (conscious) sedation prior to diagnostic or surgical intervention, Midazolam (Dormicum) is administered I.V. The dose must be individualized 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.
Special caution is required for the indication of conscious sedation in patients with impaired respiratory function, see Precautions.
Adults: The I.V. injection of Midazolam (Dormicum) 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 5-10 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 3.5-7.5 mg.
A total dose greater than 5.0 mg is usually not necessary.
In adults over 60 years of age, critically ill patients, high-risk 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 0.5-1 mg may be given as necessary. Since in these patients the peak effect may be reached less rapidly, additional Midazolam (Dormicum) should be titrated very slowly and carefully.
A total dose greater than 3.5 mg is not usually necessary.
Pediatrics: I.V. administration: Midazolam (Dormicum) should be titrated slowly to the desired clinical effect. The initial dose of Midazolam (Dormicum) should be administered over 2 to 3 minutes and, it is recommended to 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 than older children and adolescents.
Pediatric patients less than 6 months of age: Pediatric patients less than 6 months 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 unless the benefits outweigh the risks. In such cases, titration with small increments to clinical effect and careful monitoring are essential.
Pediatric 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 (see Precautions).
Pediatric patients 6 to 12 years of age: Initial dose 0.025 to 0.05 mg/kg. A total dose 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 (see Precautions).
Pediatric patients 13 to 16 years of age: Should be dosed as adults.
Rectal administration (pediatrics >6 months): The total dose of Midazolam (Dormicum) ranges from 0.3-0.5 mg/kg.
Total dose should be administered at once and repeated rectal administration avoided. The use in pediatrics less than 6 months of age is not recommended, as available data in this population are limited.
For rectal administration of Midazolam (Dormicum) see Special Instructions for Use, Handling and Disposal under Cautions for Usage.
I.M. administration (pediatrics 1-16 years): The recommended dose range is 0.05 to 0.15 mg/kg given 5-10 minutes before the beginning of the procedure. A total dose greater than 10.0 mg is not usually necessary. This route should only be used in exceptional cases.
Rectal administration should be preferred as I.M. injection may be painful.
In pediatrics 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.
Anesthesia-premedication: Premedication with Midazolam (Dormicum) given shortly before a procedure produces sedation (induction of sleepiness or drowsiness and relief of apprehension) and preoperative impairment of memory. Midazolam (Dormicum) can also be administered in combination with anticholinergics. For this indication, Midazolam (Dormicum) should be administered I.V., or I.M. (deep into a large muscle mass 20-60 minutes before induction of anesthesia), or preferably via the rectal route in pediatrics (see as follows). Adequate observation of the patient after administration is mandatory as inter-individual 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 1-2 mg I.V. repeated as needed, or 0.07-0.1 mg/kg I.M.
The dose must be reduced and individualized when Midazolam (Dormicum) is administered to adults over 60 years of age, critically ill, high-risk patients.
The recommended initial I.V. dose is 0.5 mg and should be slowly uptitrated as needed. Allow 2-3 minutes to fully evaluate the effect between doses. An I.M. dose of 0.025-0.05 mg/kg is recommended if there is no concomitant administration of narcotics. The usual dose is 2-3 mg.
Pediatrics: Rectal administration (>6 months): The total dose of Midazolam (Dormicum), usually 0.4 mg/kg, ranging from 0.3-0.5 mg/kg, should be administered 20-30 minutes before induction of anesthesia.
For rectal administration of Midazolam (Dormicum) see Special Instructions for Use, Handling and Disposal under Cautions for Usage.
The use in pediatrics less than 6 months of age is not recommended as available data are limited.
I.M. administration (1-15 years): As I.M. injection may be painful, this route should only be used in exceptional cases. Rectal administration should be preferred. However, a dose range from 0.08-0.2 mg/kg of Midazolam (Dormicum) administered I.M. has been shown to be effective and safe.
In children between ages 1 and 15, proportionally higher doses are required than in adults in relation to body weight. It is recommended that Midazolam (Dormicum) should be administered deep into a large muscle mass 30-60 minutes prior to the induction of anesthesia.
In pediatrics 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 of anesthesia: Adults: If Midazolam (Dormicum) is used for induction of anesthesia before other anesthetic 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 (Dormicum) is used before or in combination with other I.V. or inhalation agents for induction of anesthesia, the initial dose of each agent may be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.
The desired level of anesthesia is reached by stepwise titration. The I.V. induction dose of Midazolam (Dormicum) should be given slowly in increments. Each increment of not more than 5 mg should be injected over 20-30 seconds allowing 2 minutes between successive increments.
Adults below the age of 60 years: A dose of 0.2 mg/kg, administered I.V. over 20-30 seconds and allowing 2 minutes for effect, will usually suffice.
In non-premedicated patients, the dose may be higher (0.3-0.35 mg/kg), administered I.V. over 20-30 seconds and allowing about 2 minutes for effect. If needed to complete induction, increments of approximately 25% of the patient's initial dose may be used. Induction may instead be completed with volatile liquid inhalational anesthetics. 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.
Adults above the age of 60 years and/or critically ill and/or high-risk patients: In non-premedicated patients the lowest initial dose of 0.15-0.2 mg/kg is recommended.
In premedicated patients, a dose of 0.05-0.15 mg/kg administered I.V. over 20-30 seconds and allowing 2 minutes for effect, will usually suffice.
Pediatrics: The use of Midazolam (Dormicum) for the induction of anesthesia is limited to adults only as there is very limited experience in children.
Sedative component in combined anesthesia: Adults: Midazolam (Dormicum) can be given as a sedative component in combined anesthesia by either further intermittent small I.V. doses (range between 0.03 and 0.1 mg/kg) or continuous infusion of I.V. Midazolam (Dormicum) (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, critically ill and/or, high-risk patients, lower maintenance doses will be required.
Pediatrics: The use of Midazolam (Dormicum) as sedative component in combined anesthesia is limited to adults only as there is very limited experience in children.
Sedation in intensive care units: The desired level of sedation is reached by stepwise titration of Midazolam (Dormicum) followed by either continuous infusion or intermittent bolus, according to the clinical need, physical status, age and concomitant medication (see Interactions).
Adults: I.V. loading dose: 0.03-0.3 mg/kg should be given slowly in increments.
Each increment of 1-2.5 mg should be injected over 20-30 seconds allowing 2 minutes between successive increments.
In hypovolemic, vasoconstricted or hypothermic patients the loading dose should be reduced or omitted.
When Midazolam (Dormicum) is given with potent analgesics, the latter should be administered first so that the sedative effects of Midazolam (Dormicum) can be safely titrated on top of any sedation caused by the analgesic.
I.V. maintenance dose: Doses can range from 0.03-0.2 mg/kg/h. In hypovolemic, vasoconstricted or hypothermic patients the maintenance dose should be reduced. The level of sedation should be assessed regularly if the patient's condition permits. With long-term sedation, tolerance may develop and the dose may have to be increased.
Pediatrics: In preterm newborn infants, term newborn infants, and pediatrics 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.
Pediatrics up to 6 months of age: Midazolam (Dormicum) should be given as a continuous I.V. infusion: Pediatrics ≤32 weeks of gestational age: starting dose at 0.03 mg/kg/h (0.5 µg/kg/min).
Pediatrics >32 weeks of gestational age up to 6 months of age: starting dose 0.06 mg/kg/h (1 µg/kg/min).
Intravenous loading doses should not be used 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.
Pediatrics over 6 months of age: In intubated and ventilated 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 (Dormicum) 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 (Dormicum) can be administered to increase or maintain the desired effect.
When initiating an infusion with Midazolam (Dormicum) in hemodynamically compromised patients, the usual loading dose should be titrated in small increments and the patient monitored for hemodynamic instability, e.g., hypotension. These patients are also vulnerable to the respiratory depressant effects of Midazolam (Dormicum) and require careful monitoring of respiratory rate and oxygen saturation.
Special Dosage Instructions: Patients with renal impairment: In patients with severe renal impairment, Midazolam (Dormicum) may be accompanied by more pronounced and prolonged sedation possibly including clinically relevant respiratory and cardiovascular depression. Midazolam (Dormicum) should therefore be dosed carefully in this patient population and titrated for the desired effect (see as previously mentioned and Use in Special Populations under Precautions).
Hepatic Impairment: The clinical effects in patients with hepatic impairment may be stronger and prolonged. The dose of midazolam may have to be reduced and vital signs should be monitored (see Precautions and Pharmacology: Pharmacokinetics in Special Populations under Actions).

Symptoms: Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of Midazolam (Dormicum) is seldom life-threatening, if the drug is taken alone, but may lead to areflexia, apnea, hypotonia, hypotension, cardiorespiratory depression and rare cases to coma. Coma, if it occurs, usually lasts a few hours but it may be more protracted and cyclical, particularly in elderly patients. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease.
Benzodiazepines increase the effects of other central nervous system depressants, including alcohol.
Treatment: Monitor the patient's vital signs and institute supportive measures as indicated by the patient's clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects. If taken orally further absorption should be prevented using an appropriate method e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used, airway protection is imperative for drowsy patients. In case of mixed ingestion, gastric lavage may be considered, however not as a routine measure.
If CNS depression is severe consider the use of flumazenil (Anexate), a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil (Anexate), for further information on the correct use of this drug.

Midazolam (Dormicum) must not be used in patients with known hypersensitivity to benzodiazepines or any of their formulation excipients.
Film-coated tablet: Midazolam (Dormicum) must not be used in patients with: Severe respiratory insufficiency; severe hepatic impairment (benzodiazepines are not indicated to treat patients with severe hepatic impairment as they may cause encephalopathy); sleep apnea syndrome; myasthenia gravis.
Midazolam (Dormicum) tablets should not be given to children, 12 years of age and under, because the available strengths of tablets do not allow for appropriate dosing in this patient population.
Midazolam (Dormicum) tablets should not be given to patients receiving concomitant therapy with very strong CYP3A inducers or inhibitors (ketoconazole, itraconazole, voriconazole, HIV protease inhibitors including ritonavir-boosted formulations), and the HCV protease inhibitors boceprevir and telaprevir (see Interactions).

General: Film-coated tablet: Information should be given to the patients about following warnings and precautions.
Tolerance: Some loss of efficacy to the hypnotic effects of short-acting benzodiazepines may develop after repeated use for a few weeks.
Duration of treatment: The duration of treatment with benzodiazepine hypnotics should be as short as possible (see Dosage & Administration), and should not exceed 2 weeks. The tapering-off process should be tailored to the individual. Extension beyond this period should not take place without re-evaluation of the situation.
Rebound insomnia: When discontinuing Midazolam (Dormicum) therapy, insomnia may reoccur, possibly with a higher severity than before starting treatment ("rebound insomnia"). Rebound insomnia, a transient syndrome, may be accompanied by other reactions including mood changes, anxiety, and restlessness. The risk of rebound phenomena is greater after abrupt discontinuation of treatment. Therefore, it is recommended that the dosage of Midazolam (Dormicum) is decreased gradually (see Drug Abuse and Dependence as follows).
Amnesia: Midazolam (Dormicum) may cause anterograde amnesia, which occurs most frequently within the first few hours after ingesting the product. In order to reduce the risk, patients should ensure that they are able to have an uninterrupted sleep of 7-8 hours (see Adverse Reactions).
Residual effects: Provided the oral dose of Midazolam (Dormicum) is not larger than 15 mg/day and the patient is assured of at least 7 to 8 hours undisturbed sleep, no residual effect is observed following oral administration of Midazolam (Dormicum) tablet in standard patients as confirmed by clinical observations using sensitive pharmacological methods.
Psychiatric and 'paradoxical' reactions: Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, anxiety, and more rarely, delusion, anger, nightmares, hallucinations, psychoses, inappropriate behavior and other adverse behavioral effects are known to occur when using benzodiazepines.
Should this be so, use of the drug should be discontinued. These effects are more likely to occur in the elderly.
Specific patient groups: In elderly and/or debilitated patients, as well as in patients with respiratory or cardiovascular impairment, the recommended dose is 7.5 mg. These patients may be more sensitive to the clinical side effects of midazolam like cardio-respiratory depression. Thus, Midazolam (Dormicum) should be used very carefully in these patient populations and if needed a lower dose should be considered (see Special Dosage Instructions under Dosage & Administration).
Benzodiazepines are not recommended for the primary treatment of psychotic illness. Benzodiazepines should not be used alone to treat depression or anxiety associated with depression as suicide may occur in such patients.
Concomitant use of alcohol/CNS depressants: The concomitant use of Midazolam (Dormicum) with alcohol or/and CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of Midazolam (Dormicum) possibly including severe sedation that could result in coma or death, clinically relevant respiratory and/or cardio-vascular depression (see Interactions).
Medical history of alcohol or drug abuse: Midazolam (Dormicum) should be avoided in patients with a medical history of alcohol or drug abuse.
Co-medication with drugs that alter CYP3A activity: Midazolam pharmacokinetics is altered in patients receiving concomitantly compounds that inhibit or induce CYP3A. Consequently, the clinical and adverse effects may be increased or decreased respectively (see Interactions).
Lactose intolerance: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Drug Abuse and Dependence: Dependence: Use of Midazolam (Dormicum) may lead to the development of physical and psychological dependence. 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.
Withdrawal: Withdrawal symptoms may consist of headaches, diarrhea, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases, the following symptoms may occur: derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or convulsions.
Since the risk of withdrawal phenomena/rebound insomnia is higher after abrupt discontinuation of treatment, it is recommended that the dosage be decreased gradually (see Dosage & Administration and General as previously mentioned).
Laboratory Tests: No text.
Ability to Drive and Use Machines: Sedation, amnesia, impaired concentration and impaired muscular function adversely affect the ability to drive or to use machines. Prior to receiving Midazolam (Dormicum), the patient should be warned not to drive a vehicle or operate a machine until completely recovered. The physician should decide when these activities may be resumed.
If sleep duration is insufficient or alcohol is consumed, the likelihood of impaired alertness may be increased (see Interactions).
Use in Special Populations: Renal Impairment: There is a greater likelihood of adverse drug reactions in patients with severe kidney disease (see Special Dosage Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
Hepatic Impairment: See Special Dosage Instructions under Dosage & Administration and Contraindications.
Solution for injection: Midazolam should be used only when age- and size-appropriate resuscitation facilities are available, as I.V. administration of midazolam may depress myocardial contractility and cause apnea. Severe cardiorespiratory adverse events have occurred on rare occasions. These have included respiratory depression, apnea, respiratory arrest and/or cardiac arrest. Such life‑threatening incidents are more likely to occur when the injection is given too rapidly or when a high dosage is administered (see Adverse Reactions).
Benzodiazepines are not recommended for the primary treatment of psychotic illness.
In case of conscious sedation provided by non-anesthesiologist review of the latest practice guideline is strongly advised.
Premedication: When midazolam is used for premedication, adequate observation of the patient after administration is mandatory as inter-individual sensitivity varies and symptoms of overdose may occur.
High-risk patients: Special caution should be exercised when administering midazolam to high-risk patients: Adults over 60 years of age; Critically ill; Patients with impaired organ function: impaired respiratory function, impaired kidney function, impaired hepatic function (benzodiazepines may precipitate or exacerbate encephalopathy in patients with severe hepatic impairment), impaired cardiac function.
These high-risk patients require lower dosages (see Dosage & Administration) and should be continuously monitored for early signs of alterations of vital functions.
Discharging criteria: After receiving Midazolam (Dormicum), patients should be discharged from hospital or consulting room only when recommended by treating physician and if accompanied by an attendant. It is recommended that the patient is accompanied when returning home after discharge.
Tolerance: Some loss of efficacy has been reported when Midazolam (Dormicum) was used as long-term sedation in intensive care units (ICU).
Withdrawal symptoms: Since the risk of withdrawal symptoms is greater after abrupt discontinuation of treatment, especially after long-term sedation i.e. ≥2-3 days, it is recommended that the dose is decreased gradually. The following withdrawal symptoms may occur: headaches, diarrhea, muscle pain, extreme anxiety, tension, sleep disturbances, restlessness, confusion, irritability, mood changes, hallucinations and convulsions. In severe cases, the following symptoms may occur: depersonalization, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact.
Amnesia: Anterograde amnesia may occur with therapeutic doses, with the risk increasing at higher dosages. Prolonged amnesia can present problems in outpatients, who are scheduled for discharge following intervention.
Paradoxical reactions: Paradoxical reactions such as restlessness, agitation, irritability, involuntary movements (including tonic/clonic convulsions and muscle tremor), hyperactivity, hostility, delusion, anger aggressiveness, anxiety, nightmares, hallucinations, psychoses, inappropriate behavior and other adverse behavioral effects, paroxysmal excitement and assault, have been reported to occur with midazolam. These reactions may occur with higher doses and/or when the injection is given rapidly. The rare incidence of susceptibility to such reactions has been reported among children and at higher I.V. doses in elderly. Should this be so, discontinuation of the drug should be considered.
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 Interactions.
Midazolam elimination may also be delayed, in patients with liver dysfunction, low cardiac output and in newborns (see Use in Special Populations as follows).
Sleep Apnea: Midazolam ampoules should be used with extreme caution in patients with sleep apnea syndrome and patients should be regularly monitored.
Preterm infants: Due to an increased risk of apnea, extreme caution is advised when sedating preterm infants less than 36 weeks of gestational age whose trachea is not intubated. Rapid injection should be avoided in the preterm infants less than 36 weeks of gestational age. Careful monitoring of respiratory rate and oxygen saturation is required.
Pediatric patients less than 6 months: Pediatric 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 'Preterm infants' as previously mentioned).
Concomitant use of alcohol/CNS depressants: The concomitant use of Midazolam (Dormicum) with alcohol or/and CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of Midazolam (Dormicum) possibly including severe sedation that could result in coma or death, clinically relevant respiratory and/or cardiovascular depression (see Interactions).
Medical history of alcohol or drug abuse: Midazolam (Dormicum) should be avoided in patients with a medical history of alcohol or drug abuse.
Others: As with any substance with CNS depressant and/or muscle-relaxant properties, particular care should be taken when administering midazolam to a patient with myasthenia gravis.
Drug Abuse and Dependence: Dependence: When midazolam is used in long-term sedation, 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.
Laboratory Tests: No text.
Ability to Drive and Use Machines: Sedation, amnesia, impaired concentration and impaired muscular function adversely affect the ability to drive or use machines. Prior to receiving Midazolam (Dormicum), the patient should be warned not to drive a vehicle or operate a machine until completely recovered. The physician should decide when these activities may be resumed.
If sleep duration is insufficient or alcohol is consumed, the likelihood of impaired alertness may be increased (see Interactions).
Use in Special Populations: Renal Impairment: There is a greater likelihood of adverse drug reactions in patients with severe renal impairment (see Special Dosing Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions). (See Table 2.)

Click on icon to see table/diagram/image

Hepatic Impairment: Hepatic 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 have to be reduced and proper monitoring of vital signs should be established (see Dosage & Administration and Precautions).
Use in Children: Film-coated tablet: See Contraindications.
Solution for injection: See Dosage & Administration and Precautions.
In preterm newborn infants, term newborn infants, and pediatrics 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.
IV and rectal administration in pediatric patients less than 6 months of age is not recommended with exception in ICU as they are vulnerable to airway obstruction and hypoventilation.
Midazolam (Dormicum) is not indicated in children in induction of anesthesia and as a sedative component in combined anesthesia as limited data is available.
Use in the Elderly: Film-coated tablet: See Special Dosage Instructions under Dosage & Administration and General as previously mentioned.
Solution for injection: Geriatric patients ≥60 years, require lower dosages and should be continuously monitored for early signs of alterations of vital functions (see Dosage & Administration and Precautions).

Pregnancy: Film-coated tablet: Insufficient data are available on midazolam to assess its safety during pregnancy. Benzodiazepines should be avoided during pregnancy unless there is no safer alternative.
An increased risk of congenital malformation associated with the use of benzodiazepines during the first trimester of pregnancy has been suggested.
If the product is prescribed to a woman of childbearing potential, she should contact the physician regarding discontinuation of the product if she intends to become or suspects that she is pregnant.
The administration of midazolam in the last trimester of pregnancy or at high doses during labor has been reported to produce irregularities in the fetal heart rate, hypotonia, poor sucking and hypothermia and moderate respiratory depression in the neonate.
Moreover, infants born to mothers who took benzodiazepines chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period.
Solution for injection: Insufficient data are available on midazolam to assess its safety during pregnancy. Benzodiazepines should be avoided during pregnancy unless there is no safer alternative. The administration of midazolam in the last trimester of pregnancy or at high doses during labor has been reported to produce irregularities in the fetal heart rate, hypotonia, poor sucking and hypothermia and moderate respiratory depression in the neonate. Moreover, infants born to mothers who received benzodiazepines chronically during the latter stage of pregnancy may have developed physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period.
An increased risk of congenital malformation associated with the use of benzodiazepines during the first trimester of pregnancy has been suggested.
Labor and Delivery: See Pregnancy as previously mentioned.
Nursing Mothers: Film-coated tablet: Since midazolam passes into breast milk, Midazolam (Dormicum) should not be administered to breast-feeding mothers.
Solution for injection: Midazolam passes in low quantities into breast milk. Nursing mothers should be advised to discontinue breast-feeding for 24 hours following administration of midazolam.

Clinical Trials: No text.
Laboratory Abnormalities: No text.
Post Marketing: Film-coated tablet: Immune System Disorders: Hypersensitivity reactions and angioedema may occur in susceptible individuals.
Psychiatric Disorders: Confusional state, disorientation, emotional and mood disturbances. These phenomena occur predominantly at the start of therapy and usually disappear with repeated administration. Changes in libido have been reported occasionally.
Depression: Pre-existing depression may be unmasked during benzodiazepine use.
Paradoxical reactions such as restlessness, agitation, hyperactivity, nervousness, anxiety, irritability, aggressiveness, anger, nightmares, abnormal dreams, hallucinations, inappropriate behavior and other adverse behavioral effects are known to occur. Should this be the case, use of the drug should be discontinued. These effects are more likely to occur in the elderly.
Dependence: Use (even at therapeutic doses) may lead to the development of physical dependence. Abrupt discontinuation of the therapy may result in withdrawal or rebound phenomena including rebound insomnia, mood changes, anxiety and restlessness (see General under Precautions). Psychological drug dependence may occur. Abuse has been reported in poly-drug abusers.
Nervous System Disorders: Drowsiness during the day, headache, dizziness, decreased alertness, ataxia. These phenomena occur predominantly at the start of therapy and usually disappear with repeated administration.
When used as premedication, this product may contribute to post-operative sedation.
Anterograde amnesia may occur with therapeutic doses, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behavior (see General under Precautions).
Eye Disorders: Diplopia, this phenomenon occurs predominantly at the start of therapy and usually disappears with repeated administration.
Gastrointestinal Disorders: Gastrointestinal disturbances, have been reported occasionally.
Skin and Subcutaneous Tissue Disorders: Skin reactions have been reported occasionally.
Musculoskeletal and Connective Tissue Disorders: Muscle weakness, this phenomenon occurs predominantly at the start of therapy and usually disappears with repeated administration.
General Disorders and Administration Site Conditions: Fatigue, this phenomenon occurs predominantly at the start of therapy and usually disappear with repeated administration.
Injury, Poisoning and Procedural Complications: There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.
Respiratory Disorders: Respiratory depression was reported.
Cardiac Disorders: Cardiac failure including cardiac arrest was reported.
Laboratory Abnormalities: No text.
Solution for injection: The following undesirable effects have been reported to occur when Midazolam (Dormicum) is injected.
Immune System Disorders: Generalized hypersensitivity reactions (skin reactions, cardiovascular reactions, bronchospasm), angioedema, anaphylactic shock.
Psychiatric Disorders: Confusional state, disorientation, emotional and mood disturbances. Changes in libido have been reported occasionally.
Paradoxical reactions such as restlessness, agitation, irritability, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity, nervousness, hostility, anger, aggressiveness, anxiety, nightmares, abnormal dreams, hallucinations, psychoses, inappropriate behavior and other adverse behavioral effects, paroxysmal excitement and assault, have been reported, particularly among children and the elderly.
Dependence: Use of Midazolam (Dormicum) even in therapeutic doses may lead to the development of physical dependence. After prolonged I.V. administration, discontinuation, especially abrupt discontinuation of the product, may be accompanied by withdrawal symptoms including withdrawal convulsions. Abuse has been reported in poly-drug abusers.
Nervous System Disorder: Prolonged sedation, decreased alertness, headache, dizziness, ataxia, postoperative sedation, anterograde amnesia, the duration of which is directly related to the administered dose. Anterograde amnesia may still be present at the end of the procedure and in isolated cases prolonged amnesia has been reported.
Convulsions have been reported in premature infants and neonates.
Cardiac Disorders: Severe cardiorespiratory adverse events have occurred on rare occasions. These have included cardiac arrest, hypotension, bradycardia, vasodilating effects. Life-threatening incidents are more likely to occur in adults over 60 years of age and those with pre-existing respiratory insufficiency or impaired cardiac function, particularly when the injection is given too rapidly or when a high dosage is administered (see Precautions).
Respiratory Disorders: Severe cardiorespiratory adverse events have occurred on rare occasions. These have included respiratory depression, apnea, respiratory arrest, dyspnea, laryngospasm. Life-threatening incidents are more likely to occur in adults over 60 years of age and those with pre-existing respiratory insufficiency or impaired cardiac function, particularly when the injection is given too rapidly or when a high dosage is administered (see Precautions). Hiccup.
Gastrointestinal System Disorders: Nausea, vomiting, constipation, dry mouth.
Skin and Appendages Disorders: Skin rash, urticaria, pruritus.
General and Application Site Disorders: Erythema and pain on injection site, thrombophlebitis, thrombosis.
Injury, Poisoning and Procedural Complications: There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.
Laboratory Abnormalities: No text.

Pharmacokinetic Drug-Drug Interaction (DDI): Film-coated tablet: (See Contraindications and General under Precautions.)
Midazolam is almost exclusively metabolized by cytochrome P450 3A (CYP3A4 and CYP3A5). Inhibitors and inducers of CYP3A have the potential to increase and decrease the plasma concentrations and, subsequently, the pharmacodynamic effects of midazolam. No other mechanism than modulation of CYP3A activity has been proven as a source for a clinically relevant pharmacokinetic drug-drug interaction with midazolam. Midazolam is not known to change the pharmacokinetics of other drugs.
When co-administered with a CYP3A inhibitor, the clinical effects of oral midazolam may be stronger and also longer lasting and a lower dose may be required. Conversely, the effect of midazolam may be weaker and last shorter when co-administered with a CYP3A inducer and a higher dose may be required.
In case of CYP3A induction and irreversible inhibition (so-called mechanism-based inhibition), the effect on the pharmacokinetics of midazolam may persist for several days up to several weeks after administration of the CYP3A modulator. Examples of mechanism-based CYP3A inhibitors include antibacterial drugs (e.g., clarithromycin, erythromycin, isoniazid), anti-retrovirals (e.g., HIV protease inhibitors such as ritonavir, including ritonavir-boosted protease inhibitors; delavirdine), calcium channel blockers (e.g., verapamil, diltiazem), tyrosine kinase inhibitors (e.g., imatinib, lapatinib, idelalisib) or the estrogen receptor modulator raloxifene.
Ethinylestradiol combined with norgestrel or gestodene did not modify exposure to midazolam to a clinically significant degree.
Drugs that inhibit CYP3A: Classification of CYP3A inhibitors: CYP3A inhibitors can be classified according to the strength of their inhibitory effect and to the importance of the clinical modifications when they are administered concomitantly with oral midazolam.
Very strong inhibitors: Midazolam AUC increased >10-fold. The following drugs fall into this category: e.g., ketoconazole, itraconazole, voriconazole, HIV protease inhibitors including ritonavir-boosted protease inhibitors.
Combination of midazolam administered orally with very strong CYP3A inhibitors is contraindicated (see Contraindications).
Strong inhibitors: Midazolam AUC increased by 5 to 10 fold. The following drugs fall into this category: e.g., high dose clarithromycin, tyrosine kinase inhibitors (such as idelalisib) and the HCV protease inhibitors boceprevir and telaprevir.
Concomitant administration of oral midazolam and boceprevir and telaprevir is contraindicated (see Contraindications).
Moderate inhibitors: Midazolam AUC increased by 2 to 5-fold. The following drugs fall into this category: e.g., fluconazole, telithromycin, erythromycin, diltiazem, verapamil, nefazodone, NK1 receptor antagonists (aprepitant, netupitant, casopitant), tabimoreline, posaconazole.
Patients receiving midazolam with strong or moderate CYP3A inhibitors require careful evaluation because the side effects of midazolam may be potentiated (see General under Precautions).
Weak inhibitors: Midazolam AUC increased by 1.25 to <2-fold. The following drugs and herbals fall into this category: e.g., fentanyl, roxithromycin, cimetidine, ranitidine, fluvoxamine, bicalutamide, propiverine, everolimus, cyclosporine, simeprevir, grapefruit juice, Echinacea purpurea, berberine as also contained in goldenseal.
Concomitant administration of midazolam with weak CYP3A inhibitors does not usually lead to a relevant change of midazolam clinical effect.
Drugs that induce CYP3A: Patients receiving a combination of midazolam with CYP3A inducers may require a higher midazolam dose in particular if midazolam is co-administered with strong CYP3A inducers. Strong CYP3A inducers (≥80% decrease in AUC) include: e.g., rifampin, carbamazepine, phenytoin, enzalutamide and mitotane with its long lasting CYP3A4-inducing effect, while moderate CYP3A inducers (50-80% decrease in AUC) include St. John's wort and weak inducers (20-50% decrease in AUC) include efavirenz, clobazam, ticagrelor, vemurafenib, quercetin and Panax ginseng.
Solution for injection: Midazolam is almost exclusively metabolized by cytochrome P450 3A (CYP3A4, CYP3A5). Inhibitors and inducers of CYP3A have the potential to increase and decrease the plasma concentrations and, subsequently, the pharmacodynamic effects of midazolam. No other mechanism than modulation of CYP3A activity has been proven as a source for a clinically relevant pharmacokinetic drug-drug interaction with midazolam.
Midazolam is not known to change the pharmacokinetics of other drugs. When co-administered with a CYP3A inhibitor, the clinical effects of midazolam may be stronger and also longer lasting and a lower dose may be required. Conversely, the effect of midazolam may be weaker and last shorter when co-administered with a CYP3A inducer and a higher dose may be required.
In case of CYP3A induction and irreversible inhibition (so-called mechanism-based inhibition), the effect on the pharmacokinetics of midazolam may persist for several days up to several weeks after administration of the CYP3A modulator. Examples of mechanism-based CYP3A inhibitors include antibacterials (e.g. clarithromycin, erythromycin, isoniazid); anti-retroviral agents [e.g. HIV protease inhibitors such as ritonavir (including ritonavir-boosted protease inhibitors), delavirdine]; calcium channel blockers (e.g., verapamil, diltiazem); tyrosine kinase inhibitors (e.g., imatinib, lapatinib, idelalisib); or the estrogen receptor modulator raloxifene and several herbal constituents (e.g. bergamottin). In contrast to other mechanism-based inhibitors, ethinylestradiol combined with norgestrel or gestodene, used for oral contraception and grapefruit juice (200 mL) did not modify exposure to midazolam to a clinically significant degree.
The range of the inhibiting/inducing potency of drugs is wide. The antifungal ketoconazole, a very potent CYP3A inhibitor, increased the plasma concentrations of I.V. midazolam by about 5-fold. The tuberculostatic drug rifampicin belongs to the strongest inducers of CYP3A and its co-administration resulted in a decrease in the plasma concentrations of intravenous midazolam by about 60%.
The administration route of midazolam also determines the magnitude of change in its pharmacokinetics due to CYP3A modulation: The change in plasma concentrations is expected to be less for intravenous compared to oral administration of midazolam because CYP3A modulation is not confined to the liver but also occurs in the intestinal wall and hence not only affects the systemic clearance, but also the bioavailability of oral midazolam.
There are no studies investigating the effect of CYP3A modulation on the pharmacokinetics of midazolam after rectal and intramuscular administration, respectively. As after rectal administration, the drug partly bypasses the liver and the expression of CYP3A in the colon is less compared to the upper gastrointestinal tract, it is expected that the change in midazolam plasma concentrations due to CYP3A modulation will be less for the rectal than for the oral route of administration. As after intramuscular administration, the drug directly enters systemic circulation, it is expected that the effects of CYP3A modulation will be similar to those for intravenous midazolam.
In line with pharmacokinetic principles, clinical studies have shown that after I.V. single dose of midazolam the change in the maximum clinical effect due to CYP3A modulation will be minor while the duration of effect may be prolonged.
However, after prolonged dosing of midazolam, both the magnitude and duration of effect will be increased in the presence of CYP3A inhibition.
The following listing gives examples of clinical pharmacokinetic drug-drug interactions with midazolam after intravenous administration. Importantly, any drug shown to possess CYP3A modulating effects in vitro and in vivo, respectively, has the potential to change the plasma concentrations of midazolam and therefore its effects. The listing includes information from clinical drug-drug interaction studies for oral midazolam in case that for the co-administered drug in question no information on intravenous midazolam is available. However, as outlined previously, the change in plasma concentrations is expected to be less for intravenous compared to oral midazolam.
Drugs that inhibit CYP3A: Azole antifungals: Ketoconazole and voriconazole increased the plasma concentrations of intravenous midazolam by 5-fold and by 3-4-fold respectively, while the terminal half-life increased by about 3-fold. If parenteral midazolam is co-administered with these strong CYP3A inhibitors, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Staggered dosing and dosage adjustment should be considered, especially if more than a single I.V. dose of midazolam is administered.
Fluconazole and itraconazole both increased the plasma concentrations of intravenous midazolam by 2-3-fold associated with an increase in terminal half-life by 2.4-fold for itraconazole and 1.5-fold for fluconazole, respectively.
Posaconazole increased the plasma concentrations of intravenous midazolam by about 2-fold.
Macrolide antibiotics: Erythromycin resulted in an increase in the plasma concentrations of intravenous midazolam by about 1.6-2-fold associated with an increase in midazolam's terminal half-life by 1.5-1.8-fold.
Clarithromycin increased midazolam's plasma concentrations by up to 2.5-fold associated with an increase in terminal half-life by 1.5-2-fold.
Additional information from oral midazolam: Telithromycin increased the plasma levels of oral midazolam 6-fold.
Roxithromycin: The roxithromycin effects on midazolam's pharmacokinetics are less compared to erythromycin and clarithromycin. After oral administration, the plasma concentrations of midazolam were increased by about 50% compared to a 4.4- and 2.6-fold increase caused by erythromycin and clarithromycin, respectively. The mild effect on the terminal half-life of midazolam by about 30% indicates that the effects of roxithromycin on intravenous midazolam may be minor.
Intravenous anesthetics: Disposition of intravenous midazolam was also changed by intravenous propofol (AUC and half-life increased by 1.6-fold).
Protease inhibitors: Saquinavir and other HIV protease inhibitors: Upon co-administration with ritonavir-boosted lopinavir, the plasma concentrations of intravenous midazolam increased by 5.4-fold, associated with a similar increase in terminal half-life. If parenteral midazolam is co-administered with HIV protease inhibitors, treatment setting should follow the description previously mentioned for ketoconazole within azole antifungals.
HCV protease inhibitors: Boceprevir and telaprevir reduce midazolam clearance. This effect resulted in a 3.4-fold increase of midazolam AUC after I.V. administration and prolonged its elimination half-life 4-fold.
Histamine receptor 2 antagonists: Cimetidine increased the steady state plasma concentrations of midazolam by 26%.
Calcium-channel blockers: Diltiazem: A single dose of diltiazem given to patients undergoing coronary artery bypass grafting increased the plasma concentrations of intravenous midazolam by about 25% and the terminal half-life was prolonged by about 43%. This was less than the 4-fold increase seen after oral administration of midazolam.
Additional information from oral midazolam: Verapamil increased the plasma concentrations of oral midazolam by 3 fold. The terminal half-life of midazolam was increased by 41%.
Various drugs/Herbs: Atorvastatin resulted in a 1.4-fold increase in plasma concentrations of I.V. midazolam compared to control group.
Intravenous fentanyl is a weak inhibitor of midazolam's elimination: AUC and half-life of I.V. midazolam were increased by 1.5-fold in presence of fentanyl.
Additional information from oral midazolam: Fluvoxamine resulted in a mild increase in plasma concentrations of oral midazolam (28%) while the terminal half-life doubled.
Nefazodone increased the plasma concentrations of oral midazolam by 4.6-fold with an increase in terminal half-life by 1.6-fold.
Tyrosine kinase inhibitors have been shown either in vitro (imatinib, lapatinib or after oral administration in vivo (idelalisib) to be potent inhibitors of CYP3A4. After concomitant administration of idelalisib, oral midazolam exposure was increased on average 5.4-fold.
NK1 receptor antagonists (aprepitant, netupitant, casoprepitant) dose dependently increased the plasma concentrations of oral midazolam up to about 2.5-3.5-fold and increased terminal half-life by approximately 1.5-2-fold.
Chlorzoxazone decreased the ratio of the CYP3A generated metabolite 1'-hydroxymidazolam (also known as α-hydroxymidazolam) to midazolam indicating a CYP3A inhibiting effect.
For a number of drugs or herbal medicines, a weak interaction with midazolam's elimination was observed with concomitant changes in its exposure (<2-fold change in AUC) (bicalutamide, everolimus, cyclosporine, simeprevir, propiverine, berberine as also contained in goldenseal). These weak interactions are expected to be further attenuated after I.V. administration.
Drugs that induce CYP3A: Rifampicin decreased the plasma concentrations of intravenous midazolam by about 60% after 7 days of rifampicin 600 mg o.d. The terminal half-life decreased by about 50-60%.
Ticagrelor is a weak CYP3A inducer but has only small effects on intravenously administered midazolam (-12%) and 4-hydoxy-midazolam (-23%) exposures.
Additional information from oral midazolam: Carbamazepine/phenytoin: Repeat dosages of carbamazepine or phenytoin resulted in a decrease in plasma concentrations of oral midazolam by up to 90% and a shortening of the terminal half-life by about 60%.
The very strong CYP3A4 induction seen after mitotane or enzalutamide resulted in a profound and long-lasting decrease of midazolam levels in cancer patients. AUC of orally administered midazolam was reduced to 5% and 14% of normal values respectively.
Clobazam and Efavirenz are weak inducers of midazolam metabolism and reduce the AUC of the parent compound by approximately 30%. There is a resulting 4-5-fold increase in the ratio of the active metabolite (α-hydroxymidazolam) to the parent compound but the clinical significance of this is unknown.
Vemurafenib modulates CYP isozymes and inhibits CYP3A4 mildly: Repeat-dose administration resulted in a mean decrease of oral midazolam exposure of 32% (up to 80% in individuals).
Herbs and food: Echinacea purpurea root extract decreased plasma concentrations (AUC) of I.V. midazolam by 20% associated with a decrease in half-life of about 42%.
St John's wort decreased plasma concentrations of midazolam by about 20-40% associated with a decrease in terminal half-life of about 15-17%.
Additional information from oral midazolam: Quercetin (also contained in Gingko biloba) and Panax ginseng both have weak enzyme inducing effects and reduced exposure to midazolam after its oral administration to the extent of 20-30%.
Acute protein displacement: Valproic acid: Increased concentrations of free midazolam due to displacement from plasma protein binding sites by valproic acid cannot be excluded although the clinical relevance of such an interaction is not known.
Pharmacodynamic Drug-Drug Interactions (DDI): The co-administration of midazolam with other sedative/hypnotic agents, including alcohol, is likely to result in increased sedative/hypnotic effects. Examples include opiates/opioids (when they are used as analgesics, antitussives or substitutive treatments), antipsychotics, other benzodiazepines used as anxiolytics or hypnotics, barbiturates, propofol, ketamine, etomidate; sedative antidepressants, antihistamines and centrally acting antihypertensive drugs. Midazolam decreases the minimum alveolar concentration (MAC) of inhalational anesthetics. Enhanced side effects such as sedation and cardio-respiratory depression may also occur when midazolam is co-administered with any centrally acting depressants including alcohol. Alcohol should be avoided in patients receiving midazolam (see General under Precautions). See Overdosage for warning of other central nervous system depressants, including alcohol.
Drugs increasing alertness/memory like the AchE inhibitor physostigmine reversed the hypnotic effects of midazolam. Similarly, 250 mg of caffeine partly reversed the sedative effect of midazolam.
Solution for injection: It has been shown that spinal anesthesia can increase the sedative effect of I.V. midazolam. The midazolam dose may therefore have to be reduced. When lidocaine or bupivacaine, were administered intramuscularly, the dose of I.V. midazolam required for sedation was reduced.

Solution for injection: Special Instructions for Use, Handling and Disposal: Do not dilute Midazolam (Dormicum) ampoule solutions with 6% Dextran 70 in dextrose.
Do not mix Midazolam (Dormicum) ampoule solutions in alkaline injections. Midazolam precipitates in sodium bicarbonate.
The Midazolam (Dormicum) ampoule solution can be diluted with sodium chloride 0.9%, dextrose 5% and 10%, levulose 5%, Ringer's solution and Hartmann's solution in a mixing ratio of 15 mg midazolam per 100‑1000 mL infusion solution. These solutions remain physically and chemically stable for 24 hours at room temperature, or 3 days at 5°C.
To avoid potential incompatibility with other solutions, Midazolam (Dormicum) ampoule solution must not be mixed with other solutions except those mentioned previously.
From a microbiological point of view the product 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 h at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Midazolam (Dormicum) ampoules are for single use only. Discard any unused solution.
The solution should be visually inspected prior to use. Only clear solutions without particles should be used.
Rectal administration: 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.

Film-coated tablet: Store in the original container and keep blisters in outer carton in order to protect from light.
Store at temperatures not exceeding 30°C.
Solution for injection: Keep the ampoules in the outer carton in order to protect from light.
Store at temperatures not exceeding 25°C.
Precipitation may occur after freezing which dissolves completely after warming to room temperature and mixing well.

Hypnotics & Sedatives

N05CD08 - midazolam ; Belongs to the class of benzodiazepine derivatives. Used as hypnotics and sedatives.

FC tab: EDD, Rx; Soln for inj: DD, Rx