Mizormic

Package leaflet: Information for the patient

Mizormic, 5 mg/ml, solution for injection
Midazolam hydrochloride
Please read all of this leaflet carefully before using this medicine, because it contains
important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any further questions, please ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. It may harm them even if their symptoms are the same.
• If you experience any side effects, including any not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of the leaflet:

1. What Mizormic is and what it is used for
2. Important information before using Mizormic
3. How to use Mizormic
4. Possible side effects
5. How to store Mizormic
6. Contents of the pack and other information

1. What Mizormic is and what it is used for

Mizormic (midazolam) is a short-acting hypnotic medicine belonging to a group of medicines called benzodiazepines.
Mizormic is used:

• to induce mild sedation (a state of calmness or drowsiness while maintaining consciousness) in adults and children,
• to induce sedation in adults and children in intensive care units,
• for anaesthesia in adults (premedication before anaesthetic induction, induction of anaesthesia, or as a sedative component with other medicines used in anaesthesia),
• for premedication before anaesthetic induction in children.

2. Important information before using Mizormic

When not to use Mizormic

• if the patient is allergic to midazolam, other benzodiazepines, or any of the other ingredients of Mizormic (listed in section 6),
• if the patient has severe respiratory insufficiency or acute respiratory depression – in the case of light sedation.

Warnings and precautions
When using Mizormic for premedication, the patient's reactions will be closely observed to ensure the appropriate dose is administered due to individual differences in sensitivity.
Paradoxical reactions and anterograde amnesia (inability to remember recent events) have been reported with the use of Mizormic (see section 4, "Possible side effects").
Special caution is required if:

• the patient is over 60 years of age,
• the patient has chronic illness or is debilitated (e.g. chronic respiratory insufficiency, chronic renal insufficiency, liver or heart dysfunction),
• the patient has muscle weakness (severe neuromuscular disease characterized by reduced muscle strength),
• the patient is currently misusing or has previously misused alcohol or drugs,
• the patient is taking any other medicines, including those obtained without a prescription (for more information, see section "Mizormic and other medicines"),
• the patient is pregnant or suspects she may be pregnant.

Long-term treatment
With prolonged use of Mizormic, the patient may develop tolerance (reduced effectiveness of the drug) or dependence.
After discontinuation of long-term treatment (e.g. in an intensive care unit), the following withdrawal symptoms may occur: headache, muscle pain, anxiety, tension, psychomotor agitation, disorientation, irritability, insomnia, mood changes, hallucinations, and seizures. To prevent these symptoms, the physician will gradually reduce the dose of the drug.

Children and adolescents
Extreme caution must be exercised when using Mizormic in children, especially those under 6 months of age (including newborns and premature infants). Inform the physician if the child has been diagnosed with a cardiovascular disorder. In such cases, the child will be closely monitored and the dose adjusted accordingly.

Mizormic and other medicines
Inform your doctor about all medicines currently used or recently taken, as well as any medicines you plan to take. This is very important because taking more than one medicine at the same time may enhance or reduce the effects of the medicines.
The effect of Mizormic may be enhanced by the following medicines:

• neuroleptics, hypnotics, sedatives,
• antidepressants,
• opioid analgesics (very strong painkillers),
• anaesthetics,
• certain antiallergic medicines (antihistamines),
• medicines used to treat fungal infections (ketoconazole, voriconazole, fluconazole, itraconazole, posaconazole),
• antibiotics (erythromycin, clarithromycin),
• medicines used to treat high blood pressure (diltiazem),
• medicines used to treat HIV infection (saquinavir and other HIV protease inhibitors),
• cholesterol-lowering medicines (atorvastatin).

Concomitant use of Mizormic and opioids (strong painkillers, medicines used in substitution therapy for addiction, and some antitussive medicines) increases the risk of drowsiness, breathing difficulties (respiratory depression), coma, and may be life-threatening.
For this reason, concomitant use should only be considered when no other treatment options are available.
If the doctor prescribes Mizormic together with opioids, the dose and duration of concomitant treatment should be minimized.
Inform your doctor about all opioids being taken and strictly follow medical advice. It may be helpful to inform friends or family members about these symptoms. If such symptoms occur, contact your doctor immediately.

The effect of Mizormic may be reduced by the following medicines:

• medicines used to treat mycobacterial infections, e.g. tuberculosis (rifampicin),
• St. John's wort (Hypericum perforatum) preparations (herbal medicine used in the treatment of depression).

Taking Mizormic with food, drink, and alcohol
Alcohol may enhance the sedative effect of Mizormic and should therefore be avoided during treatment.

Pregnancy, breastfeeding, and fertility
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or plans to have a child, she should consult a doctor or pharmacist before using this medicine.
Midazolam may pass into human milk; therefore, breastfeeding women should not breastfeed for 24 hours after taking Mizormic.

Driving and operating machinery
Mizormic may cause drowsiness, memory disturbances, reduced concentration, and impaired motor coordination. These effects may adversely affect the ability to perform tasks requiring precision, such as driving or operating machinery. After receiving Mizormic, the patient should not drive or operate machinery until the effects of the medicine have completely worn off. The decision on when the patient may resume these activities should be made by the doctor.
After treatment, the patient should return home accompanied by another person.

Mizormic contains sodium
Mizormic contains less than 1 mmol of sodium (23 mg) per dose, meaning the medicine is considered "sodium-free".

3. How to use Mizormic

Mizormic should be administered only by experienced physicians and by personnel
adequately trained in recognizing and managing expected adverse reactions,
in a fully equipped facility with monitoring and supportive equipment for respiratory and
cardiovascular system functions.
Dosage and method of administration
The appropriate dose for each patient will be determined by the physician. Doses may vary depending on the planned treatment and the desired level of sedation. The dose received by the patient may also be influenced by: body weight, age, general health status, response to the drug, and the need for concomitant administration of other medications.
If the patient requires administration of strong analgesic drugs, these will be given first, followed by Mizormic at an appropriately adjusted dose.
Mizormic is administered slowly as an intravenous injection (intravenous bolus), by continuous intravenous infusion, as an intramuscular injection (intramuscular administration), or by rectal administration.
Administration of a higher than recommended dose of Mizormic
This medicine will be administered by a physician.
In case of accidental overdose, symptoms such as drowsiness, ataxia (problems with coordination and balance), speech disturbances, involuntary eye movements, loss of reflexes, apnea, low blood pressure, respiratory and circulatory depression (slowed and shallow breathing and reduced heart rate), and coma may occur. Overdose may require close monitoring of vital signs, symptomatic treatment of respiratory and cardiovascular disturbances, and administration of a benzodiazepine antagonist (a drug that reverses the effects of midazolam).
If you have any further doubts regarding the use of this medicine, consult your doctor or pharmacist.

4. Possible adverse reactions

Like any medicine, this medicine can cause adverse reactions, although not everyone will experience them.
Treatment with Mizormic should be discontinued and a doctor should be contacted immediately if the patient experiences any of the following adverse reactions. These may be life-threatening and may require immediate treatment:

• Anaphylactic shock (a life-threatening allergic reaction). Symptoms may include sudden rash, itching or raised rash (urticaria), and swelling of the face, lips, tongue, or other parts of the body. The patient may also experience shortness of breath, wheezing, or difficulty breathing, or pale skin, weak and rapid pulse, or feeling faint. Additionally, chest pain may occur, which could be a symptom of a serious allergic reaction called Kounis syndrome.
• Generalized allergic reactions (skin reactions, reactions affecting the heart and circulatory system, e.g. low blood pressure, wheezing)
• Shortness of breath and difficulty breathing (sometimes leading to respiratory arrest), apnea.
• Laryngospasm causing choking.
• Cardiac arrest (heart stops beating). Symptoms include loss of consciousness associated with absence of pulse.

The following adverse reactions have also been reported with the use of this medicine:
Very rare (may occur in fewer than 1 in 10,000 patients):

• Disorientation, euphoria, hallucinations
• Paradoxical reactions (opposite to expected effects), mainly occurring in children and elderly patients: agitation, involuntary (uncontrolled) body movements, including muscle tension and tremors, excessive activity, hostility, anger outbursts, aggression, episodic excitement, physical aggression
• Physical dependence on the drug, withdrawal symptoms, including seizures
• Prolonged sedation, reduced alertness, drowsiness, headache, dizziness, coordination and balance problems
• Transient memory loss (the patient does not remember events that occurred shortly after administration of the drug; the duration of memory loss depends on the administered dose)
• Seizures in premature infants and newborns
• Low blood pressure, bradycardia, vasodilation (manifesting as, e.g., flushing, fainting, and headache)
• Hiccups
• Nausea, vomiting, constipation, dry mouth
• Skin rash, urticaria, itching
• Fatigue
• Redness and pain at the injection site, thrombophlebitis, thrombosis (formation of blood clots in veins)
• Falls, fractures.

Reporting of adverse reactions
If any adverse symptoms occur, including any adverse symptoms not listed in this leaflet, inform a doctor, pharmacist, or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products:
Al. Jerozolimskie 181C
02-222 Warsaw
Phone: 22 49-21-301
Fax: 22 49-21-309
Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorization holder.
Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store Mizormic

Keep out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the cardboard box and label following: EXP. The expiry date refers to the last day of the stated month.
The abbreviation "Lot" indicates the batch number.
Do not store above 25°C. Do not freeze. Store in the original packaging to protect from light.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. Such measures help protect the environment.

6. Contents of the pack and other information

What Mizormic contains

• The active substance is midazolam. 1 ml of solution contains 5 mg of midazolam (as hydrochloride).
• The other components are: sodium chloride, hydrochloric acid, sodium hydroxide, and water for injections.

What Mizormic looks like and contents of the pack
A clear, colourless solution, free from visible particles.
Colourless ampoules made of neutral glass type I, packed in cardboard boxes.
Pack sizes: 10 ampoules of 1 ml, 3 ml or 10 ml.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Bausch Health Ireland Limited
3013 Lake Drive
Citywest Business Campus
Dublin 24, D24PPT3
Ireland
Tel: +48 17 865 51 00
Manufacturer
HBM Pharma s.r.o.
Sklabinska 30
036 80 Martin
Slovakia

Information intended exclusively for medical professionals:

Standard dosing
Midazolam is a potent sedative medication requiring individualized dose titration and slow administration for each patient. Individual dose titration is strongly recommended, as it allows safe achievement of the desired level of sedation appropriate to clinical needs, the patient's physical condition, age, and concomitant medications. In adults over 60 years of age, in debilitated or chronically ill patients, and in children and adolescents, dosing should be determined cautiously and with consideration of individual risk factors. Typical dosing is provided in the table below.
Additional detailed information is given in the text following the table.

Dosage for Mild Sedation
To achieve mild sedation prior to a diagnostic or surgical procedure, midazolam is administered intravenously. The dose must be individually adjusted and, if necessary, gradually increased—it should not be administered rapidly or as a single bolus. The onset of sedative effect varies after administration, depending on the patient's physical condition and specific circumstances of drug administration (e.g., rate of administration, dose size). Additional doses may be given as needed, depending on individual requirements. The onset of action occurs approximately 2 minutes after injection. Maximum effect is achieved within about 5–10 minutes.

Adults
Intravenous injection of midazolam should be performed slowly, at a rate of approximately 1 mg per 30 seconds.
For adults under 60 years of age, the initial dose is 2.0–2.5 mg administered 5–10 minutes before the start of the procedure. If necessary, additional doses of 1 mg may be given. It has been observed that the average total dose administered ranges from 3.5–7.5 mg. Usually, it is not necessary to exceed a total dose of 5 mg.
For adults over 60 years of age and for debilitated or chronically ill patients, the initial dose should be reduced to 0.5–1.0 mg administered 5–10 minutes before the start of the procedure. If necessary, additional doses of 0.5–1.0 mg may be given. Because the maximum effect may be achieved more slowly in these patients, additional doses of midazolam should be administered at much longer intervals and with caution. Usually, it is not necessary to exceed a total dose of 3.5 mg.

Children
Intravenous administration. The dose of midazolam should be gradually increased until the desired clinical effect is achieved. The initial dose should be administered over 2–3 minutes. An additional 2–5 minutes should be allowed to assess the full sedative effect before starting the procedure or administering another dose. If deeper sedation is required, the dose should be increased in small increments until the appropriate level of sedation is reached. Infants and young children under 5 years of age may require significantly higher doses per kilogram of body weight than older children and adolescents.

• Children under 6 months of age: children under 6 months are particularly susceptible to airway obstruction and hypoventilation. Therefore, the use of midazolam for mild sedation is not recommended in children under 6 months of age.
• Children aged 6 months to 5 years: the initial dose is 0.05–0.10 mg/kg body weight. A total dose up to 0.6 mg/kg body weight may be necessary to achieve the desired effect, but the total dose should not exceed 6 mg. Use of higher doses may be associated with prolonged sedation and risk of hypoventilation.
• Children aged 6 to 12 years: the initial dose is 0.025–0.050 mg/kg body weight. A total dose up to 0.4 mg/kg body weight, maximum 10 mg, may be necessary. Use of higher doses may be associated with prolonged sedation and risk of hypoventilation.
• Children and adolescents aged 12 to 16 years: dosing as in adults.

Rectal administration. The total dose of midazolam usually ranges from 0.3–0.5 mg/kg body weight. Rectal administration of the solution from an ampoule should be performed using a plastic applicator attached to the end of a syringe. If the volume of solution to be administered is too small, it may be diluted with water to a total volume of 10 ml. The total dose should be administered at once—repeated rectal administration should be avoided.
The use of this method is not recommended in children under 6 months of age due to limited data in this population.
Intramuscular administration. Doses used range from 0.05–0.15 mg/kg body weight. Usually, it is not necessary to exceed a total dose of 10 mg. This route of administration should be used only in exceptional cases. Rectal administration is preferred, as intramuscular injection is painful.
In children with body weight less than 15 kg, midazolam solutions with a concentration exceeding 1 mg/ml should not be used. Solutions with higher concentrations should be diluted to a concentration of 1 mg/ml.

Dosage in Anesthesia
Premedication
Premedication with midazolam administered immediately before a procedure induces sedation (drowsiness or lethargy and reduced anxiety) and anterograde amnesia (impaired memory of events before surgery). Midazolam may also be administered in combination with anticholinergics. In this indication, midazolam should be administered intravenously or intramuscularly (deeply into a large muscle) 20–60 minutes before induction of anesthesia, with rectal administration being the preferred route in children (see below). After premedication, strict and continuous monitoring of the patient is mandatory, as sensitivity to the drug varies individually and symptoms of overdose may occur.

Adults
The recommended dose for preoperative sedation and anterograde amnesia in adult patients of ASA risk groups I and II under 60 years of age is 1–2 mg intravenously (which may be repeated if necessary) or 0.07–0.10 mg/kg body weight intramuscularly. In patients over 60 years of age, debilitated or chronically ill patients, the dose should be reduced and individually adjusted. The recommended initial intravenous dose is 0.5 mg, which may be slowly increased if necessary. For intramuscular administration, a dose of 0.025–0.050 mg/kg body weight is recommended. When opioids are administered concomitantly, the dose of midazolam should be reduced. The usual dose used is 2–3 mg.

Children and Adolescents
Newborns and infants under 6 months of age:
The use of midazolam is not recommended in children under 6 months of age due to limited available data.

Children over 6 months of age
Rectal administration: the total dose, usually in the range of 0.3–0.5 mg/kg body weight, should be administered 15–30 minutes before induction of anesthesia. Rectal administration of the solution from an ampoule should be performed using a plastic applicator attached to the end of a syringe. If the volume of solution to be administered is too small, it may be diluted with water to a total volume of 10 ml.
Intramuscular administration: due to the pain associated with intramuscular injection, this route should be used only in exceptional cases. The rectal route is preferred. However, intramuscular midazolam administered in doses of 0.08–0.20 mg/kg body weight has been shown to be effective and safe. Children aged 1–15 years require proportionally higher doses per kilogram of body weight than adults.
In children with body weight less than 15 kg, midazolam solutions with a concentration exceeding 1 mg/ml should not be used. Solutions with higher concentrations should be diluted to a concentration of 1 mg/ml.

Induction of Anesthesia
Adults
When midazolam is used for induction of anesthesia before administration of other anesthetic agents, patient response is highly variable. The dose should be gradually increased to achieve the desired effect, adjusted according to age and clinical condition. When midazolam is used before or in combination with other intravenous or inhalational agents for induction of anesthesia, the initial dose of each should be significantly reduced, even to 25% of the usual initial dose.
The desired level of anesthesia is achieved by gradual dose titration. The intravenous dose of midazolam for induction of anesthesia should be administered slowly in small increments. Doses should not be increased by more than 5 mg administered over 20–30 seconds, with a 2-minute interval between doses.

• In adults under 60 years of age who have received premedication, an intravenous dose of 0.15–0.20 mg/kg body weight is usually sufficient.
• In adults under 60 years of age who have not received premedication, a higher dose (0.30–0.35 mg/kg body weight intravenously) may be required. If necessary, additional doses increased by approximately 25% of the initial dose given to the patient may be administered to complete induction. Induction may also be completed using inhalational anesthetics. In resistant cases, a total dose up to 0.6 mg/kg body weight may be used, but such high doses may prolong emergence from anesthesia.
• In adults over 60 years of age who have received premedication, and in debilitated or chronically ill patients, the dose should be significantly reduced, e.g., to a range of 0.05–0.15 mg/kg body weight administered intravenously over 20–30 seconds, with a 2-minute wait for effect.
• In adults over 60 years of age who have not received premedication, a higher dose of midazolam is usually required to induce anesthesia. An initial dose of 0.15–0.30 mg/kg body weight is recommended. Severely ill or debilitated patients who have not received premedication usually require smaller doses of midazolam to achieve induction. An initial dose of 0.15–0.25 mg/kg body weight is usually sufficient.

Component with Sedative Effect in Combined Anesthesia
Adults
Midazolam may be used as a sedative component in combined anesthesia, either as intermittent small intravenous doses (in the range of 0.03–0.10 mg/kg body weight) or as a continuous intravenous infusion (in the range of 0.03–0.10 mg/kg body weight/h), usually in combination with analgesics. The dose and intervals between doses depend on the individual patient's response.
In adults over 60 years of age and in debilitated or chronically ill patients, lower maintenance doses will be required.

Sedation in the Intensive Care Unit (ICU)
The desired level of sedation is achieved by gradually increasing the dose of midazolam, followed by continuous infusion or repeated boluses—depending on clinical needs, patient status, age, and concomitant medications.

Adults
Intravenous loading dose: 0.03–0.30 mg/kg body weight, administered slowly in divided doses. Each divided dose in the range of 1.0–2.5 mg should be administered over 20–30 seconds, with a 2-minute interval before the next dose. In patients with hypovolemia, vasoconstriction, or hypothermia, the loading dose should be reduced or omitted. When midazolam is administered in combination with potent analgesics, the analgesics should be given first, so that the sedative effect of midazolam can be safely titrated against the potential sedative effect of the analgesics.
Intravenous maintenance dose: doses may range from 0.03–0.20 mg/kg body weight/h. The maintenance dose should be reduced in patients with hypovolemia, vasoconstriction, or hypothermia. The level of sedation should be regularly monitored. With prolonged sedation, tolerance may develop, requiring dose escalation.

Newborns and Infants under 6 Months of Age
Midazolam should be administered as a continuous intravenous infusion, starting at a dose of 0.03 mg/kg body weight/h (0.5 micrograms/kg body weight/min) in newborns born before 32 weeks of gestation, or at a dose of 0.06 mg/kg body weight/h (1 microgram/kg body weight/min) in newborns born after 32 weeks of gestation and infants under 6 months of age.
In newborns and infants under 6 months of age, intravenous loading doses are not recommended. Instead, the infusion may be run at a higher rate during the first few hours to achieve therapeutic plasma concentrations. The infusion rate should be carefully and frequently evaluated, especially after the first 24 hours, to administer the lowest effective dose and reduce the risk of drug accumulation.
Careful monitoring of respiratory rate and hemoglobin oxygen saturation is mandatory.

Children over 6 Months of Age
In intubated and mechanically ventilated pediatric patients, to achieve the desired clinical effect, an intravenous loading dose of 0.05–0.20 mg/kg body weight should be administered slowly over at least 2–3 minutes. Midazolam should not be administered as a rapid intravenous injection. After administration of the loading dose, a continuous intravenous infusion should be started at a rate of 0.06–0.12 mg/kg body weight/h (1–2 micrograms/kg body weight/min). If necessary, the infusion rate may be increased or decreased (usually by 25% of the initial or subsequent rate), or additional intravenous doses of midazolam may be administered to increase or maintain the desired effect.
When initiating midazolam infusion in hemodynamically unstable patients, the usual loading dose may be gradually increased in small increments, and the patient should be monitored for signs of hemodynamic instability, such as hypotension. These patients are also susceptible to midazolam-induced respiratory depression and require careful monitoring of respiratory rate and hemoglobin oxygen saturation.
In preterm infants, term newborns, and children with body weight below 15 kg, midazolam solutions with a concentration exceeding 1 mg/ml should not be used. Solutions with higher concentrations should be diluted to a concentration of 1 mg/ml.

Patients with Renal Impairment
In patients with renal impairment (creatinine clearance <10 ml/min), the pharmacokinetics of free midazolam after single intravenous administration are similar to those in healthy volunteers. However, during prolonged intravenous infusion in ICU patients, the mean duration of sedative effect was significantly longer in patients with renal impairment, likely due to accumulation of α-hydroxymidazolam glucuronide.
There are no specific data on patients with severe renal impairment (creatinine clearance <30 ml/min) receiving midazolam for induction of anesthesia.

Patients with Hepatic Impairment
Hepatic impairment reduces the clearance of intravenously administered midazolam, prolonging the elimination half-life. This may result in enhanced and prolonged clinical effects of the medicinal product. The required dose of midazolam may be reduced, with appropriate monitoring of vital signs.

Elderly Patients, Children, and Adolescents
See table above.

Special Warnings and Precautions for Use
Midazolam should be administered only by experienced physicians in a fully equipped facility with monitoring and life support equipment for respiratory and circulatory systems, and by personnel adequately trained in recognizing and managing expected adverse reactions, including cardiopulmonary resuscitation.
Severe adverse reactions affecting the cardiovascular and respiratory systems have been reported. These include respiratory depression, apnea, respiratory arrest, and (or) cardiac arrest. The risk of such life-threatening events is higher with too rapid injection or administration of excessive doses.
Particular caution is required when using mild sedation in patients with impaired respiratory function.
Infants under 6 months of age are particularly susceptible to airway obstruction and hypoventilation; therefore, it is essential to increase the dose in small increments to achieve the appropriate clinical effect and to carefully monitor respiratory rate and hemoglobin oxygen saturation.
After administration of midazolam for premedication, appropriate monitoring of the patient is mandatory, as sensitivity to the drug varies individually and symptoms of overdose may occur.
Particular caution is required when administering midazolam to high-risk patients, including:

• adults over 60 years of age,
• chronically ill or debilitated patients, e.g., those with chronic respiratory insufficiency, chronic renal failure, hepatic impairment, or cardiac dysfunction,
• children and adolescents, especially hemodynamically unstable patients.

Patients in these high-risk groups require lower doses (see above) and should be continuously monitored for early signs of vital function impairment.
As with all substances that may cause central nervous system (CNS) depression and (or) skeletal muscle relaxation, particular caution should be exercised when administering midazolam to patients with myasthenia gravis.

Tolerance
Reduced efficacy of midazolam has been reported when used in prolonged sedation in intensive care units (ICU).

Dependence
It should be remembered that physical dependence may develop in patients receiving midazolam for prolonged sedation in the ICU. The risk of dependence increases with dose and duration of treatment and is also higher in patients with a history of alcohol and (or) drug abuse.

Withdrawal Symptoms
Prolonged use of midazolam in ICU patients may lead to physical dependence. Therefore, abrupt discontinuation of the drug may cause withdrawal symptoms. These may include headache, muscle pain, anxiety, tension, psychomotor agitation, disorientation, irritability, insomnia with dream recall, mood changes, hallucinations, and seizures. Because the risk of withdrawal symptoms is higher with abrupt discontinuation, gradual dose reduction is recommended.

Amnesia
Midazolam causes anterograde amnesia (an effect often highly desirable before or during surgical and diagnostic procedures), the duration of which is proportional to the dose administered. Prolonged amnesia may be problematic in outpatients scheduled for discharge immediately after the procedure. After parenteral administration of midazolam, the patient may leave the hospital or outpatient facility only in the company of a caregiver.

Paradoxical Reactions
Paradoxical reactions after midazolam administration have been reported, including psychomotor agitation, involuntary movements (including tonic-clonic seizures and muscle twitching), hyperactivity, hostility, rage attacks, aggression, episodic excitement, and violent acts. These reactions may occur after high doses and (or) rapid injection. The highest frequency of such reactions has been observed in children and elderly patients.

Reduced Elimination of Midazolam
The elimination of midazolam may be reduced by substances that inhibit or induce CYP3A4; therefore, appropriate dose adjustments of midazolam may be necessary.
Elimination of midazolam may also be delayed in patients with hepatic impairment, low cardiac output, and in newborns.

Preterm Infants and Newborns
Due to the increased risk of apnea, particular caution is advised during sedation of non-intubated preterm infants and prematurely born newborns who no longer show signs of prematurity. Careful monitoring of respiratory rate and hemoglobin oxygen saturation is mandatory.
Rapid injection of the drug should be avoided in newborns.
Newborns have reduced and (or) immature organ function and are susceptible to excessive and (or) prolonged effects of midazolam.
Cardiovascular adverse reactions have been observed in hemodynamically unstable pediatric patients; therefore, rapid intravenous administration should be avoided in this patient group.

Infants under 6 months of age
In this patient population, midazolam may be used for sedation only under ICU conditions. Infants under 6 months of age are particularly susceptible to airway obstruction and hypoventilation; therefore, it is essential to increase the dose in small increments to achieve the appropriate clinical effect and to carefully monitor respiratory rate and hemoglobin oxygen saturation (see section above titled "Preterm Infants and Newborns").

Concomitant Use of Alcohol/CNS-Depressant Substances
Concomitant use of midazolam with alcohol and (or) CNS-depressant substances should be avoided, as they may potentiate the clinical effects of midazolam, including enhanced sedation or clinically significant respiratory depression.

History of Alcohol or Drug Abuse
In patients with a history of alcohol or drug abuse, the use of midazolam and other benzodiazepines should be avoided.

Discharge Criteria
After receiving midazolam, a patient may leave the hospital or outpatient facility only upon decision by the attending physician and only in the company of a caregiver. It is recommended that another person accompany the patient after discharge.