Talentum

Package leaflet: Information for the user

TALENTUM 5 mg/1 ml solution for injection, 15 mg/3 ml solution for injection

Midazolam
Generic medicine
Read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or nurse.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor or nurse. See section 4.

Contents of this leaflet:

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

1. What TALENTUM is and what it is used for

This medicinal product contains the active substance midazolam, which belongs to a group of medicines called benzodiazepines.
TALENTUM acts quickly, causing drowsiness or sleep. It also calms you and relaxes your muscles.
TALENTUM is indicated in adults:

• as a general anaesthetic to induce drowsiness or maintain sleep (anaesthesia induction, as a sedative component in combined anaesthesia).

TALENTUM is indicated in adults and children to induce sleep (short-acting hypnotic effect) in the following cases:

• if they are in intensive care. This is called "sedation",
• before and during medical examinations or procedures to achieve a deep calming effect on the body, with or without anaesthesia (conscious sedation);
• before administration of an anaesthetic (premedication prior to anaesthesia induction).

2. What you need to know before using TALENTUM

Do not be given TALENTUM if:

• you are allergic (hypersensitive) to midazolam, to other benzodiazepines, or to any of the other ingredients of this medicine (listed in section 6);
• you have severe breathing problems (severe respiratory insufficiency or acute respiratory depression) and need to receive Talentum for "conscious sedation". TALENTUM must not be administered to you if either of the above conditions applies to you. If you are unsure, speak with your doctor or nurse before receiving this medicine.

Warnings and precautions
Talk to your doctor or nurse before being given TALENTUM.
This medicine will only be administered by medical personnel and in a specialized facility to monitor your health status (respiratory and cardiovascular function) and to allow intervention in case of emergencies.
TALENTUM will be administered to you with great caution if:

• you are over 60 years old;
• you have breathing problems (chronic respiratory insufficiency), kidney problems (chronic renal insufficiency), liver problems (impaired liver function), or heart problems (reduced cardiac function);
• you currently abuse or have previously abused alcohol, drugs, or medicines;
• you suffer from myasthenia gravis, a disease causing muscle weakness and fatigue;
• you suffer from sleep apnea. If any of the above conditions apply to you (or you are unsure), speak with your doctor or nurse before being given Talentum.

If this medicine is about to be given to your child:

• Talk to the doctor or nurse if any of the above conditions apply to your child.
• In particular, inform the doctor or nurse if your child has heart or breathing problems.

TALENTUM must not be administered together with substances acting on the central nervous system, as this may cause excessive drowsiness and breathing problems (see section “TALENTUM with alcohol”).
This medicine may cause you:

• Tolerance: i.e., reduced effectiveness after prolonged use of the medicine.
• Dependence: i.e., the need to continue taking the medicine. The risk increases with dose and duration of treatment. The risk is higher if you have previously abused drugs or alcohol. In some cases, an excessive need to take the medicine (abuse) may occur.
• Withdrawal symptoms: abruptly stopping treatment may cause symptoms such as headache, diarrhoea, muscle pain, anxiety, restlessness, confusion, irritability, difficulty sleeping (insomnia), mood changes, hallucinations, and involuntary movements (seizures). Therefore, it is advisable that your dose be gradually reduced.
• Memory loss (anterograde amnesia), the duration of which increases with dose.
• Paradoxical reactions such as restlessness, agitation, irritability, involuntary movements (tonic/clonic seizures and muscle tremors), and inappropriate behavior (hyperactivity, hostility, delirium, rage, aggression, anxiety, nightmares, hallucinations, psychosis, paroxysmal excitement, and aggression). These reactions may occur with high doses and/or when the injection is administered rapidly. These reactions are more likely if you are elderly or if the patient is a child. After receiving TALENTUM, you will be discharged from hospital or outpatient care only upon the doctor's instruction and only if someone is present to accompany you.

Premature infants and newborns
TALENTUM must be administered with extreme caution in premature infants (premature and ex-premature infants not undergoing intubation), as it may cause breathing problems (apnea).
In newborns (under 6 months of age), TALENTUM must be administered only in intensive care units, with extreme caution, and rapid injection must be avoided. Rapid intravenous injection may cause circulatory problems in newborns with heart or circulation issues. The doctor must monitor the infant's condition (respiratory rate and oxygen saturation) during treatment.

Other medicines and TALENTUM
Inform your doctor or nurse if you are taking, have recently taken, or might take any other medicine.
In particular, inform your doctor if you are taking any of the following medicines:

• Antifungals, medicines used to treat fungal infections (such as ketoconazole, voriconazole, fluconazole, itraconazole, posaconazole);
• Antibiotics, medicines used to treat bacterial infections (such as erythromycin, clarithromycin, telithromycin, roxithromycin, or rifampicin);
• HIV protease inhibitors, medicines used to treat AIDS (such as lopinavir, ritonavir, and saquinavir);
• Hepatitis C virus protease inhibitors (such as boceprevir and telaprevir);
• Diltiazem and verapamil and antihypertensives (central-acting) used for high blood pressure;
• Atorvastatin, used for high cholesterol;
• Aprepitant, used to prevent vomiting;
• Nefazodone, used for depression;
• Carbamazepine and phenytoin, medicines used for epileptic seizures;
• Opioids, used for pain or cough;
• Other benzodiazepines;
• Barbiturates, sedative medicines;
• Anaesthetics such as propofol, ketamine, etomidate;
• Sedative antidepressants, medicines used as sedatives and for conditions such as depression;
• H1 antihistamines (non-recent), medicines used for allergies;
• St. John’s wort (hypericum), used for depression;
• Medicines that interfere with the metabolism and elimination of midazolam. Concomitant use of Talentum and opioids (strong analgesics, medicines for addiction treatment, and some cough 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. However, if your doctor prescribes Talentum together with opioids, the dose and duration of concomitant treatment must be limited by the doctor. Inform your doctor about all opioid medicines you are taking and carefully follow the doctor's dose recommendations. It may be helpful to inform friends or family members to watch for the signs and symptoms listed above. Contact your doctor if you experience any of these symptoms.

TALENTUM with alcohol
Do not drink alcohol after receiving TALENTUM, as it may cause excessive drowsiness and breathing problems (respiratory depression).

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor or nurse before this medicine is administered to you.
Pregnancy
Avoid taking this medicine during pregnancy, as it may cause serious harm to both you and the newborn.
Breastfeeding
Stop breastfeeding for 24 hours after taking the medicine, as TALENTUM may pass into breast milk.

Driving and using machines
This medicine may cause sedation, impair memory, and reduce concentration. After receiving TALENTUM, avoid driving and operating tools or machinery until your doctor tells you it is safe to do so. It is also advisable to have someone accompany you home after discharge.

TALENTUM contains sodium
TALENTUM contains less than 1 mmol (23 mg) of sodium per vial, i.e., essentially “sodium-free”.

3. How to use TALENTUM

This medicine will be administered to you by specialized healthcare personnel, in a setting equipped to monitor you and treat any adverse effects. This could be a hospital, clinic, or outpatient facility. Specifically, your breathing, heart, and circulation will be monitored. If you have any doubts, consult your doctor or nurse.

The use of Talentum is not recommended in neonates and children under 6 months of age. However, if the doctor considers it necessary, it may be administered to a neonate or child under 6 months of age in intensive care.

This medicine will be administered to you in one of the following ways:

• by slow injection into a vein (intravenous injection)
• through an intravenous infusion into one of your veins (intravenous infusion)
• by injection into a muscle (intramuscular injection)
• by rectal administration

The dose of Talentum varies from patient to patient. Your doctor will decide how much to administer based on your age, body weight, and general health condition. It also depends on the reason for which you require the medicine, your response to treatment, and whether you are receiving other medicines at the same time.

After treatment, you must be accompanied home by an adult who can monitor you. This is because Talentum may cause drowsiness or impair your memory. It may also affect your concentration and coordination.

If Talentum is administered to you over a prolonged period, such as in intensive care, your body may begin to adapt to the medicine. This means it could become less effective.

If you use more TALENTUM than you should

This medicine will be administered by specialized personnel, so it is unlikely that you will receive an excessive dose.

However, following an overdose of this medicine, drowsiness, loss of coordination (ataxia), difficulty speaking (dysarthria), and involuntary eye movements (nystagmus) may occur. Other symptoms may include absence of reflexes (areflexia), breathing difficulties (apnea), low blood pressure (hypotension), heart problems (cardiocirculatory depression), and, in rare cases, coma.

If you think you have been given too much of this medicine, contact your doctor or nurse immediately.

If you have any doubts about using this medicine, consult your doctor or nurse.

Long-term treatment with Talentum for sedation in intensive care

If Talentum has been administered to you over a long period, the following may occur:

• The medicine may gradually become less effective.
• You may develop dependence on the medicine and experience withdrawal symptoms when you stop taking it (see section ‘Stopping Talentum’ below).

Stopping Talentum

If Talentum has been administered to you over a prolonged period, such as in intensive care, you may experience withdrawal symptoms when you stop taking it. These include:

• Mood changes
• Seizures
• Headache
• Muscle pain
• Sleep disturbances (insomnia)
• Intense feelings of worry (anxiety), tension, fatigue, confusion, or irritability
• Seeing and possibly hearing things that are not actually present (hallucinations)

Your doctor will gradually reduce your dose. This will help prevent or reduce withdrawal symptoms.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
Stop taking Talentum and contact a doctor immediately if you notice any of the following side effects.
They may be life-threatening and may require urgent medical treatment:

• Allergic reactions, even severe (skin reactions, reactions affecting the heart and blood circulation, bronchospasm, anaphylactic shock), swelling of the face, larynx, tongue (angioedema), or other parts of the body, or pale skin, weak and rapid pulse, or feeling faint. You may also experience chest pain, which could be a sign of a potentially serious allergic reaction called Kounis syndrome. Heart attack (cardiac arrest). Signs may include chest pain.
• Breathing problems, which have sometimes led to respiratory arrest.
• Muscle spasm around the airways, causing suffocation. Potentially fatal side effects are more likely to occur in adults over 60 years of age and in people who already have respiratory or cardiac problems. These side effects are also more likely if the medicine is injected too quickly or at a high dose.

Other possible side effects:
The following side effects have been reported (frequency not known, as it cannot be estimated from the available data).

• Mental disorders: confusion, disorientation, emotional and mood disturbances, hallucinations, inappropriate behaviour (agitation, hostility, anger outbursts, aggression, excitement)* Physical dependence (i.e. the need to continue taking the medicine) and withdrawal syndrome, abuse
• Nervous system disorders: drowsiness and sedation (prolonged and postoperative), reduced alertness, lethargy, headache, dizziness, difficulty in muscle coordination (ataxia), memory loss (anterograde amnesia) which may persist even after stopping treatment and in isolated cases may last for prolonged periods, involuntary movements (including tonic/clonic movements and muscle tremors)*, hyperactivity*, seizures due to withdrawal syndrome
• Cardiac disorders: serious events have occurred, such as heart attacks (cardiac arrest), decreased heart rate (bradycardia).
• Vascular disorders: reduction in blood pressure (hypotension), vasodilation, blood circulation problems (thrombophlebitis, thrombosis)
• Respiratory disorders: serious events have occurred, such as respiratory complications, which have sometimes led to respiratory arrest, apnoea, shortness of breath (dyspnoea), sudden blockage of the airways (laryngospasm), hiccups.
• Potentially fatal incidents are more likely to occur in adults over 60 years of age and in people who have already experienced breathing difficulties or heart problems, especially when the medicine is injected too rapidly or at a high dosage (see section 2, paragraph “TALENTUM will be administered with great caution if”).
• Gastrointestinal disorders: nausea, vomiting, constipation, dry mouth.
• Skin disorders: skin irritation (skin rash, urticaria, pruritus).
• General disorders and administration site conditions: fatigue, redness (erythema), pain at the injection site (erythema)
• Injury, poisoning and procedural complications: falls and fractures, particularly in elderly subjects and in people taking substances such as alcohol that have sedative effects.
• Social circumstances: aggression*
• *These reactions have been reported mainly in children and the elderly (see section 2, Warnings and precautions).
• Dependence: the use of midazolam – even at therapeutic doses – may lead to the development of physical dependence. After prolonged intravenous administration, discontinuation of the product, especially if abrupt, may be accompanied by withdrawal symptoms including seizures (see section 2). Cases of abuse have been reported.

Additional side effects in premature infants and newborns
Frequency not known (frequency cannot be estimated from the available data)

• Involuntary muscle contractions (seizures).

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse . By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store TALENTUM

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after the term "EXPIRY". The expiry date refers to the last day of that month. Do not use this medicine if you notice any visible signs of deterioration.
Keep the vial in the outer packaging to protect the medicine from light.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What TALENTUM 5 mg/1 ml injectable solution contains

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

What TALENTUM 15 mg/3 ml injectable solution contains

• The active substance is midazolam (as midazolam hydrochloride). Each 3 ml vial of solution contains 15 mg of midazolam.
• The other components are: sodium chloride, diluted hydrochloric acid, water for injections.

Description of the appearance of TALENTUM and contents of the pack
TALENTUM 5 mg/1 ml injectable solution is available in:

• pack of 1 glass vial of 1 ml;
• pack of 5 glass vials of 1 ml;
• pack of 10 glass vials of 1 ml.

TALENTUM 15 mg/3 ml injectable solution is available in:

• pack of 1 glass vial of 3 ml;
• pack of 5 glass vials of 3 ml;
• pack of 10 glass vials of 3 ml.

Marketing Authorization Holder and Manufacturer
FISIOPHARMA S.r.l. – NUCLEO INDUSTRIALE 84020 PALOMONTE (SA) - Italy

The following information is intended for healthcare professionals only

CLINICAL INFORMATION
Instructions for use
Compatibility with infusion solutions: midazolam solution can be diluted with 0.9% sodium chloride, 5% and 10% glucose, 5% fructose, Ringer's solution in a mixture of 15 mg midazolam per 100–1000 mL of infusion solution.
Dosage and method of administration
Midazolam is a potent sedative agent requiring dose adjustment and slow administration. Dose titration is strongly recommended to safely achieve the desired level of sedation according to clinical need, physical condition, age, and concomitant medication.
In adults over 60 years of age, debilitated patients, patients with chronic illness, and pediatric patients, the dose should be determined cautiously, and individual risk factors for each patient should be considered.
Standard dosages are reported in the table below.
Further information is provided after the table.

DOSING FOR CONSCIOUS SEDATION
In conscious sedation, midazolam is administered intravenously before a diagnostic or surgical procedure. The dose must be individualized with dose titration and should not be administered as a rapid injection or single bolus. The onset of sedation may vary individually depending on the patient's physical condition and specific dosing circumstances (e.g., rate of administration, total dose amount). If necessary, additional doses may be administered according to individual needs. Sedation begins approximately 2 minutes after injection. The maximum effect is achieved about 5–10 minutes later.

Adults
Midazolam should be administered slowly by intravenous route at a rate of approximately 1 mg every 30 seconds.
In adults under 60 years of age, the initial dose is about 2–2.5 mg given 5–10 minutes before the start of the procedure. Additional doses of 1 mg may be administered if needed. The average total dose ranges between 3.5 and 7.5 mg. Generally, a total dose exceeding 5 mg is not required. In adults over 60 years of age, debilitated patients, or those with chronic diseases, the initial dose should be reduced to 0.5–1 mg, administered 5–10 minutes before the start of the procedure. Subsequent doses of 0.5–1 mg may be given as needed. In these patients, the peak effect may be reached more slowly; therefore, additional midazolam should be administered very slowly and cautiously. Generally, a total dose exceeding 3.5 mg is not required.

Children
Intravenous administration: midazolam dosing should be slowly titrated to achieve the desired clinical effect. The initial dose should be administered over 2–3 minutes. Wait 2–5 minutes to fully assess the sedative effect before starting the procedure or repeating the dose. If further sedation is required, continue dose titration with small increments until the appropriate level of sedation is achieved.
Children under 5 years of age may require substantially higher doses (mg/kg) compared to older children and adolescents.

• Pediatric patients under 6 months of age: pediatric patients under 6 months are particularly susceptible to airway obstruction and hypoventilation. Therefore, use in conscious sedation should be avoided in children under 6 months of age.
• Pediatric patients from 6 months to 5 years of age: the initial dose is 0.05–0.1 mg/kg. A total dose up to 0.6 mg/kg may be necessary to achieve the desired effect, but the total dose must not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with higher doses.
• Pediatric patients from 6 to 12 years of age: the initial dose is 0.025–0.05 mg/kg. A total dose up to 0.4 mg/kg may be required, up to a maximum of 10 mg. Prolonged sedation and risk of hypoventilation may be associated with higher doses.
• Pediatric patients from 12 to 16 years of age: adult dosing should be applied.

Rectal administration: the total dose of midazolam generally ranges from 0.3 to 0.5 mg/kg. Rectal administration of the vial solution is performed using a plastic applicator attached to the end of the syringe. If the volume to be administered is too small, water may be added to achieve a total volume of 10 ml. The total dose should be administered only once, and repeated rectal administration should be avoided.
Rectal administration in children under 6 months of age should be avoided due to limited available data in this population.
Intramuscular administration: the dose used ranges between 0.05 and 0.15 mg/kg. A total dose exceeding 10 mg is generally not necessary. This route of administration should only be used in exceptional cases. Rectal administration is preferred, as intramuscular injection is painful.
In children weighing less than 15 kg, midazolam solutions with concentrations greater than 1 mg/ml should be avoided. Higher concentrations must be diluted to 1 mg/ml.

DOSING FOR ANESTHESIA
PREMEDICATION
Premedication with midazolam administered shortly before surgery produces sedation (drowsiness or sleepiness and reduced anxiety) and preoperative memory reduction. Midazolam may also be administered in combination with anticholinergics.
For this indication, midazolam should be administered intravenously or intramuscularly into deep muscle mass 20 to 60 minutes before anesthesia induction, or preferably rectally in children (see above). Careful and continuous monitoring of patients after premedication is mandatory due to individual sensitivity and the possibility of overdose symptoms.

Adults
For preoperative sedation and reduction of preoperative memory, the recommended dose for ASA Physical Status I and II adults under 60 years of age is 1–2 mg intravenously, repeated as needed, or 0.07–0.1 mg/kg administered intramuscularly. The dose should be reduced and individualized when midazolam is administered to adults over 60 years of age, debilitated patients, or those with chronic diseases. The recommended initial intravenous dose is 0.5 mg, slowly increased as needed. The recommended intramuscular dose ranges from 0.025 to 0.05 mg/kg. When administered concomitantly with narcotics, the midazolam dose should be reduced. The usual dose is 2–3 mg.

Children
Neonates and children up to 6 months of age
Use in children under 6 months of age should be avoided due to limited available data in this population.
Children over 6 months of age
Rectal administration: the total midazolam dose, generally between 0.3 and 0.5 mg/kg, should be administered 15–30 minutes before anesthesia induction. Rectal administration of the vial solution is performed using a plastic applicator attached to the end of the syringe. If the volume to be administered is too small, water may be added to achieve a total volume of 10 ml.
Intramuscular administration: since intramuscular injection is painful, this route should be used only in exceptional cases. The rectal route is preferred. However, a dosage between 0.08 and 0.2 mg/kg of midazolam administered intramuscularly has proven effective and safe. Children aged 1 to 15 years require proportionally higher doses relative to body weight compared to adults.
In children weighing less than 15 kg, midazolam solutions with concentrations greater than 1 mg/ml should be avoided. Higher concentrations must be diluted to 1 mg/ml.

INDUCTION
Adults
When midazolam is used for anesthesia induction before administration of other anesthetic agents, individual response is variable. The dose should be adjusted to achieve the desired effect, taking into account the patient's age and clinical status. When midazolam is administered for anesthesia induction before or in combination with other intravenous or inhaled drugs, the initial dose of each drug must be significantly reduced, sometimes to 25% of the usual initial dose of each individual agent. The desired level of anesthesia is achieved through incremental titration. The intravenous dose of midazolam for anesthesia induction must be increased slowly. Each increment of no more than 5 mg should be injected over 20–30 seconds, with an interval of at least 2 minutes between successive increments.

• In premedicated adults under 60 years of age, an intravenous dose of 0.15–0.2 mg/kg is generally sufficient. In unpremedicated adults under 60 years of age, the dose may be higher (0.3–0.35 mg/kg i.v.). If complete induction is required, doses may be increased by approximately 25% above the patient's initial dose. Alternatively, induction may be completed with inhaled anesthetics. In resistant cases, a total dose up to 0.6 mg/kg may be administered for induction, but such high doses may prolong recovery time.
• In premedicated adults over 60 years of age, debilitated patients, or chronically ill patients, the dose must be significantly reduced, e.g., 0.05–0.15 mg/kg administered intravenously over 20–30 seconds, waiting 2 minutes for the effect to manifest. In unpremedicated adults over 60 years of age, higher midazolam doses are generally required for induction; an initial dose of 0.15–0.3 mg/kg is recommended. Unpremedicated patients with severe systemic disease or other debilitating conditions require a lower induction dose of midazolam. An initial dose of 0.15–0.25 mg/kg is generally sufficient.

SEDATIVE COMPONENT IN COMBINED ANESTHESIA
Adults
Midazolam may be administered as a sedative component in combined anesthesia either as small intermittent intravenous doses (0.03–0.1 mg/kg) or by continuous intravenous infusion of midazolam (0.03–0.1 mg/kg/h), typically in combination with analgesics. The dose and intervals between doses vary according to the individual patient's response.
Lower maintenance doses are required in adults over 60 years of age, debilitated patients, or chronically ill patients.

SEDATION IN INTENSIVE CARE
The desired level of sedation is achieved through stepwise titration of midazolam, followed by continuous infusion or intermittent boluses, depending on clinical requirements, physical status, age, and concomitant medication (see section “Interactions”).
Adults
Loading intravenous dose: 0.03–0.3 mg/kg should be slowly increased. Each increment of 1–2.5 mg should be injected over 20–30 seconds, with an interval of at least 2 minutes between successive increments. In hypovolemic, vasoconstricted, or hypothermic patients, the loading dose should be reduced or avoided.
When midazolam is administered with strong analgesics, the analgesics should be given first so that the sedative effect of midazolam can be safely titrated based on the maximum sedation produced by the analgesic.
Maintenance intravenous dose: dosing may range from 0.03 to 0.02 mg/kg/h. In hypovolemic, vasoconstricted, or hypothermic patients, the maintenance dose should be reduced. The level of sedation must be regularly monitored. With prolonged sedation, tolerance may develop. In such cases, the dose may be increased.
Children over 6 months of age
In intubated and ventilated pediatric patients, a loading dose of 0.05–0.2 mg/kg administered intravenously should be given slowly over at least 2–3 minutes to achieve the desired clinical effect. Midazolam must not be administered rapidly intravenously. The loading dose is followed by a continuous intravenous infusion of 0.06–0.12 mg/kg/h (1–2 µg/kg/min). The infusion rate may be increased or decreased (typically by 25% of the initial or subsequent rates) as needed, or supplemental intravenous doses of midazolam may be administered to increase or maintain the desired effect.
When initiating midazolam infusion in hemodynamically compromised patients, the usual loading dose should be titrated with small increments, and the patient should be monitored for hemodynamic instability, e.g., hypotension. These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.
Neonates and children up to 6 months of age
Midazolam should be administered as a continuous intravenous infusion starting at 0.03 mg/kg/h (0.5 micrograms/kg/min) in neonates with a gestational age ≤32 weeks, or 0.06 mg/kg/h (1 microgram/kg/min) in neonates with a gestational age >32 weeks and in children up to 6 months.
Loading intravenous doses should be avoided in premature infants, neonates, and children up to 6 months of age. Instead, a faster infusion may be used during the first hours to achieve therapeutic plasma levels. The infusion rate must be carefully and frequently adjusted, especially after the first 24 hours, to deliver the lowest effective dose possible and reduce the risk of potential drug accumulation.
Careful monitoring of respiratory rate and oxygen saturation is required.
In premature infants, neonates, and children weighing less than 15 kg, midazolam solutions with concentrations exceeding 1 mg/ml should be avoided. Higher concentrations must be diluted to 1 mg/ml.

Use in specific patient populations
Renal impairment
In patients with severe renal impairment, midazolam may cause more pronounced and prolonged sedation, sometimes with clinically relevant respiratory and cardiovascular depression. Therefore, midazolam should be administered cautiously in this patient population, with dose titration to achieve the desired effect.
Hepatic impairment
Hepatic impairment reduces the clearance of intravenously administered midazolam, resulting in a prolonged terminal half-life. Consequently, clinical effects may be more pronounced and prolonged. The required dose of midazolam may be lower, and appropriate monitoring of vital signs should be established (see section 4.4).
Pediatric population
See above and “premature infants and neonates.”

Overdose
Symptoms
Like other benzodiazepines, midazolam frequently causes drowsiness, ataxia, dysarthria, and nystagmus. Midazolam overdose is rarely potentially fatal when taken alone, but may lead to areflexia, apnea, hypotension, cardiorespiratory depression, and in rare cases, coma. Coma, if it occurs, usually lasts a few hours but may be prolonged and cyclic, particularly in elderly patients. Respiratory depressant effects of benzodiazepines are more severe in patients with respiratory diseases.
Benzodiazepines enhance the effects of other agents that depress the central nervous system, including alcohol.

Treatment
Monitor the patient's vital signs and institute supportive measures according to the patient's clinical condition. In particular, patients may require symptomatic treatment for cardiorespiratory or central nervous system effects.
If administered orally, further absorption should be prevented by an appropriate method, such as activated charcoal administered within 1–2 hours. When using activated charcoal, airway protection is mandatory in drowsy patients. Gastric lavage may be considered in cases of mixed ingestion, but it is not a routine measure.
In cases of severe CNS depression, consider using flumazenil, a benzodiazepine antagonist. Flumazenil should be administered only under strictly controlled conditions. The drug has a short half-life (approximately one hour), so patients who have received flumazenil must be monitored after its effects wear off. Flumazenil must be used with extreme caution in the presence of drugs that lower the seizure threshold (e.g., tricyclic antidepressants).
For further information on the correct use of flumazenil, consult the product information leaflet of flumazenil.

Incompatibilities
Do not dilute the product with 6% macrodex in dextrose. Do not mix midazolam vials with alkaline solutions. Midazolam precipitates in the presence of sodium bicarbonate.

Special storage precautions
Store in the original packaging to protect from light.
TALENTUM vials must not be frozen, as they may break.