Active ingredients: Midazolam
Ipnovel 5 mg / 1 ml solution for injection
Ipnovel 15 mg / 3 ml solution for injection
Indications Why is Ipnovel used? What is it for?
Ipnovel contains a medicine called midazolam. This belongs to a group of medicines called 'benzodiazepines'.
Ipnovel works quickly causing you to feel drowsy or sleepy. It also makes her calm and relaxes her muscles.
Ipnovel is used in adults:
- As a general anesthetic to induce drowsiness or to maintain sleep.
Ipnovel is also used in adults and children:
- To make them calm and sleepy if they are in intensive care. This is called "sedation"
- Before and during a medical exam or procedure during which they need to stay awake. It makes them calm and sleepy. This is called "conscious sedation".
- To make them calm and sleepy before they are given an anesthetic.
Contraindications When Ipnovel should not be used
You should not be given Ipnovel se
- You are allergic (hypersensitive) to midazolam or to any of the ingredients of the product (listed in Section 6: Further information).
- He is allergic to other benzodiazepines, such as diazepam or nitrazepam.
- She has severe breathing difficulties and must take Ipnovel for "conscious sedation".
You should not be given Ipnovel if any of the above applies to you. If you are not sure, talk to your doctor or nurse before you are given this medicine.
Precautions for use What you need to know before taking Ipnovel
Take special care with Ipnovel
Tell your doctor or nurse before you are given Ipnovel if:
- He is over 60 years old.
- You have a chronic illness, for example breathing problems, kidney, liver or heart problems.
- She has a disease that makes her feel very weak, dejected and low in energy.
- You have a disease called "myasthenia gravis" which is characterized by weakness of the muscles.
- Have you ever had alcohol problems.
- Have you ever had drug problems.
If any of the above applies to you (or you are not sure), talk to your doctor or nurse before you are given Ipnovel.
If your child is about to be given this medicine:
- Talk to your doctor or nurse if any of the above applies to your baby.
- In particular, tell the doctor or nurse if your child has heart or breathing problems.
Interactions Which drugs or foods can modify the effect of Ipnovel
Taking Ipnovel with other medicines
Tell your doctor or nurse if you are taking or have recently taken any other medicines, including non-prescription and herbal medicines. This is because Ipnovel can change the way other medicines work. Other medicines can also change the way you work. which Ipnovel acts.
In particular, tell your doctor or nurse if you are taking any of the following medicines:
- Medicines for depression.
- Hypnotic medicines (to help you sleep).
- Sedatives (to calm or put you to sleep).
- Tranquilizer medicines (for anxiety or to help you sleep).
- Carbamazepine or phenytoin (these can be used for seizures or fits).
- Rifampicin (for tuberculosis).
- HIV medicines called "protease inhibitors" (such as saquinavir).
- Antibiotics called "macrolides" (such as erythromycin and clarithromycin).
- Medicines to treat fungal infections (such as ketoconazole, voriconazole, fluconazole, itraconazole, posaconazole).
- Powerful pain relievers.
- Atorvastatin (for high cholesterol).
- Anti-histamines (for allergic reactions).
- St. John's wort (a "medicinal herb for depression).
- Medicines for high blood pressure called "calcium channel blockers" (such as diltiazem).
If any of the above applies to you (or you are not sure), talk to your doctor or nurse before you are given Ipnovel.
Alcohol
Do not drink alcohol if you have been given Ipnovel. This is because it can make you very sleepy and cause breathing problems.
Warnings It is important to know that:
Pregnancy and breastfeeding
- Tell your doctor before you are given Ipnovel if you are pregnant or think you are pregnant. Your doctor will decide if this medicine is suitable for you.
- After you have been given Ipnovel, do not breastfeed for 24 hours. This is because Ipnovel can pass into her milk.
Driving and using machines
- After taking Ipnovel, do not drive or use any tools or machines until your doctor tells you that you can.
- This is because Ipnovel can make you drowsy or cloud your memory. It can also affect his concentration and coordination. This can make you unable to drive or use tools and machines.
- After the treatment, you need to be accompanied home by an adult who can check you.
Important information about some of the ingredients of Ipnovel
Ipnovel is essentially "sodium free" as it contains less than 1 mmol sodium (23 mg) per glass bottle (vial).
Dose, Method and Time of Administration How to use Ipnovel: Posology
Ipnovel will be given to you by a doctor or nurse. It will be given to you in a place where there is "equipment to monitor you and treat any side effects. This could be a hospital, clinic or doctor's office. In particular, your breathing, heart and circulation will be monitored."
The use of Ipnovel in infants and children under 6 months of age is not recommended. However, if your doctor deems it necessary, you can administer it to a newborn or infant under 6 months in intensive care.
How Ipnovel will be given to you
You will be given Ipnovel in one of the following ways:
- By slow injection into a vein (intravenous injection).
- Through a drip in one of your veins (intravenous infusion).
- By injection into the muscle (intramuscular injection).
- For rectal administration.
How much Ipnovel will be given to you
The dose of Ipnovel varies from patient to patient. Your doctor will decide how much to administer. It depends on your age, weight and general health. It also depends on why you need the medicine, how you respond to the treatment, and also whether you will be given other medicines at the same time.
After you have been given Ipnovel
After the treatment, you need to be accompanied home by an adult who can check you. This is because Ipnovel can make you drowsy or cloud your memory. It can also affect his concentration and coordination. If you are given Ipnovel for a long time, such as in intensive care, your body may start getting used to the medicine. This means it may be less effective.
Overdose What to do if you have taken too much Ipnovel
If you are given more Ipnovel than you should
The medicine will be given to you by your doctor or nurse. This means that you are unlikely to be given too much. However, if you are given too much by mistake, you may observe the following:
- Sense of sleepiness and loss of coordination and reflexes.
- Problems with speech and involuntary eye movements.
- Low blood pressure. This can make you dizzy or feel lightheaded.
- Slowed or blocked breathing or heartbeat and unconsciousness (coma).
Long-term treatment with Ipnovel for sedation in intensive care
If you have been given Ipnovel for a long time, the following could happen:
- It may begin to be less effective.
- You may become addicted to the medicine and have withdrawal symptoms when you stop taking it (see section "Stopping Ipnovel" below).
Discontinue Ipnovel
If you have been given Ipnovel for a long time, such as in intensive care, you may have withdrawal symptoms when you stop taking it. These include:
- Mood changes.
- Fits (convulsions).
- Headache.
- Muscular pain.
- Problems with sleep (insomnia).
- Strong feelings of worry (anxiety), tension, tiredness, confusion or bad temper (irritability).
- Seeing and possibly hearing things that are not really there (hallucinations).
Your doctor will gradually reduce the dosage. This will help block the withdrawal symptoms you are experiencing.
Side Effects What are the side effects of Ipnovel
Like all medicines, Ipnovel can cause side effects, although not everybody gets them. The following undesirable effects have been reported (frequency not known; cannot be estimated from the available data).
Stop taking Ipnovel and see a doctor immediately if you experience any of the following side effects. They can be life threatening and you may need urgent medical treatment:
- A severe allergic reaction (anaphylactic shock). The signs may include sudden erythema, itchy or swollen erythema (hives) and swelling of the face, lips, tongue or other parts of the body. You may also have shortness of breath, wheezing or trouble breathing.
- Heart attack (cardiac arrest). The signs may include chest pain.
- Breathing problems, sometimes resulting in stopping of breathing.
- Muscle spasm around the airways, causing choking.
Life-threatening side effects are more likely to occur in adults over 60 and in people who already have breathing or heart problems. These side effects are also more likely to occur if the medicine is injected too quickly or at a high dose.
Other possible side effects:
Nervous system and mental problems
- Attention reduction.
- Sense of confusion.
- Sense of extreme happiness or excitement (euphoria).
- Feeling tired or sleepy or being sedated for a long time.
- Seeing or possibly hearing things that are not really there (hallucinations).
- Headache
- Dizziness
- Difficulty with muscle coordination.
- Attacks (convulsions) in premature babies and infants.
- Temporary loss of memory. The duration depends on how much Ipnovel has been given to you. Occasionally this lasted for a long time.
- Sense of agitation, nervousness, anger or aggression. You may also have muscle spasms or shaking of the muscles that you cannot control (tremors). These effects are more likely to occur if you have been given a high dose of Ipnovel or if it has been given too quickly. They are also more likely to occur in children and elderly people.
Heart and circulation
- Fainting.
- Slow heartbeat.
- Redness of the face and neck (flushing).
- Low blood pressure. This can make you dizzy or feel lightheaded.
Breathing
- Hiccup.
- Shortness of breath.
Mouth, stomach and intestines
- Dry mouth.
- Constipation.
- Feeling sick (nausea) or being sick (vomiting).
Skin
- Sense of itching.
- Erythema, including swollen erythema (urticaria).
- Redness, pain, blood clots or swelling of the skin at the injection site.
General
- Allergic reactions including skin erythema and wheezing.
- Withdrawal symptoms (see above section 3 "Withdraw Ipnovel")
- Falls and fractures. The risk of fractures is increased in patients concomitantly taking other medicines known to cause drowsiness (for example, sedatives or sleeping pills), or alcohol.
Older people
- Older people who take benzodiazepines, such as Ipnovel, have a higher risk of falling and breaking their bones.
- Life-threatening side effects are also more likely to occur in adults over 60 years of age.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or nurse.
Expiry and Retention
- Your doctor or pharmacist is responsible for storing Ipnovel. They are also responsible for the proper disposal of any unused Ipnovel.
- Keep Ipnovel out of the reach and sight of children.
- Do not use Ipnovel after the expiry date which is stated on the carton. The expiry date refers to the last day of the month.
- Do not use Ipnovel if the vial or packaging is damaged.
- Keep the ampoules in the outer carton to protect the medicine from light.
Composition and pharmaceutical form
What Ipnovel contains
- The active substance is midazolam (as midazolam hydrochloride). Each ml of liquid contains 5 mg of midazolam (as midazolam hydrochloride).
- The other ingredients are sodium chloride, hydrochloric acid, sodium hydroxide and water for injections.
What Ipnovel looks like and contents of the pack
Ipnovel comes in a clear glass vial (small bottle). It is a clear, colorless liquid ("solution for injection").
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
IPNOVEL INJECTABLE SOLUTION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains 5 mg of midazolam (as midazolam hydrochloride).
One 1 ml ampoule contains 5 mg of midazolam.
One 3 ml ampoule contains 15 mg of midazolam.
This medicinal product contains less than 1 mmol (23 mg) sodium per vial, ie it is essentially "sodium-free". For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Solution for injection, infusion or rectal administration.
Clear and colorless solution.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Ipnovel is a short-acting hypno-inducing drug indicated 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
Children
• CONSCIOUS SEDATION before and during diagnostic or therapeutic procedures with or without local anesthesia;
• ANESTHESIA
• Premedication before induction of anesthesia
• SEDATION IN INTENSIVE CARE
04.2 Posology and method of administration
STANDARD DOSAGE
Midazolam is a potent sedative agent requiring dosage adjustment and slow administration. Adjustment of dosage is strongly recommended to safely achieve the desired level of sedation based on clinical need, physical status, age and concomitant drug administration. In adults over 60, debilitated or in chronic disease patients and pediatric patients, the dose should be determined with caution and the risk factors for each patient should be considered.
Standard dosages are shown in the following table.
Further information is given after the table.
CONSCIOUS SEDATION DOSAGE
In conscious sedation, midazolam is administered intravenously prior to diagnostic or surgical intervention. The dose should be individualized with a dosage adjustment and should not be given as a rapid injection or single bolus. The initiation of sedation may vary individually to depending on the physical state of the patient and the particular conditions of the dosage (e.g. rate of administration, amount of dose). If necessary, according to individual needs, additional doses may be given. Sedation begins approximately 2 minutes after injection. Maximum effect is achieved after approximately 5 to 10 minutes.
Adults
Midazolam should be administered slowly intravenously at a rate of approximately 1 mg every 30 seconds.
In adults under the age of 60 the initial dose is approximately 2-2.5 mg given 5 to 10 minutes before the start of surgery. Additional doses of 1 mg can be given as needed. The mean total dose ranged from 3.5 to 7.5 mg. A total dose greater than 5 mg is generally not required.
In adults over the age of 60, debilitated or chronically ill, the initial dose should be reduced to 0.5-1.0 mg and given 5-10 minutes before the start of the procedure. Subsequent doses of 0.5-1 mg may be given as needed. In these patients this can occur. that the maximum effect is achieved less rapidly, so the administration of further midazolam should be done very slowly and with caution. A total dose greater than 3.5 mg is generally not required.
Children
Intravenous administration: The dosage of midazolam should be slowly adjusted until the desired clinical effect is achieved. The initial dose of midazolam should be administered over 2-3 minutes. It is necessary to wait 2-5 minutes to fully assess the sedative effect before starting the procedure or repeat the dose. If further sedation is required, continue adjusting the dosage in small increments until the correct degree of sedation is achieved.
Children less than 5 years of age may require substantially higher doses (mg / kg) than other older children and adolescents.
• Pediatric patients less than 6 months of age: pediatric patients less than 6 months of age are particularly susceptible to airway obstructions and hypoventilation. For this reason, use in conscious sedation in children under the age of 5 should be avoided. at 6 months.
• Pediatric patients from 6 months to 5 years of age: the starting dose is 0.05-0.1 mg / kg. A total dose of up to 0.6 mg / kg may be required to achieve the desired effect, but the total dose should not exceed 6 mg. Prolonged sedation and risk of hypoventilation may be associated with higher doses.
• Pediatric patients 6 to 12 years of age: the starting dose is 0.025-0.05 mg / kg. A total dose of up to 0.4 mg / kg may be needed, up to a maximum of 10 mg. Prolonged sedation and risk of hypoventilation may be associated with higher doses.
• Pediatric patients 12 to 16 years of age: the adult dosage should be adopted.
Rectal administration: the total dose of midazolam generally ranges from 0.3 to 0.5 mg / kg. Rectal administration of the vial solution is carried out by means of a plastic applicator attached to the end of the syringe. If the volume to be administered is too small, water can be added up to a total volume of 10 ml. The total dose should be administered only once and repeated rectal administration avoided.
Rectal administration in infants less than 6 months of age should be avoided as data available in this population are limited.
Intramuscular administration: the dose used varies between 0.05 and 0.15 mg / kg. A total dose greater than 10 mg is generally not necessary. This route of administration should only be used in exceptional cases. Rectal administration should be preferred as i.m. it's painful.
In children weighing less than 15 kg, midazolam solutions with concentrations greater than 1 mg / ml should be avoided.Higher concentrations should be diluted to 1 mg / ml.
DOSAGE IN ANESTHESIA
PREMEDICATION
Premedication with midazolam administered shortly before surgery produces sedation (induction of somnolence or drowsiness and decreased apprehension) and preoperative memory impairment. Midazolam can also be administered in combination with anticholinergics. For this indication, midazolam should be administered intravenously. or intramuscular, in deep muscle mass, 20 to 60 minutes before induction of anesthesia, or preferably rectally in the child (see below). Careful and continuous monitoring of patients after administration of premedication is mandatory due to individual sensitivity and the possibility of overdose symptoms.
Adults
For preoperative sedation and to decrease preoperative memory, the recommended dose for adults in ASA Physical Status I and II and under the age of 60 is 1-2 mg intravenously to be 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 or in patients with chronic diseases. The recommended starting intravenous dose is 0.5 mg which is slowly increased as needed. The recommended dose ranges from 0.025 to 0.05 mg / kg administered intramuscularly. In case of concomitant administration of narcotics, the dose of midazolam should be reduced. The usual dose is 2 - 3 mg.
Pediatric patients
Babies and children up to 6 months of age:
Use in children less than 6 months of age should be avoided as limited data is available in this population.
Children over 6 months of age
Rectal administration: The total dose of midazolam, generally between 0.3 and 0.5 mg / kg, should be administered 15-30 minutes before the induction of anesthesia. Rectal administration of the vial solution is carried out by means of a plastic applicator attached to the end of the syringe. If the volume to be administered is too small, water can be added up to a total volume of 10 ml.
Intramuscular administration: As intramuscular injection is painful, this route of administration should only be used in exceptional cases. The rectal route should be preferred.
However, a dose ranging from 0.08 to 0.2 mg / kg of midazolam administered intramuscularly has proved effective and safe. In children aged 1 to 15 years proportionally higher doses are required than in adults in relation to body weight.
In children weighing less than 15 kg, midazolam solutions with concentrations greater than 1 mg / ml should be avoided. Higher concentrations should be diluted to 1 mg / ml.
INDUCTION
Adults
If midazolam is used for the induction of anesthesia prior to the administration of other anesthetic agents the individual response is variable. The dose should be adjusted in order to achieve the desired effect taking into account the patient's age and clinical status. When midazolam is administered, for the induction of anesthesia, before or in combination with other intravenous or inhaled drugs, the starting dose of each drug must be significantly reduced, sometimes up to 25% of the usual starting dose of the individual drugs. The desired level of anesthesia is achieved through successive increments. The intravenous dose of midazolam for induction of anesthesia should be slowly increased. Each increase of no more than 5 mg should be injected over 20-30 seconds with an interval of at least 2 minutes between two successive increases.
• In premedicated adults under the age of 60 an intravenous dose of 0.15 to 0.2 mg / kg is generally sufficient.
• In non-premedicated adults under the age of 60 the dose could be higher (from 0.3 - 0.35 mg / kg i.v.). If complete induction is required, dosages with approximately 25% increases from the patient's starting dose can be administered. Alternatively, induction can be supplemented with inhaled anesthetics. In resistant cases, a total dose of up to 0.6 mg / kg can be given for induction, but such high doses can prolong the recovery time.
• In premedicated adults over the age of 60, debilitated or in chronically ill patients, the dose should be significantly reduced, for example down to 0.05-0.15 mg / kg administered intravenously over 20-30 seconds, waiting 2 minutes for the effect to appear.
• In non-premedicated adults over 60 years of age Higher doses of midazolam are generally required for induction; an initial dose of 0.15 to 0.3 mg / kg is recommended. Non-premedicated patients with severe systemic disease or other debilitating conditions require a lower dose of midazolam for induction . An initial dose of 0.15 to 0.25 mg / kg is usually sufficient.
SEDATIVE COMPONENT IN COMBINED ANESTHESIA
Adults
Midazolam can be administered as a sedative component in combined anesthesia with both small intermittent intravenous doses (between 0.03 and 0.1 mg / kg) and by continuous intravenous infusion of midazolam (between 0.03 and 0.1 mg / kg). kg / h) typically in combination with analgesics The dose and the intervals between doses vary according to the individual patient reaction.
Lower maintenance doses are required in adults over 60 years of age, debilitated or in chronically ill patients.
INTENSIVE CARE SEDATION
The desired level of sedation is achieved through successive increases in the dosage of midazolam followed by continuous infusion or intermittent boluses, depending on clinical requirement, physical status, age and concomitant drug administration (see section 4.5).
Adults
Loading dose intravenous: 0.03 to 0.3 mg / kg should be increased slowly. Each increase from 1 to 2.5 mg should be injected over 20-30 seconds with an interval of at least 2 minutes between two successive increases. In hypovolaemic, vasoconstricted or hypothermic patients the loading dose should be reduced or avoided.
When midazolam is administered with major analgesics, these should be given first so that the sedative effect of midazolam is safely regulated based on the maximal sedation induced by the analgesic.
Intravenous maintenance dose: the dosage can range from 0.03 to 0.2 mg / kg / h. In hypovolaemic, vasoconstricted or hypothermic patients the maintenance dose should be reduced. The level of sedation should be checked regularly. For prolonged sedation, tolerance can develop. In this case the dose can be increased.
Babies 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 mg / kg / min) in infants less than 32 weeks of gestational age or 0.06 mg / kg / h (1 mg / kg / min) in infants of gestational age greater than 32 weeks and in infants up to 6 months.
Loading doses intravenously should be avoided in premature babies, newborns and infants up to 6 months; rather, in the first few hours, the infusion can be given more quickly to reach therapeutic plasma levels.
The infusion rate should be carefully and frequently reset, especially after the first 24 hours, to administer the lowest possible effective dose and reduce the risk of drug accumulation.
Careful control of respiratory rate and oxygen saturation is required.
Children older than 6 months
In intubated and ventilated pediatric patients, a loading dose of 0.05 to 0.2 mg / kg intravenously should be administered slowly over at least 2 - 3 minutes to establish the desired clinical effect. Midazolam should not be administered rapidly. The loading dose is followed by a continuous intravenous infusion of 0.06 to 0.12 mg / kg / h (1 to 2 mg / kg / min). The infusion rate may be increased or decreased (generally by 25% of the initial or subsequent infusion rates) as required, or supplemental intravenous doses of midazolam may be administered to increase or maintain the desired effect.
When initiating midazolam infusion in haemodynamically compromised patients, the usual loading dose should be adjusted in small increments and the patient monitored for haemodynamic instability, eg. hypotension. These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.
In premature babies, infants and children weighing less than 15 kg, midazolam solutions with concentrations above 1 mg / ml should be avoided. Higher concentrations should be diluted to 1 mg / ml.
Use in special patient populations
Altered kidney function
In patients with renal impairment (unbound midazolam pharmacokinetic creatinine clearance after single iv dose administration is similar to that reported in healthy volunteers. The mean sedative effect in the population with renal insufficiency was significantly higher, most likely due to the accumulation of α-hydroxymidazolam glucuronide.
There are no specific data in patients with severe renal insufficiency (creatinine clearance below 30 ml / min) treated with midazolam for induction of anesthesia.
Altered liver function
Impaired liver function reduces the clearance of intravenous midazolam with a consequent increase in the terminal half-life. The clinical effects may therefore be more pronounced and prolonged. The required dose of midazolam may become lower and proper monitoring of vital signs should be instituted. (See section 4.4).
Pediatric population
See above and section 4.4.
04.3 Contraindications
Administration of midazolam in patients with known hypersensitivity to benzodiazepines or to the excipients of the product.
Use of this medicinal product for conscious sedation in patients with severe respiratory failure or acute respiratory depression.
04.4 Special warnings and appropriate precautions for use
Midazolam should only be administered by experienced physicians, in a well-equipped environment for monitoring and support of respiratory and cardiovascular function, and by individuals who have received specific training in recognizing and managing expected adverse events, including respiratory resuscitation and cardiac. Serious cardiorespiratory adverse events have been reported. These include respiratory depression, apnea, respiratory arrest and / or cardiac arrest. Such life-threatening effects are more frequent when injection is given too quickly or when high doses are administered (see section 4.8). Particular caution should be exercised in the indication of conscious sedation in patients with impaired respiratory function.
Pediatric patients less than 6 months of age are particularly susceptible to airway obstructions and hypoventilation, therefore small increases in dosage are essential to achieve clinical effect and accurate control of respiratory rate and oxygen saturation.
When midazolam is administered for premedication, adequate monitoring of the patient after administration is mandatory as individual sensitivity varies and symptoms of overdose may occur.
Special precautions must be taken when midazolam is administered to high-risk patients:
• adults over 60 years of age
• chronically ill or debilitated patients such as:
• patients with chronic respiratory insufficiency
• patients with chronic renal failure, decreased liver function or with decreased heart function
• pediatric patients especially those with cardiovascular instability.
These high-risk patients require lower dosages (see section 4.2) and should be continuously monitored for early signs of impaired vital functions.
As with any substance with CNS depressant and / or muscle relaxant properties, special care is required when midazolam is administered to patients with myasthenia gravis.
Tolerance
Some loss of efficacy has been reported when midazolam was administered in long-term sedation in the ICU.
Dependence
When midazolam is administered in intensive care for long-term sedation, it should be remembered that physical dependence on midazolam may develop. The risk of dependence increases with dose and duration of treatment, and is also higher in patients with a history of alcohol and / or psychoactive substance abuse (see section 4.8).
Withdrawal symptoms
Physical dependence may develop during prolonged treatment with midazolam in the ICU, therefore abrupt discontinuation of treatment will be accompanied by withdrawal symptoms.
The following symptoms may occur: headache, muscle pain, anxiety, tension, restlessness, confusion, irritability, rebound insomnia, mood swings, hallucinations and seizures. Because the risk of withdrawal symptoms is greater after stopping abrupt treatment, it is recommended to decrease the dosage gradually.
Amnesia
Midazolam causes anterograde amnesia (frequently this is a particularly desirable effect in situations such as: before and during surgical and diagnostic procedures), the duration of which is directly proportional to the administered dose. Prolonged amnesia may present problems in outpatients who are scheduled to be discharged after surgery. After parenteral administration of midazolam, patients should only be discharged from the hospital or outpatient clinic if accompanied.
Paradoxical reactions
Paradoxical reactions such as agitation, involuntary movements (including tonic / clonic seizures and muscle tremors), hyperactivity, hostility, angry reactions, aggression, paroxysmal arousal and assaults have been reported after administration of midazolam. These reactions can occur at high doses and / or when the injection is given rapidly. The highest incidence of similar reactions has been reported in children and the elderly.
Altered elimination of midazolam
Midazolam elimination may be impaired in patients receiving CYP3A4 inhibiting or inducing drugs and the dose may need to be adjusted accordingly (see section 4.5).
Elimination of midazolam may also be delayed in patients with hepatic dysfunction, low cardiac output and in neonates (see section 5.2).
Premature babies and newborns
Extreme caution is required in the sedation of premature and former premature infants not undergoing intubation, due to an increased risk of apnea. Careful control of respiratory rate and oxygen saturation is required.
Rapid injection should be avoided in the neonatal population. Neonates have impaired or immature body function and are also susceptible to the profound and / or prolonged respiratory effects of midazolam. Haemodynamic adverse events have been reported in pediatric patients with cardiovascular instability; rapid administration intravenous injection in this population should be avoided.
Pediatric patients less than 6 months of age:
In this population, midazolam is indicated for sedation in intensive care units only.
Pediatric patients less than 6 months of age are particularly exposed to airway obstruction and hypoventilation so it is essential to make small dose increases to achieve clinical effect and to carefully monitor respiratory rate and respiratory rate. oxygen saturation (see also "Premature babies" above).
Concomitant use of alcohol / CNS depressing agents:
The concomitant use of midazolam with alcohol and / or CNS depressant agents should be avoided. Such concomitant use may enhance the clinical effects of midazolam, including potentially inducing severe sedation or clinically relevant respiratory depression. (see section 4.5).
Medical history of alcohol or psychoactive substance abuse:
In patients with a history of alcohol or psychoactive substance abuse, the use of midazolam, like other benzodiazepines, should be avoided.
Criteria for discharge
After taking midazolam, patients should be discharged from the hospital or outpatient clinic only on the recommendation of the doctor who is treating the patient and only if the latter has someone accompanying him. It is recommended that the patient be accompanied by someone to return home after discharge.
This medicinal product contains less than 1 mmol (23 mg) sodium per vial, ie it is essentially "sodium-free".
04.5 Interactions with other medicinal products and other forms of interaction
Pharmacokinetic interactions
Midazolam is metabolised by CYP3A4.
CYP3A inhibitors and inducers may respectively increase and decrease the plasma concentrations and, consequently, the effects of midazolam, thus requiring appropriate dose adjustments.
Pharmacokinetic interactions with CYP3A4 inhibitors or inducers are more pronounced for oral administration of midazolam than for IV, particularly because CYP3A4 is also present in the upper gastrointestinal tract.This happens because in oral administration both systemic clearance and availability are modified, while in parenteral administration only systemic clearance is actually altered.
Following inhibition of CYP3A4, the maximal clinical effect result after a single dose of i.v. it will be shorter, but the duration of the effect may be prolonged. However, after prolonged administration of midazolam under conditions of inhibition of CYP3A4, both the magnitude and the duration of the effect will be greater.
No studies are available on the modulation of the pharmacokinetics of midazolam by CYP3A4 after rectal and intramuscular administration. Such interactions are assumed to be less pronounced for the rectal route than for the oral route, since the gastrointestinal tract is avoided, while, after intramuscular administration, the effects of CYP3A4 modulation are not expected to be substantially different from those observed with the iv midazolam
During the use of midazolam, careful monitoring of clinical effects and vital signs is therefore recommended, taking into account that these may be more pronounced and last longer after concomitant administration of a CYP3A4 inhibitor, even once taken only. It should be emphasized that the administration of high doses or long-term infusions of midazolam to patients receiving strong CYP3A4 inhibitors, e.g. in the ICU, may cause long-lasting hypnotic effects, delayed awakening and respiratory depression; this requires dose adjustments.
As far as induction is concerned, it must be considered that the inductive process takes several days to reach the maximum effect and as many to fade away. Contrary to what occurs in a treatment of several days with an inducer, it is assumed that a short-term treatment results in a less apparent interaction with midazolam. However, for strong inducers a "relevant induction even after short-term treatment cannot be ruled out."
Midazolam does not appear to modify the pharmacokinetics of other drugs.
Drugs that inhibit CYP3A4
Azole antifungals
• Ketoconazole increased plasma concentrations of intravenous midazolam by 5-fold, with an approximately 3-fold extension of the terminal half-life. Parenteral administration of midazolam concomitantly with the strong CYP3A4 inhibitor ketaconazole should be performed in an intensive care unit (ICU) or similar setting that ensures close clinical monitoring and adequate medical management in case of respiratory depression and / or prolonged sedation. Divided dose administration and dose adjustments should be considered, especially if multiple doses of midazolam are administered intravenously. The same recommendation can also be applied to the other azole antifungals (see below), with which an increase in the sedative effects of i.v. midazolam is reported, albeit to a lesser extent.
• Voriconazole increased exposure to intravenous midazolam by 3-fold, extending its elimination half-life by approximately 3-fold.
• Both fluconazole and itraconazole increased the plasma concentrations of intravenous midazolam by 2 to 3-fold, related to a 2.4-fold increase in terminal half-life for itraconazole and 1.5-fold for itraconazole, respectively. fluconazole.
• Posaconazole increased the plasma concentrations of intravenous midazolam approximately 2-fold.
• It should be borne in mind that, by administering midazolam orally, the exposure will be significantly higher than mentioned above, especially with ketoconazole, itraconazole and voriconazole.
Oral administration of midazolam ampoules is not indicated.
Macrolides
• Erythromycin resulted in an approximately 1.6-2-fold increase in intravenous midazolam plasma concentrations, related to a 1.5-1.8-fold increase in the terminal half-life of midazolam.
• Clarithromycin increased the plasma concentrations of midazolam up to 2.5 times, extending the terminal half-life by 1.5-2 times.
Further information from oral administration of midazolam
• Roxithromycin: While no information is available on roxithromycin in combination with intravenous midazolam, its moderate effect on the terminal half-life of the oral midazolam tablet, which increases by 30%, indicates that the effects of roxithromycin on midazolam intravenously should be minor.
HIV protease inhibitors
• Saquinavir and other HIV protease inhibitors: Co-administration with protease inhibitors could cause a sharp increase in the concentration of midazolam. Following concomitant administration with lopinavir combined with a boosting dose of ritonavir, plasma concentrations of midazolam for intravenously increased 5.4-fold, with a similar increase in the terminal half-life. If midazolam is co-administered with HIV protease inhibitors, the treatment setting should follow the description given in the previous section for azole antifungals for ketoconazole.
Further information from oral administration of midazolam
• Based on data obtained with other CYP3A4 inhibitors, plasma concentrations of midazolam are expected to reach significantly higher levels after oral administration. Consequently, protease inhibitors should not be administered concomitantly with oral midazolam.
Calcium channel blockers
• Diltiazem: A single administration of diltiazem increased the plasma concentrations of intravenous midazolam by approximately 25% and extended the terminal half-life by 43%.
Further information from oral administration of midazolam
• Verapamil and diltiazem increased the plasma concentrations of oral midazolam 3-fold and 4-fold, respectively. The terminal half-life of midazolam increased by 41% and 49%, respectively.
Other drugs / medicinal herbs
• Atorvastatin has been shown to increase plasma concentrations of i.v. midazolam 1.4-fold compared to the control group.
Further information from oral administration of midazolam
• Nefazodone increased the plasma concentrations of oral midazolam by 4.6-fold, with a 1.6-fold extension of the terminal half-life.
• aprepitant dose-dependent increased plasma concentrations of oral midazolam by 3.3-fold with 80 mg / day, in association with an approximately 2-fold prolongation of the terminal half-life.
Drugs that induce CYP3A4
• Rifampicin, after 7 days at a dose of 600 mg / day, reduced the plasma concentrations of intravenous midazolam by approximately 60%. The terminal half-life was reduced by approximately 50-60%.
Further information from oral administration of midazolam
• Rifampicin, in healthy subjects, reduced the plasma concentrations of oral midazolam by 96%, almost completely neutralizing its psychomotor effects.
• Carbamazepine and phenytoin: repeated administration of carbamazepine or phenytoin resulted in a reduction in plasma concentrations of oral midazolam by up to 90%, and a shortening of the terminal half-life by 60%.
• Efavirenz: The 5-fold increase in the ratio of the metabolite α-hydroxymidazolam, generated by CYP3A4, to midazolam confirms the induction effect on CYP3A4.
Medicinal herbs and food
• St. John's wort reduced plasma concentrations of midazolam by approximately 20-40%, with a shortening of the terminal half-life by approximately 15-17%. The induction effect on CYP3A4 may vary based on the specific type of St John's wort extract.
Pharmacodynamic Drug-Drug Interactions (DDI)
Concomitant administration of midazolam with other sedative / hypnotic drugs and CNS depressant agents, including alcohol, is likely to result in potentiation of sedation and respiratory depression.
Examples include derivatives of opiates (used as analgesics, antitussives or for substitution treatments), antipsychotics, other benzodiazepines used as anxiolytics or hypnotics, barbiturates, propofol, ketamine, etomidate; sedative antidepressants, non-recent H1 antihistamines and centrally acting antihypertensive agents.
Alcohol can significantly increase the sedative effect of midazolam. The consumption of alcohol should be absolutely avoided when administering midazolam (see section 4.4).
Midazolam reduces the minimum alveolar concentration (MAC) of inhaled anesthetics.
04.6 Pregnancy and lactation
There are insufficient data available on midazolam to evaluate its safety for use in pregnancy.
Animal studies have not shown teratogenic effects, while fetotoxicity has been observed, as with other benzodiazepines.
There are no data on pregnancies exposed to midazolam during the first two trimesters of pregnancy.
The administration of midazolam in high doses, in the last trimester of pregnancy, during labor or for the induction of anesthesia for cesarean section, caused adverse effects for the mother and the fetus (risk of aspiration for the mother, irregularity in fetal heart rate, weak sucking, hypotonia, hypothermia and respiratory depression for the newborn).
In addition, infants of mothers who have chronically taken benzodiazepines during the latter stage of pregnancy may develop physical dependence and may experience withdrawal symptoms during the postnatal stage.
Consequently midazolam can be used during pregnancy if clearly necessary, but it is preferable to avoid its use in caesarean section.
The risk to the neonate should be considered if midazolam is administered for surgery near term of pregnancy.
Midazolam is excreted in breast milk in small amounts.
Breastfeeding mothers should be advised to stop breastfeeding during the 24 hours following the administration of midazolam.
04.7 Effects on ability to drive and use machines
Sedation, amnesia, reduced attention and muscle function can impair the ability to drive or use machines.
Before receiving midazolam, patients should be advised not to drive or operate machines before they are fully recovered.
The physician should decide when it is possible for the patient to return to these activities.
It is recommended that the patient be accompanied home after discharge.
04.8 Undesirable effects
For midazolam given by injection, the following side effects have been reported (frequency not known as it cannot be estimated from the available data):
The categories of attendance are as follows:
Very common: ≥1 / 10;
Common ≥1 / 100 y
Uncommon ≥1 / 1,000 to
Rare ≥1 / 10,000 y
Very rare
Not known (frequency cannot be estimated from the available data)
* These paradoxical drug reactions have been reported particularly in children and the elderly (see section 4.4).
** Anterograde amnesia may remain at the end of the procedure and in a few cases prolonged amnesia has been reported (see section 4.4).
Dependence: The use of midazolam even at therapeutic doses can lead to the development of physical dependence. After prolonged intravenous administration, its discontinuation, particularly abrupt withdrawal, may be accompanied by withdrawal symptoms including the onset of convulsions (see section 4.4).
*** The risk of falls and fractures is increased in patients taking concomitant sedatives (including alcoholic beverages) and in elderly patients.
Serious cardiorespiratory adverse events have been reported. Fatal accidents are more likely to occur in adult patients over 60 years of age and in patients with pre-existing respiratory insufficiency or impaired heart function, particularly when the injection is given too quickly or when a high dose of the drug is administered. (see section 4.4).
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. at the address http://www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
Symptoms
Like other benzodiazepines, midazolam frequently causes somnolence, ataxia, dysarthria and nystagmus. Overdose of midazolam is only infrequently life threatening if the drug is taken alone, but can induce areflexia, apnea, hypotension, cardiorespiratory depression and, in rare cases, coma. The latter, if it occurs, usually lasts a few hours, but can also be protracted and cyclical, especially in elderly patients. The respiratory depression effects of benzodiazepines are more severe in patients with respiratory diseases.
Benzodiazepines enhance the effects of other central nervous system depressants, including alcohol.
Treatment
Monitor the patient's vital signs and institute supportive measures based on the patient's clinical condition. In particular, patients may require symptomatic treatment for cardiorespiratory or central nervous system effects.
In case of oral administration, further absorption should be prevented by a suitable method, such as treatment with activated charcoal within 1-2 hours. When using activated charcoal, airway protection is mandatory in drowsy patients. In the "eventuality of a" mixed ingestion, gastric lavage can be considered, which however is not a routine measure.
In the presence of severe CNS depression, consider using flumazenil, a benzodiazepine antagonist.
Flumazenil should only be administered under strictly controlled conditions. The half-life of the drug is short (about one hour) and therefore it is necessary to monitor patients who have taken flumazenil once its effects have worn off. Flumazenil should be used with extreme caution in the presence of drugs that lower the seizure threshold (e.g. tricyclic antidepressants). For more information on the correct use of the drug please refer to the Summary of Product Characteristics for flumazenil.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Hypnotics and sedatives: Benzodiazepine derivatives, ATC code: N05CD08.
Midazolam is a derivative belonging to the imidazo-benzodiazepine group. The free base is a lipophilic substance with low water solubility.
The basic nitrogen in position 2 of the imidazo-benzodiazepine ring allows the active portion of midazolam to form water-soluble salts with the acids.
This makes it possible to produce a stable and well tolerated solution for injection.
The pharmacological action of midazolam is characterized by a short duration of action due to a rapid metabolism. Midazolam produces a sedative and hypnotic effect of pronounced intensity. It also has an anxiolytic, anticonvulsant and muscle relaxant effect.
After i.m. administration or i.v. short-lived anterograde amnesia occurs (the patient does not remember the events that occurred during the phase of maximum activity of the compound).
05.2 Pharmacokinetic properties
Absorption after intramuscular injection
Absorption of midazolam from muscle tissue is rapid and complete. Maximum plasma concentration is reached within 30 minutes. Absolute bioavailability after IM injection is greater than 90%.
Absorption after rectal administration
After rectal administration, midazolam is rapidly absorbed. The maximum plasma concentration is reached in about 30 minutes. Absolute bioavailability is approximately 50%.
Distribution
When midazolam is administered intravenously, the plasma concentration-time curve shows one or two distinct distribution phases. The steady state volume of distribution is 0.7-1.2 L / kg. The plasma protein binding of midazolam is 96-98%. The major fraction of plasma protein binding is due to "albumin. C" is a low and insignificant passage of midazolam into the cerebrospinal fluid. In humans, midazolam crosses the placenta and enters the fetal circulation. Small amounts of midazolam are excreted in human milk.
Metabolism
Midazolam is almost entirely eliminated by biotransformation and the fraction of the dose extracted from the liver has been estimated to be 30-60%. Midazolam is hydroxylated by the cytochrome P4503A4 isoenzyme and the major urinary plasma metabolite is alpha-hydroxymidazolam. Plasma concentrations of alpha-hydroxymidazolam are 12% of those of the parent compound. Alpha-hydroxymidazolam is pharmacologically active, but contributes only minimally (approximately 10%) to the effects of midazolam administered intravenously.
Elimination
In healthy volunteers, the elimination half-life of midazolam is between 1.5-2.5 hours. Plasma clearance is in the range of 300-500 ml / min. Midazolam is mainly excreted via the kidney (60-80% of the injected dose) and recovered as glucuroconjugated alpha-hydroxymidazolam. Less than 1% of the dose is recovered in the urine as unchanged drug. The elimination half-life of alpha-hydroxymidazolam is less than 1 hour. When midazolam is given by intravenous infusion, its elimination kinetics do not differ from that following a bolus injection.
Pharmacokinetics in special types of patients
Senior citizens
In adults over 60 years of age, the elimination half-life can be prolonged up to 4 times.
Children
The rate of rectal absorption in children is similar to that in adults but the bioavailability is lower (5-18%). The elimination half-life after intravenous and rectal administration is shorter in children aged 3 to 10 years (1-1.5 hours) compared to that in adults. The difference is an increased metabolic clearance in children.
Babies
In neonates, the elimination half-life averages 6-12 hours, possibly due to hepatic immaturity and clearance is reduced (see section 4.4).
Obese
The mean half-life is longer in obese than in non-obese patients (5.9 vs 2.3 hours). This is due to an approximately 50% increase in the volume of distribution corrected for total body weight. Clearance does not differ significantly among obese and non-obese patients.
Patients with impaired hepatic function
The elimination half-life in cirrhotic patients may be longer and the clearance lower compared to that in healthy volunteers (see section 4.4).
Patients with impaired renal function
The elimination half-life in patients with chronic renal failure is similar to that in healthy volunteers.
Critical patients
The elimination half-life of midazolam is prolonged up to 6-fold in critically ill patients.
Patients with heart failure
The elimination half-life in patients with congestive heart failure is longer than that in healthy subjects (see section 4.4).
05.3 Preclinical safety data
There are no preclinical data of relevant importance to the physician that have not already been reported in other sections of the SmPC.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Sodium chloride
Hydrochloric acid
Sodium hydroxide
Water for injections
06.2 Incompatibility
Do not dilute the contents of Ipnovel vials with 6% macrodex in dextrose.
Do not mix the contents of Ipnovel ampoules with alkaline injectable solutions. Midazolam precipitates in the presence of sodium bicarbonate.
The contents of the Ipnovel ampoules must not be mixed with other solutions except those mentioned in section 6.6.
06.3 Period of validity
5 years.
The diluted solution is chemically and physically stable for 24 hours at room temperature or for 3 days at 5 ° C.
From a microbiological point of view, the product should be used immediately. In the event that use is not immediate, the user is to be held responsible for the storage times and conditions, which normally should not exceed 24 hours at a temperature between 2 ° C and 8 ° C, unless the dilution took place under controlled and validated aseptic conditions (for dilution, see also section 6.6).
06.4 Special precautions for storage
Keep the vial in the outer carton to protect the medicine from light.
For storage conditions of the diluted medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
Vials: type I colorless glass.
Packs:
1ml glass vials: pack of 1, 5, 6, 10, 25
3ml glass vials: pack of 1, 2, 5, 6
10ml glass vials: pack of 1, 5, 6
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Compatibility with the following infusion solutions:
• sodium chloride 0.9%
• glucose 5%
• glucose 10%
• levulose 5%
• Ringer's solution
• Hartmann's solution
Chemically and physically stable for 24 hours at room temperature or for 3 days at 5 ° C.
From a microbiological point of view, the product should be used immediately. In the event that use is not immediate, the user is to be held responsible for the storage times and conditions, which normally should not exceed 24 hours at a temperature between 2 ° C and 8 ° C, unless the dilution took place under controlled and validated aseptic conditions.
To avoid possible incompatibility with other solutions, the contents of Ipnovel ampoules must not be mixed with other solutions except those mentioned above (see section 6.2 Incompatibilities).
Ipnovel ampoules are for single dose only. Discard the unused solution.
The solution should be visually checked before use. Use only clear solutions without suspended particles.
07.0 MARKETING AUTHORIZATION HOLDER
Roche S.p.A. - Piazza Durante 11 - Milan
08.0 MARKETING AUTHORIZATION NUMBER
"5 mg / 1 ml solution for injection" 1 ampoule of 1 ml AIC n ° 026109037
"15 mg / 3 ml solution for injection" 1 ampoule of 3 ml AIC n ° 026109049
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Renewal: June 2008.
10.0 DATE OF REVISION OF THE TEXT
May 2015
