Active ingredients: Remifentanil
Remifentanil Teva 1 mg 2 mg 5 mg Powder for concentrate for solution for injection or infusion
Why is Remifentanil used - Generic drug? What is it for?
Remifentanil belongs to a group of general anesthetics known as opioids. Remifentanil is used as an anesthetic before surgery, to keep you asleep and to prevent pain during an operation. If you are 18 years of age or older, it is also used to prevent pain while undergoing surgery. to treatment in an intensive care unit.
Contraindications When Remifentanil should not be used - Generic drug
DO NOT take Remifentanil Teva
- if you are allergic (hypersensitive) to remifentanil or other similar medicines or to any of the other ingredients of Remifentanil Teva
- as an injection into the spine
- as the only anesthetic
Precautions for use What you need to know before taking Remifentanil - Generic drug
Take special care with Remifentanil Teva
- If you are elderly, debilitated or hypovolaemic (if you are dehydrated or have lost a lot of blood), when remifentanil is used you may be more predisposed to side effects that can affect the heart.
- If you have lung problems or severe liver problems, you may be slightly more sensitive to the breathing difficulties that remifentanil can cause.
- If you are expected to feel pain after the surgical procedure, you will be given another form of analgesic before stopping remifentanil treatment. This will be chosen specifically for you, taking into account the surgical procedure and the level of postoperative care you will receive. If you are given another opioid medicine, your doctor will further consider the risk of developing breathing difficulties. Once you wake up from the surgery, you may experience the following symptoms: tremor, agitation, rapid heartbeat and / or dizziness. In this case, tell your doctor immediately.
- While in the operating room, the doctor may insert a tube into the trachea to ensure that the airways remain clear. It will be closely monitored and will not feel any disturbance from the tube.
Tell your doctor if you feel:
severe muscle stiffness when you are given this medicine for the first time (see section 4, Possible side effects).
Remifentanil can be addictive.
For those who carry out sporting activities: the use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.
Interactions Which drugs or foods can modify the effect of Remifentanil - Generic drug
Tell your doctor or anesthetist if you are taking or have recently taken any other medicines, including herbal medicines and those obtained without a prescription. This is because they can affect the way remifentanil works in your body and can cause effects. unwanted.
Tell your doctor or anesthetist if you are taking (or intend to take) other medicines, such as:
- medicines for heart disease, such as beta-blockers (which include atenolol, metoprolol and bisoprolol), as they can increase the side effects of remifentanil, affecting the heart (including low blood pressure and slow heart rate)
- calcium channel blocking agents (including amlodipine, diltiazem and nifedipine), as they may increase the side effects of remifentanil affecting the heart (including low blood pressure and slow heart rate)
- Inhaled or intravenous anesthetics and benzodiazepines (e.g. diazepam): your doctor or pharmacist will adjust the dose of these medicines if you are being given Remifentanil Teva.
Taking Remifentanil Teva with food and drink
After receiving Remifentanil Teva you should not take alcohol until you are fully recovered.
Warnings It is important to know that:
Pregnancy and breastfeeding
Remifentanil should not be used during pregnancy unless considered strictly necessary. It is recommended that breastfeeding be discontinued for 24 hours after administration of Remifentanil Teva.
Tell your doctor or anesthetist if you are pregnant or think you are pregnant, or if you are breastfeeding.
Remifentanil is not recommended during labor or caesarean section.
Ask your doctor or pharmacist for advice before taking any medicine.
- Driving and using machines
This medicine can cause problems with concentration, coordination, movement and alertness. If you are discharged from the hospital on the same day as the operation, do not drive or use machines.
It can be dangerous to drive shortly after surgery, so it is recommended that you be accompanied when you get home.
Important information about some of the ingredients of Remifentanil Teva
This medicinal product contains less than 1 mmol sodium (23 mg) per ml, ie it is basically "sodium free".
Dosage and method of use How to use Remifentanil - Generic drug: Posology
Remifentanil Teva will only be given to you in a facility where trained medical staff can monitor your heart and breathing.
A doctor or anesthetist will give you this medicine, so it is unlikely that you will receive the wrong dose. How this medicine is given and the doses administered will vary according to the patient and will be decided by your doctor or anesthetist. This will depend on the type of surgery you will have and how long you need to be asleep.
- Remifentanil will be given to you as an injection / infusion, separately from other medicines.
- Remifentanil will be given to you as a single injection or as a slow continuous infusion into a vein.
- Remifentanil should not be given as an injection into the spine.
- Remifentanil should only be given in combination with other medicines that help you fall asleep.
Dosage in special patient groups
In obese or severely ill patients, the starting dose will be adequately reduced and increased based on response. No dose reduction is required in patients with hepatic or renal insufficiency and in those undergoing neurosurgery.
Overdose What to do if you have taken an overdose of Remifentanil - Generic drug
As a doctor or anesthetist will closely monitor your condition during the procedure, it is unlikely that you will be given too much Remifentanil Teva. If you receive too much Remifentanil Teva, your doctor will stop your therapy and treat your symptoms.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Remifentanil - Generic drug
Like all medicines, Remifentanil Teva can cause side effects, although not everybody gets them.
You may feel muscle stiffness when you are given remifentanil for the first time to put you to sleep. If the stiffness becomes severe, your doctor will give you a medicine to relax the muscles. If you feel muscle stiffness while being given remifentanil as an analgesic, your doctor will reduce the dose or stop the administration. Muscle stiffness will subside within minutes of stopping remifentanil.
The following side effects have been reported with approximate frequencies indicated:
Frequency:
- Very common (affects more than 1 in 10 patients)
- Common (affects 1 to 10 users in 100)
- Uncommon (affects 1 to 10 users in 1,000)
- Rare (affects 1 to 10 users in 10,000)
- Very rare (affects less than 1 user in 10,000)
- Not known (frequency cannot be estimated from the available data)
You should tell your nurse or doctor immediately if you start to experience any of the following symptoms:
Very common:
- Muscle stiffness
- Fainting or dizziness (possible symptoms of low blood pressure)
- Nausea and / or vomiting
Common:
- Unusually slow heartbeat
- Slowing or stopping of breathing
- Itching
- Tremor (after surgery)
- Dizziness or "flushing" sensations after surgery (possible symptoms of high blood pressure)
Uncommon:
- Constipation
- Pain (after surgery)
- Feelings of agitation or confusion, bluish skin color and / or shortness of breath (possibly indicating a lack of oxygen reaching body tissues)
Rare:
- Absence / arrest of heartbeat
- Somnolence (after surgery)
- Allergic reactions, such as shortness of breath, rash all over the body, sudden wheezing or swelling of the face / tongue have been observed in patients taking remifentanil and one or more anesthetics.
Frequency not known:
- Dependence
Before you are discharged from the intensive care unit, your doctor will make sure that you are fully conscious and that you do not have any post-operative side effects, such as difficulty breathing, unusual heartbeat and / or dizziness. If you experience these side effects, your doctor will treat them appropriately.
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
Keep out of the reach and sight of children.
Do not use Remifentanil Teva after the expiry date which is stated on the vial and carton after EXP. The expiry date refers to the last day of the month.
Conservation conditions
Before opening: This medicinal product does not require any special storage conditions.
After reconstitution / dilution: This product can be stored for 24 hours at 25 ° C. However, the product must be used immediately. If not used immediately, the storage period and conditions prior to use are the responsibility of the user. The storage times of the diluted product do not usually exceed 24 hours at 2-8 ° C, unless the reconstitution / dilution has taken place in controlled and validated aseptic conditions. Your doctor will make sure that the medicine is kept in the correct storage conditions.
For single use only. Unused solution must be discarded.
Remifentanil Teva will not be used if your doctor notices any visible signs of deterioration.
Medicines should not be disposed of via wastewater or household waste.
Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other information
What Remifentanil Teva contains
The active ingredient is remifentanil. One vial contains 1 mg 2 mg 5 mg remifentanil.
The excipients are:
- glycine (E640)
- hydrochloric acid (E507)
- sodium hydroxide (E524)
What Remifentanil Teva looks like and contents of the pack
Remifentanil Teva 1 mg powder for concentrate for solution for injection or infusion is a white to off-white or yellowish compact powder contained in a colorless glass vial closed with a rubber stopper and a white capsule. It is available in packs of 1 and 5 vials.
Remifentanil Teva 2 mg powder for concentrate for solution for injection or infusion is a white to off-white or yellowish compact powder contained in a colorless glass vial closed with a rubber stopper and a gray capsule. It is available in packs of 1 and 5 vials.
Remifentanil Teva 5 mg powder for concentrate for solution for injection or infusion is a white to off-white or yellowish compact powder contained in a colorless glass vial closed with a rubber stopper and a blue capsule. It is available in packs of 1 and 5 vials.
Not all pack sizes may be marketed.
The following information is intended for medical and healthcare professionals only
Incompatibility
Remifentanil Teva must not be mixed with Lactated Ringer's for injection or Lactated Ringer's and glucose 50 mg / ml (5%) solution for injection. Remifentanil Teva must not be mixed with propofol in the same mixed solution for intravenous administration. Remifentanil Teva is compatible with propofol when administered into an intravenous infusion catheter.
Administration of Remifentanil Teva in the same intravenous line as blood / serum / plasma is not recommended as nonspecific esterase in blood products may result in the hydrolysis of remifentanil to its inactive metabolite.
Remifentanil Teva must not be mixed with other therapeutic agents prior to administration.
Special precautions for disposal and handling
Reconstitution:
Remifentanil Teva must be prepared for intravenous use by adding the appropriate volume (as shown in the table below) of one of the diluents listed below to give a reconstituted solution with a concentration of approximately 1 mg / ml of remifentanil.
Shake until completely dissolved. The reconstituted solution should be clear, colorless and free from visible particles.
Further dilution:
After reconstitution, Remifentanil Teva 1 mg 2 mg 5 mg should not be administered without further dilution at concentrations between 20 and 250 μg / ml (50 μg / ml is the recommended dilution for adults and 20 - 25 μg / ml for pediatric patients 1 year of age and older) with one of the intravenous solutions listed below.
For target-controlled infusion (TCI), the recommended dilution of Remifentanil Teva is 20-50 μg / ml.
The dilution depends on the technical capability of the infusion device and the patient's requirements.
For dilution, one of the following solutions should be used:
- Water for injections
- Glucose 50 mg / ml (5%) solution for injection
- Glucose 50 mg / ml (5%) solution for injection and sodium chloride 9 mg / ml (0.9%) solution for injection
- Sodium chloride 9 mg / ml (0.9%) solution for injection
- Sodium chloride 4.5 mg / ml (0.45%) solution for injection.
When administered into a running intravenous catheter, the following intravenous fluids can be used:
- Injectable Lactated Ringer's
- Lactated Ringer's and glucose 50 mg / ml (5%) solution for injection
Remifentanil Teva is compatible with propofol when administered into a running intravenous catheter.
No other diluents should be used. The solution should be visually inspected for the presence of particulates prior to administration. The solution should be used if it is clear and free of particles.
Remifentanil intravenous infusions should preferably be prepared at the time of administration. The contents of the vial are for single use only. Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
For tables relating to Remifentanil Teva infusion rate guidelines for manually controlled infusion and tables providing TCI equivalent blood concentration of remifentanil for different manually controlled infusion rates at steady state (steady state ), please refer to the Summary of Product Characteristics (SmPC) of Remifentanil Teva.
Conservation information
See section 5, "How to store Remifentanil Teva".
After the first opening
Physico-chemical stability in use has been demonstrated for 24 hours at 25 ° C after initial reconstitution with:
- Water for injections
- Glucose 50 mg / ml (5%) solution for injection
- Glucose 50 mg / ml (5%) solution for injection and sodium chloride 9 mg / ml (0.9%) solution for injection
- Sodium chloride 9 mg / ml (0.9%) solution for injection
- Sodium chloride 4.5 mg / ml (0.45%) solution for injection
- Injectable Lactated Ringer's
- Lactated Ringer's and glucose 50 mg / ml (5%) solution for injection
The chemical-physical stability in use has been demonstrated for 24 hours at 25 ° C after further dilution with:
- Water for injections
- Glucose 50 mg / ml (5%) solution for injection
- Glucose 50 mg / ml (5%) solution for injection and sodium chloride 9 mg / ml (0.9%) solution for injection
- Sodium chloride 9 mg / ml (0.9%) solution for injection
- Sodium chloride 4.5 mg / ml (0.45%) solution for injection.
The chemical-physical stability in use has been demonstrated for 8 hours at 25 ° C after further dilution with:
- Injectable Lactated Ringer's
- Lactated Ringer's and glucose 50 mg / ml (5%) solution for injection
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8 ° C, unless the solution is reconstituted / diluted under aseptic controlled and validated.
Any unused residue must be discarded.
Method of administration
Remifentanil Teva is for intravenous use only and must not be administered by epidural or intrathecal injection.
Remifentanil Teva must not be administered without further dilution after reconstitution of the lyophilized powder.
Continuous infusions of remifentanil should be administered via a calibrated infusion device into a fast-flowing intravenous line or through a dedicated intravenous line. The infusion line should be connected or placed close to a venous cannula to minimize potential dead space.
Care should be taken to avoid clogging or detachment of the infusion lines and to clean the lines properly to remove remifentanil residues after use. The intravenous / infusion line system should be removed once its use is complete to avoid inadvertent administration.
Remifentanil can be administered by target-controlled infusion (TCI), using an approved infusion device that incorporates the pharmacokinetic model of Minto with covariant for age and lean body mass (LBM).
Refer to the Summary of Product Characteristics (SmPC) of Remifentanil Teva for specific guidelines on manual and target-controlled infusion. Information and posologies for induction, maintenance and discontinuation of Remifentanil Teva can be found in adults, children and patients. who require special care, such as the elderly, patients with impaired renal function, heart disease and ICU patients.
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
REMIFENTANIL TEVA POWDER FOR CONCENTRATE FOR SOLUTION FOR INJECTION OR FOR INFUSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One vial contains remifentanil hydrochloride equivalent to 1 mg of remifentanil.
One vial contains remifentanil hydrochloride equivalent to 2 mg of remifentanil.
One vial contains remifentanil hydrochloride equivalent to 5 mg of remifentanil.
After reconstitution according to instructions, each ml of Remifentanil Teva 1 mg 2 mg 5 mg powder for concentrate for solution for injection or infusion contains 1 mg of remifentanil.
Excipients:
This medicinal product contains less than 1 mmol sodium (23 mg) per ml, ie essentially "sodium free".
Each 1 mg vial of powder for concentrate for solution for injection or infusion contains 0-0.054 mmol (1.23 mg) sodium.
Each 2 mg vial of powder for concentrate for solution for injection or infusion contains 0-0.054 mmol (1.23 mg) sodium.
Each 5 mg vial of powder for concentrate for solution for injection or infusion contains 0-0.064 mmol (1.47 mg) sodium.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Powder for concentrate for solution for injection or infusion.
Compact, white to off-white or yellowish powder.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Remifentanil Teva is indicated as an analgesic agent for use during the induction and / or maintenance of general anesthesia.
Remifentanil Teva is indicated for the induction of analgesia in patients aged 18 years and over in the ICU receiving mechanical ventilation.
04.2 Posology and method of administration
Remifentanil should only be administered in a facility fully equipped for the monitoring and support of respiratory and cardiovascular function and with personnel specifically qualified in the use of anesthetic drugs and in the identification and management of adverse events expected from potent opioids, including resuscitation. respiratory and cardiac. Personnel training should include the ability to re-establish and maintain a patient's airway and assisted ventilation.
Continuous infusions of remifentanil should be administered via a calibrated infusion device into a fast-flowing intravenous line or through a dedicated intravenous line. This infusion line should be connected or placed close to a venous cannula, to minimize potential dead space (see section 6.6 for further information and section 4.2.5 for tables with examples of infusion rates by body weight, for help. titration of remifentanil according to the patient's anesthetic needs).
Care should be taken to avoid clogging or detachment of the infusion lines and to clean the lines properly, to remove remifentanil residues after use (see section 4.4). The intravenous / infusion line system should be removed once its use is complete to avoid inadvertent administration.
Remifentanil can be administered by target-controlled infusion (TCI), using an approved infusion device incorporating the pharmacokinetic model of Minto with covariant for age and lean body mass (lean body mass - LBM).
Remifentanil Teva is indicated for intravenous use only and must not be administered by epidural or intrathecal injection (see section 4.3).
Dilution
Remifentanil Teva must not be administered without further dilution after reconstitution of the lyophilized powder. See section 6.3 for storage conditions and section 6.6 for recommended diluents and instructions on reconstitution / dilution of the product before administration.
General anesthesia
The administration of remifentanil should be adapted according to the patient's response.
Adults
Administration by manually controlled infusion (MCI)
Table 1: Dosing guidelines for adults
Remifentanil should be administered for at least 30 seconds if induction is by bolus injection.
Remifentanil, used at the doses recommended above, significantly reduces the amount of hypnotic drug required to maintain anesthesia. Therefore, isoflurane and propofol should be administered at the doses recommended above, in order to avoid an increase in haemodynamic effects (hypotension and bradycardia) of remifentanil.
There are no data on the recommended dosage in concomitant use of remifentanil with other hypnotics other than those listed in the table.
Induction of anesthesia
For induction of anesthesia, remifentanil must be administered with a hypnotic agent, such as propofol, thiopental or isoflurane. Administration of remifentanil after a hypnotic agent reduces the incidence of muscle stiffness. Remifentanil can be administered at an infusion rate of 0.5 to 1 mcg / kg / min, with or without an initial bolus injection of 1 mcg / kg administered over at least 30 seconds. A bolus injection is not required if endotracheal intubation is to be performed 8-10 minutes after starting the remifentanil infusion.
Maintenance of anesthesia in ventilated patients
After endotracheal intubation, the infusion rate of remifentanil should be reduced, according to the anesthetic technique employed, as indicated in the table above. Due to the rapid onset and short duration of action of remifentanil, the rate of administration during anesthesia it can be titrated up by increments from 25 to 100% or down by decrements from 25 to 50%, every 2-5 minutes in order to obtain the desired level of response of the mc-opioid receptors. Following light anesthesia, supplemental bolus injections may be given slowly every 2-5 minutes.
Anesthesia in spontaneously breathing anesthetized patients with a clear airway (e.g. laryngeal mask anesthesia)
Respiratory depression is likely to occur in spontaneously breathing anesthetized patients with a clear airway. Therefore, attention should be paid to the respiratory effects possibly associated with muscle stiffness. Particular attention should be paid to adjusting the dose according to the patient's needs and assisted ventilation may be required. Adequate equipment must be available to monitor patients given remifentanil. It is essential that these facilities are fully equipped to manage all degrees of respiratory depression (intubation equipment should be available) and / or muscle stiffness (for further information, see section 4.4). The recommended initial infusion rate for supplemental analgesia in anesthetized, breathing patients spontaneously is 0.04 mcg / kg / min, with titration until effect is achieved. An infusion rate range of 0.025 to 0.1 mcg / kg / min has been studied. Bolus injections are not indicated in spontaneously breathing anesthetized patients.
Remifentanil should not be used as an analgesic in procedures in which patients remain conscious or receive no ventilatory support during the procedure.
Concomitant medication
Remifentanil decreases the amounts or doses of inhaled anesthetics, hypnotics and benzodiazepines required for anesthesia (see section 4.5).
The concomitant use of remifentanil allowed the reduction of doses up to 75% of the following anesthetic agents: isoflurane, thiopental, propofol, temazepam.
Guidelines for discontinuation in the immediate post-operative period
After discontinuation of dosing, due to the rapid cessation of action of remifentanil, there will be no residual opioid activity within 5-10 minutes. For those patients undergoing surgical procedures known to generally result in post-operative pain, analgesics should be administered before discontinuing remifentanil administration.Sufficient time should be allowed for the longer acting analgesic to reach its maximum effect. The choice of analgesic should be appropriate for the patient's surgery and the level of postoperative care.
In the event that the longer acting analgesic has not reached the appropriate effect before the end of the surgery, remifentanil can be continued to maintain analgesia during the immediate postoperative period, until it is achieved. of the maximum effect of the analgesic with longer duration of action.
If the administration of remifentanil continues after surgery, it must only be administered in a facility fully equipped for the monitoring and support of respiratory and cardiovascular function, under the careful supervision of personnel specifically qualified for the recognition and management of respiratory effects. of potent opioids. In addition, careful postoperative monitoring of patients for pain, hypotension and bradycardia is recommended.
Further information on administration to mechanically ventilated intensive care patients is provided in section 4.2.3.
In spontaneously breathing patients, the initial infusion rate of remifentanil can be reduced to 0.1 mcg / kg / min and subsequently increased or decreased every 5 minutes with changes of 0.025 mcg / kg / min, to balance the level of analgesia with respect to the degree of respiratory depression.
In spontaneously breathing patients, bolus doses for analgesia during the postoperative period are contraindicated.
Administration by target-controlled infusion (TCI)
Induction and maintenance of anesthesia in ventilated patients
TCI remifentanil should be used in combination with an intravenous or inhaled hypnotic agent during induction and maintenance of anesthesia in ventilated adult patients (see Table 1 above for manually controlled infusion). In combination with these agents. , adequate analgesia for induction of anesthesia and surgery can generally be achieved with target blood remifentanil concentrations ranging from 3 to 8 ng / mL. Remifentanil should be titrated based on the individual patient response. For particularly painful surgery, target blood concentrations up to 15 ng / mL may be required.
At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required for maintenance of anesthesia. Therefore, isoflurane and propofol should be administered as recommended above in order to avoid an increase in the haemodynamic effects (hypotension and bradycardia) of remifentanil (see the previous table 1 for the manual control infusion).
The following table provides the equivalent blood concentration of remifentanil obtained using a TCI approach for several manually controlled steady-state infusion rates:
Table 2. Remifentanil blood concentrations (nanograms / mL) estimated using the Minto pharmacokinetic model in a 40-year-old, 70 kg, 170 cm male patient for different manually controlled infusion rates (mcg / kg / min) at steady state.
Since insufficient data exist, administration of remifentanil by TCI for spontaneously ventilated anesthesia is not recommended.
Guidelines for the interruption / continuation of administration in the immediate post-operative period
At the end of surgery, when the TCI infusion is interrupted or the target concentration is reduced, spontaneous breathing is likely to restore to calculated remifentanil concentrations in the range of 1-2 ng / mL. As with manually controlled infusion, postoperative analgesia should be established before the end of the procedure with longer acting analgesics (see also Guidelines for interruption / continuation in the immediate post-operative period in the previous paragraph relating to "Manual control infusion).
Since insufficient data exist, administration of remifentanil by TCI in the management of postoperative analgesia is not recommended.
Pediatric patients (1 to 12 years of age)
Co-administration of remifentanil with other agents for induction of anesthesia has not been studied.
The use of remifentanil for induction of anesthesia by TCI in patients aged 1 to 12 years is not recommended as no data is available for this patient population.
Maintenance of anesthesia
The following doses of remifentanil are recommended for maintenance of anesthesia (see table 3):
Table 3: Dosing guidelines for pediatric patients (1 to 12 years of age)
* co-administered with nitrogen oxide / oxygen in a ratio of 2: 1.
Remifentanil, when injected as a bolus, should be administered for not less than 30 seconds. Surgery should begin no earlier than at least 5 minutes after the start of the remifentanil infusion, if a bolus dose has not been administered at the same time. For nitric oxide (70%) administration alone, the rates of infusion of remifentanil for maintenance of anesthesia should be between 0.4 and 3 mcg / kg / min. Data obtained from adult patients suggest that 0.4 mcg / kg / min may represent an appropriate starting dose, although specific studies are lacking.
Pediatric patients should be monitored and the dose titrated to the point of analgesia appropriate for surgery.
Concomitant medication
At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent needed to maintain anesthesia. Therefore, isoflurane, halothane and sevoflurane should be administered at the doses recommended above to avoid an increase in the haemodynamic effects (hypotension and bradycardia) of remifentanil. . No data are available to make dosage recommendations for the concomitant use of remifentanil and other hypnotics (see in the previous section: Administration by Manually Controlled Infusion (MCI), Concomitant medication).
Guidelines for patient management in the immediate post-operative period / Institution of alternative analgesia prior to discontinuation of remifentanil.
Due to the rapid disappearance of the effect of remifentanil, no residual activity will be present within 5-10 minutes of its discontinuation. In patients undergoing surgical procedures known to cause postoperative pain, analgesics should be administered before stopping the administration of Remifentanil: Sufficient time must be allowed for the longer acting analgesic to reach its therapeutic effect. The choice of drug (s), dose and time of administration must be planned in advance and adapted to the needs of the individual patient, so that it is suitable for the patient's surgery and for the level of post-operative care expected (see paragraph 4.4).
Infants and children (under 1 year of age)
The pharmacokinetic profile of remifentanil in neonates / infants (aged less than 1 year, see section 5.1) is comparable to that observed in adults after correction for body weight differences (see section 5.2). However, as there are insufficient clinical data, administration of remifentanil is not recommended for this age group.
Use for Total Intravenous Anesthesia (TIVA): Experience in clinical trials of performing TIVA anesthesia using remifentanil in infants is limited (see section 5.1). However, clinical data are insufficient and cannot be made. no recommendations regarding posology.
Special patient groups
For dosing recommendations in special patient groups (elderly and obese patients, patients with renal and hepatic impairment, patients undergoing neurosurgery and ASA III / IV patients) see section 4.2.4.
Cardiac surgery
Administration by manually controlled infusion
For dosing recommendations in patients undergoing cardiac surgery see table 4 below:
Table 4: Dosage guidelines for anesthesia in cardiac surgery
Period of induction of anesthesia
Following administration of a hypnotic to achieve loss of consciousness, remifentanil should be administered at an initial infusion rate of 1 mcg / kg / min. In patients undergoing cardiac surgery, the use of bolus injections of remifentanil during induction of anesthesia is not recommended. Endotracheal intubation should only occur after at least 5 minutes have elapsed since the start of the infusion.
Maintaining the period of anesthesia
After endotracheal intubation, the infusion rate of remifentanil should be titrated to the patient's needs. Supplemental bolus doses may also be given if necessary. For high-risk cardiac patients, such as those undergoing valve surgery or with poor function left ventricular, a maximum bolus dose of 0.5 mcg / kg should be administered.
These dosing recommendations also apply when performing hypothermic cardiopulmonary bypasses (see section 5.2).
Concomitant medication
At the doses recommended above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anesthesia. Therefore, isoflurane and propofol should be administered as recommended above to avoid an increase in the haemodynamic effects (hypotension and bradycardia) of remifentanil. Not available. data to provide dosing recommendations for concomitant use of remifentanil and other hypnotics (see in the previous section: Administration by manually controlled infusion, Concomitant medication).
Guidelines for the postoperative treatment of the patient
Post-operative continuation of remifentanil to provide analgesia prior to extubation
It is recommended that the remifentanil infusion be maintained at the final intra-operative rate during patient transfer to the postoperative ward. Upon arrival in this ward, the patient's level of analgesia and sedation should be closely monitored and the rate of recovery. remifentanil infusion should be tailored to the individual patient's needs (for further information on the management of ICU patients, see section 4.2.3).
Establishment of "alternative analgesia prior to discontinuation of remifentanil"
Due to the very rapid cessation of the effect of remifentanil, no residual opioid activity will be present within 5-10 minutes of discontinuation. Before stopping the administration of remifentanil, patients should be given alternative analgesics and sedative agents sufficiently in advance to allow the effect of these substances to take place. It is therefore recommended that the choice of drug (s), dose and time administration is scheduled, before the patient is removed from assisted ventilation.
Guidelines for discontinuation of remifentanil administration
Due to the rapid cessation of the effect of remifentanil, hypertension, chills and pain have been reported in cardiac patients soon after discontinuation of remifentanil (see section 4.8). To minimize the risk of these occurrences, adequate alternative analgesia (as described above) should be established before the remifentanil infusion is stopped. The infusion rate should be reduced by 25% decrements at intervals of at least 10 minutes until the infusion is stopped.
During respirator detachment, remifentanil infusion should not be increased and only decreased titration should occur, supported by alternative analgesics as needed. Hemodynamic changes, such as hypertension and tachycardia, should be appropriately treated with alternative agents.
When other opioids are given as part of the transition regimen to alternative analgesia, the patient should be closely monitored. The benefit of adequate postoperative analgesia should always be weighed against the potential risk of respiratory depression caused by these drugs.
Administration by target-controlled infusion (TCI)
Induction and maintenance of anesthesia
Remifentanil with TCI modality should be used in combination with a hypnotic agent administered intravenously or by inhalation, during the induction and maintenance of anesthesia in ventilated adult patients (see Table 4, Dosing guidelines for anesthesia in interventions In combination with these drugs, "adequate analgesia for cardiac surgery is generally achieved at the upper limit of the range of target blood concentrations of remifentanil used for general surgical procedures. After titration" of remifentanil based on individual patient response, blood concentrations up to 20 ng / mL have been used in clinical trials. Remifentanil, used at previously recommended doses, significantly reduces the amount of hypnotic agent required to maintain anesthesia. Therefore, isoflurane and propofol should be administered at the doses recommended above in order to avoid an increase in the haemodynamic effects (hypotension and bradycardia) of remifentanil (see Table 4, Dosage guidelines for anesthesia in cardiac surgery).
For information on remifentanil blood concentrations obtained by infusion with manual control, see Table 2, Blood concentrations of remifentanil (ng / mL) estimated using the Minto model in section 4.2.1.1.
Guidelines for discontinuation / continuation of dosing during the immediate postoperative period
At the end of surgery, when TCI infusion is interrupted or the target concentration is reduced, spontaneous respiration is likely to recover with remifentanil concentrations calculated in the range of 1-2 ng / mL. Similar to manual-controlled infusion, postoperative analgesia should be instituted before the end of surgery, with longer-acting analgesics (see Guidelines for discontinuation of remifentanil in paragraph 4.2.1.1).
Since insufficient data exist, administration of remifentanil by TCI modality is not recommended for the management of postoperative analgesia.
Intensive care
Adults
Remifentanil can be used to induce analgesia in ICU patients receiving mechanical ventilation. If necessary, additional sedative medications should be given.
Remifentanil has been studied in ICU patients in appropriately controlled clinical trials for up to three days. As patients have not been studied beyond three days, no evidence of safety and efficacy has been established for longer treatment. Therefore use for longer than three days is not recommended.
Due to lack of data, administration of remifentanil in TCI is not recommended in ICU patients.
In adults, it is recommended that remifentanil be administered with an initial infusion rate between 0.1 mcg / kg / min (6 mcg / kg / h) and 0.15 mcg / kg / min (9 mcg / kg / h). The infusion rate should be titrated in increments of 0.025 mcg / kg / min (1.5 mcg / kg / h) to achieve the desired level of sedation and analgesia. There should be a period of at least 5 minutes between one dose increase and the next. The level of sedation and analgesia should be carefully monitored and regularly reassessed and the infusion rate of remifentanil should be adjusted accordingly. If an infusion rate of 0.2 mcg / kg / min (12 mcg / kg / h) is achieved and the desired sedation level has not been achieved, it is recommended that an appropriate sedative dose be initiated (see below). following). The sedative dose should be titrated to achieve the desired sedation level. If additional analgesia is required, the infusion rate of remifentanil may be further increased in increments of 0.025 mcg / kg / min (1.5 mcg / kg / h).
The table below summarizes the initial infusion rates and the typical dose range for achieving analgesia in individual patients:
Table 5: Dosing guidelines for the use of remifentanil in the ICU
Bolus doses of remifentanil are contraindicated in the intensive care unit.
The use of remifentanil reduces the necessary dosage of any concomitant sedative agent.Typical starting doses for sedative agents, if required, are given below:
Table 6: Recommended starting doses of sedative agents, if required :
To allow for separate titration of individual agents, sedatives should not be administered in combination.
Additional analgesia for ventilated patients undergoing painful procedures
An increase in the ongoing remifentanil infusion rate may be required to provide additional analgesic coverage to ventilated patients undergoing pacing and / or painful procedures such as endotracheal aspiration, wound dressing and physiotherapy. It is recommended to maintain for at least 5 minutes a remifentanil infusion rate of at least 0.1 mcg / kg / min (6 mcg / kg / h), before starting the pacing procedure. Further dose adjustments can be made every 2-5 minutes in increments 25% -50% before, or in response to, additional analgesia requests. A mean infusion rate of 0.25 mcg / kg / min (15 mcg / kg / h), maximum 0.74 mcg / kg / min (45 mcg / kg / h), was administered to provide additional analgesia during painful stimulation procedures.
Establishment of "alternative analgesia prior to discontinuation of remifentanil"
Due to the very short duration of action of remifentanil, no residual opioid activity will be present within 5-10 minutes after discontinuation regardless of the duration of the infusion. After administration of remifentanil, consideration should be given to the possibility tolerance and hyperalgesia develop. Therefore, before discontinuation of remifentanil administration, patients should be timely treated with alternative analgesics and sedatives to allow the therapeutic effects of these drugs to stabilize and to prevent the development of hyperalgesia and associated hemodynamic changes. It is therefore recommended that the choice of drug (s), dose and timing of administration be planned before stopping the administration of remifentanil. Long-acting analgesics or local or intravenous analgesics, which can be controlled by the nursing staff or by the patient, are an "alternative" for analgesia and should be chosen carefully according to the patient's needs.
Prolonged administration of opioid-receptor agonists can induce the development of tolerance.
Guidelines for extubation and discontinuation of remifentanil
To ensure smooth recovery from the remifentanil-based regimen, the infusion rate of remifentanil should be titrated in steps from 0.1 mcg / kg / min (6 mcg / kg / hour), over a period of up to 1 hour. before extubation.
After extubation, the infusion rate should be reduced by 25% decrements at intervals of at least 10 minutes until the infusion is stopped. During respirator detachment the remifentanil infusion should not be increased and only down titration should occur, supported, as required, by alternative analgesics.
Upon discontinuation of remifentanil, the intravenous cannula should be discarded or removed to avoid subsequent inadvertent administration.
When other opioids are administered as part of the transition regimen to alternative analgesia, the patient should be closely monitored. The benefit of providing adequate analgesia must always be weighed against the potential risk of respiratory depression.
Pediatric population in intensive care
The use of remifentanil in pediatric ICU patients cannot be recommended as no data are available for this patient population.
Severely compromised ICU patients
No adjustment of the doses recommended above is necessary in patients with renal impairment, including those undergoing renal replacement therapy, however the clearance of the carboxylic acid metabolite is reduced in patients with renal insufficiency (see section 5.2).
Special patient groups
Elderly (over 65 years old)
General anesthesia
Care should be taken when administering remifentanil to this population. The starting dose of remifentanil given to patients over 65 years of age should be half the recommended adult dose and should then be titrated to the individual patient's needs, as increased sensitivity to drugs has been seen in this patient population. pharmacodynamic effects of remifentanil. This dose adjustment applies to all phases of anesthesia, including induction, maintenance and immediate postoperative analgesia.
Due to the increased sensitivity of elderly patients to remifentanil, when administering remifentanil in TCI in this population, the initial target concentration should be between 1.5 and 4 ng / mL, with subsequent titration based on individual patient response.
Anesthesia during cardiac surgery
No reduction of the starting dose is required (see section 4.2.2).
Intensive care
No reduction of the starting dose is required (see section Intensive care).
Obese patients
For manually controlled infusion, it is recommended that remifentanil dosing is reduced and calculated on the basis of ideal body weight for obese patients, since remifentanil clearance and volume of distribution are better correlated with ideal body weight rather than with the real one.
With the lean body mass (LBM) calculation used in the Minto model, LBM is likely to be underestimated in female patients, with a body mass index (BMI) greater than 35 kg / m2 and in male patients with a body mass index (BMI) greater than 40 kg / m2. To avoid underdosing in these patients, remifentanil in TCI should be carefully titrated based on individual response.
Patients with renal insufficiency
Based on the studies conducted so far, no dose adjustment is necessary in patients with renal insufficiency, including those in intensive care; however, such patients have a reduction in clearance of the carboxylic acid metabolite.
Patients with hepatic insufficiency
No starting dose adjustment is required from that used in healthy adults as the pharmacokinetic profile of remifentanil is unchanged in this patient population. However, patients with severe hepatic impairment may be slightly more sensitive to the effects of respiratory depression caused by remifentanil (see section 4.4). These patients should be carefully monitored and the remifentanil dose titrated to the individual patient's needs.
Patients undergoing neurosurgery
Limited clinical experience in patients undergoing neurosurgery has shown that no special dosage recommendation is necessary.
ASA III / IV patients
General anesthesia
Since the haemodynamic effects of potent opioids may be more pronounced in ASA III / IV patients, caution should be exercised when administering remifentanil to this population. An initial dose reduction and subsequent titration until effect is therefore recommended.
As there is insufficient data, it is not possible to provide dosage recommendations for children. For TCI, a lower initial target of 1.5 - 4 ng / mL should be used in ASA III or IV patients and titrated to response thereafter.
Anesthesia in cardiac surgery
No reduction of the starting dose is required (see section 4.2.2).
Guidelines for infusion rates of remifentanil for manually controlled infusion
Table 7: Remifentanil infusion rates (ml / kg / h)
Table 8: Remifentanil infusion rates (ml // h) for a solution of 20 mcg / ml
Table 9: Remifentanil infusion rates (ml // h) for a solution of 25 mcg / ml
Table 10: Remifentanil infusion rates (ml // h) for a solution of 50 mcg / ml
Table 11: Remifentanil infusion rates (ml // h) for a solution of 250 mcg / ml
04.3 Contraindications
Remifentanil Teva is contraindicated for epidural and intrathecal use due to the presence of glycine in the formulation (see section 5.3).
Remifentanil Teva is contraindicated in patients with hypersensitivity to remifentanil and other fentanyl analogues or to any of the excipients.
Remifentanil is contraindicated for use as the sole agent for induction of anesthesia.
04.4 Special warnings and appropriate precautions for use
Remifentanil should only be administered in a facility that is fully equipped for the monitoring and support of respiratory and cardiovascular function and with personnel specifically qualified in the use of anesthetic drugs and in the identification and treatment of expected adverse opioid events, including resuscitation. respiratory and cardiac. Staff training should also include the ability to re-establish and maintain a patient's airway and assisted ventilation. Since ICU patients receiving mechanical ventilation have not been studied for more than three days, there is no clinical evidence on safety and efficacy profiles for longer term treatment. Therefore, prolonged use is not recommended in ICU patients.
Quick disappearance of the effect
Due to the rapid disappearance of the effect of remifentanil, patients can recover quickly from anesthesia without the presence of any residual opioid activity within 5-10 minutes of discontinuing remifentanil administration. During administration of remifentanil as a mc receptor agonist of opioids, attention should be paid to the potential development of tolerance and hyperalgesia. Therefore, before discontinuing remifentanil, patients should be timely treated with alternative analgesics and sedatives to allow the therapeutic effects of these drugs to stabilize and to prevent development hyperalgesia and concomitant haemodynamic changes. In patients undergoing surgical procedures for which post-operative pain is expected, analgesics should be administered before remifentanil is discontinued. Sufficient time should be allowed for the longer acting analgesic. achieve maximum effect to. The choice of analgesic should be appropriate for the patient's surgical procedure and the level of postoperative care. When other opioids are given as part of the treatment regimen for switching to an "alternative analgesia, the benefit of providing" appropriate postoperative analgesia must be be weighed against the potential risk of respiratory depression with these agents.
Discontinuation of treatment
Symptoms following discontinuation of remifentanil, including tachycardia, hypertension and agitation, have been reported rarely with abrupt cessation, particularly after prolonged administration for more than 3 days. When found, reintroduction and reduction of the infusion have been shown to be helpful. The use of Remifentanil Teva in mechanically ventilated intensive care patients is not recommended for treatment longer than 3 days.
Muscle stiffness: prevention and management
At the recommended doses, muscle stiffness may develop. As with other opioids, the incidence of muscle stiffness is related to the dose and rate of administration. Therefore, bolus injections should be administered over not less than 30 seconds.
Muscle stiffness induced by remifentanil should be treated in the context of the patient's clinical condition, with appropriate supportive measures, including ventilatory support. Excessive muscle stiffness that occurs during induction of anesthesia should be treated by administering a neuromuscular blocker and / or additional hypnotic agents. Muscle stiffness observed while using remifentanil as an analgesic can be treated by stopping or by reducing the rate of administration of remifentanil. Resolution of muscle stiffness after stopping the remifentanil infusion occurs within minutes. Alternatively, an opioid mc receptor antagonist may be administered. However, this may cancel or attenuate the analgesic effect of remifentanil.
Respiratory depression - preventive measures and treatment
As with all potent opioids, profound analgesia is accompanied by severe respiratory depression. Therefore remifentanil should only be used in facilities equipped to monitor and treat respiratory depression. Particular care is needed in patients with pulmonary dysfunction and severe hepatic insufficiency. These patients may be slightly more sensitive to the respiratory depressive effects of remifentanil These patients should be closely monitored and the remifentanil dose titrated to individual patient needs.
The onset of respiratory depression should be managed appropriately, including reducing the infusion rate by 50% or temporarily stopping the infusion. Unlike the other fentanyl analogues, remifentanil did not cause recurrent respiratory depression, even after prolonged administration. However, in the presence of complications (eg, inadvertent administration of bolus doses - see next section - and coadministration of longer acting opioids), respiratory depression has been reported up to 50 minutes post-treatment. discontinuation of the infusion. Since numerous factors can influence post-operative recovery, it is important to ensure that the patient is fully conscious and has achieved adequate spontaneous ventilation before being discharged from the intensive care unit.
Cardiovascular effects
Hypotension and bradycardia can cause asystole and cardiac arrest (see sections 4.5 and 4.8), can be managed by reducing the infusion rate of remifentanil or the dose of concomitant anesthetics or by administering intravenous solutions, vasopressors or anticholinergics if necessary.
Debilitated, hypovolaemic and elderly patients may be more sensitive to the cardiovascular effects of remifentanil.
Inadvertent administration
Remifentanil may be present in the dead space of the intravenous line and / or cannula in sufficient quantity to cause respiratory depression, apnea and / or muscle stiffness if the line is flushed with intravenous solutions or other drugs. This can be avoided by administering remifentanil into a fast-flowing intravenous line or through a dedicated intravenous line, which is removed when remifentanil is stopped.
Babies and children
No conclusive data on infants and children under 1 year of age are available so far.
Drug abuse
As with other opioids, remifentanil can be addictive.
04.5 Interactions with other medicinal products and other forms of interaction
Remifentanil is not metabolised by plasmacholinesterase and therefore no interactions with drugs metabolised by this enzyme are expected.
As with other opioids, remifentanil, either administered by manually controlled infusion or by TCI, decreases the amounts or doses of inhaled and intravenous anesthetics and benzodiazepines required for anesthesia (see section 4.2). of co-administered CNS depressant drugs are not reduced, patients may experience an increased incidence of adverse effects associated with these agents. Information on drug interactions with other opioids in relation to anesthesia is very limited.
The cardiovascular effects of remifentanil (hypotension and bradycardia) may be exacerbated in patients taking concomitant cardiodepressants, such as beta-blockers and calcium channel blockers (see also sections 4.4 and 4.8).
04.6 Pregnancy and breastfeeding
Pregnancy
There are no adequate and well-controlled studies on the use of remifentanil in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). No teratogenic effects were observed in rats or rabbits. The potential risk to humans. humans are unknown, therefore Remifentanil Teva should not be used during pregnancy unless clearly considered necessary.
The safety profile of remifentanil during labor or delivery has not been demonstrated. There are insufficient data to recommend remifentanil during labor and caesarean section. Remifentanil crosses the placental barrier and fentanyl analogs can cause respiratory depression in the baby.
Feeding time
It is unknown whether remifentanil is excreted in human milk.However, as fentanyl analogues are excreted in human milk and remifentanil-related compounds have been found in the milk of remifentanil-treated rats, caution should be exercised and nursing mothers should be advised to stop breastfeeding for 24 hours. following the administration of remifentanil.
04.7 Effects on ability to drive and use machines
Remifentanil impairs the ability to drive or use machines. If discharge is planned shortly after administration of remifentanil following treatment with anesthetics, patients should be advised not to drive or use machines. It is recommended that the patient be accompanied when he returns home and that alcoholic beverages are avoided.
04.8 Undesirable effects
The most common adverse events associated with the use of remifentanil are a direct consequence of the mc-opioid agonist activity.
The following terminology was used to classify the occurrence of undesirable effects:
Very common ≥1 / 10
Common ≥1 / 100,
Uncommon ≥1 / 1,000,
Rare ≥1 / 10,000,
Very rare
not known (frequency cannot be estimated from the available data)
The incidence is listed below for each system of the body:
Disorders of the immune system
Rare: Hypersensitivity reactions, including anaphylaxis, have been reported in patients administered remifentanil together with one or more anesthetics
Psychiatric disorders
Not known: addiction
Nervous system disorders
Very common: musculoskeletal stiffness
Rare: sedation (during awakening after general anesthesia)
Cardiac pathologies
Common: bradycardia
Rare: asystole / cardiac arrest with previous bradycardia in patients treated with remifentanil in combination with other anesthetics
Vascular pathologies
Very common: hypotension
Common: postoperative hypertension
Respiratory, thoracic and mediastinal disorders
Common: acute respiratory depression, apnea
Uncommon: hypoxia
Gastrointestinal disorders
Very common: nausea, vomiting
Uncommon: constipation
Skin and subcutaneous tissue disorders
Common: itching
General disorders and administration site conditions
Common: postoperative chills
Uncommon: postoperative pain
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. "address www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
As with all potent opioid analgesics, overdose tends to manifest itself as an extension of the predictable pharmacological action of remifentanil. Due to the particularly short duration of action of remifentanil, the potential for harmful effects following overdose is limited to the time period. immediately following the administration of the drug. Response to drug discontinuation is rapid, with return to baseline within ten minutes.
In the event of an overdose or suspected overdose, take the following measures: discontinue administration of remifentanil, maintain a patent airway of the patient, initiate assisted or controlled ventilation with oxygen and maintain adequate cardiovascular function. associated with respiratory depression, a neuromuscular blocker may be required to facilitate controlled or assisted breathing. Intravenous solutions and vasopressors may be used to treat hypotension and other supportive therapies.
Intravenous administration of an opioid antagonist such as naloxone can be used as a specific antidote, in addition to ventilatory support, to manage severe respiratory depression. The duration of respiratory depression after remifentanil overdose is unlikely to exceed the duration of action of the opioid antagonist.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Opioid anesthetics, ATC code: N01A H06
Remifentanil is a selective mc-opioid receptor agonist with a rapid onset and very short duration of action. The mc-opioid activity of remifentanil is antagonized by narcotic antagonists, such as naloxone.
Histamine assays in healthy patients and volunteers showed no increase in histamine levels after administration of remifentanil at bolus doses up to 30 micrograms / kg.
Infants / children (under 1 year of age):
In a multicenter, randomized (2: 1 ratio, remifentanil: halothane), open-label, parallel-group study conducted in 60 children and infants aged ≤ 8 weeks (mean age 5.5 weeks) with physical status ASA I and II undergoing pyloromyotomy, the efficacy and safety of remifentanil (given as an initial continuous infusion of 0.4 mcg / kg / min plus supplemental doses or changes in infusion rate as needed) were compared with that of halothane (given at 0.4% with additional increments as needed.) Maintenance of anesthesia was achieved with additional administration of 70% nitrous oxide (N20) plus 30% oxygen. Recovery times from anesthesia were higher in the remifentanil group than in the halothane group (no significant difference).
Use for Total Intravenous Anesthesia (TIVA) - children aged 6 months to 16 years
Three randomized, open-label studies compared the TIVA technique with the use of remifenanil in pediatric surgery with inhalation anesthesia. The results are summarized in the following table.
In the lower abdominal / urological surgery study comparing remifentanil / propofol with remifentanil / sevoflurane, hypotension occurred significantly more often with remifentanil / sevoflurane, while bradycardia was observed significantly more often with remifentanil / propofol. In ENT surgery comparing remifentanil / propofol with desflurane / nitrous oxide, significantly higher heart rate was observed in subjects who received desflurane / nitrous oxide compared to subjects treated with remifentanil / propofol and with reference to baseline values.
05.2 Pharmacokinetic properties
After administration of recommended doses of remifentanil, the effective biological half-life is 3-10 minutes. clearance mean of remifentanil in healthy juveniles is 40 ml / min / kg, the central volume of distribution is 100 ml / kg and the steady-state volume of distribution is 350 ml / kg. Blood concentrations of remifentanil are proportional to the administered dose over the entire recommended dose range. For each increase from 0.1 mcg / kg / min in the intravenous infusion rate, the blood concentration of remifentanil will increase by 2.5 ng / ml. remifentanil has a high affinity for plasma proteins (approximately 70%).
Metabolism
Remifentanil is an esterase metabolised opioid, sensitive to metabolism by nonspecific blood and tissue esterases. The metabolism of remifentanil results in the formation of an essentially inactive carboxylic acid metabolite (in a potency ratio of 1: 4600 to remifentanil). Studies in humans indicate that the entire pharmacological activity is associated with the parent compound. Therefore, the activity of this metabolite is devoid of any clinical consequence. The terminal half-life of the metabolite in healthy adults is 2 hours. In patients with normal renal function, approximately 95% of remifentanil, as the carboxylic acid metabolite, is recovered in the urine. Remifentanil is not a substrate for plasma cholinesterase.
Passage through the placenta and milk
In a clinical study in humans, mean concentrations of remifentanil in the mother were approximately double those seen in the fetus. In some cases, however, fetal concentrations were similar to those in the mother. The arteriovenous-umbilical ratio of concentration of remifentanil was approximately 30%, suggesting a metabolism of remifentanil in the neonate Remifentanil-related material is excreted in the milk of lactating rats.
Anesthesia in cardiac surgery
There clearance of remifentanil is reduced by approximately 20% during cardiopulmonary bypass in hypothermia (28 ° C). The reduction in body temperature reduces the clearance 3% elimination per degree centigrade.
Kidney failure
Rapid recovery from sedation and analgesia with remifentanil is not affected by renal function.
The pharmacokinetics of remifentanil are not significantly changed in patients with varying degrees of renal insufficiency, even after administration for up to 3 days in the ICU.
In patients with renal insufficiency, the clearance of the carboxylic acid metabolite is reduced. In ICU patients with moderate / severe renal impairment, the concentration of the carboxylic acid metabolite is expected to reach approximately 100 times the steady-state level of remifentanil. Clinical data demonstrate that metabolite accumulation does not result in clinically relevant mc-opioid effects, even after administration of remifentanil by infusion in these patients for up to 3 days. To date, there are data available on the safety and pharmacokinetic profile of the metabolite. following remifentanil infusion for more than 3 days.
There is no evidence that remifentanil is extracted during renal transplant therapy.
The carboxylic acid metabolite is 25-35% extracted during hemodialysis. In patients with anuria, the half-life of the carboxylic acid metabolite is increased to 30 hours.
Hepatic insufficiency
The pharmacokinetic profile of remifentanil is not changed in patients with severe hepatic insufficiency awaiting liver transplantation, nor during the anhepatic phase of liver transplant surgery. Patients with severe hepatic impairment may be slightly more sensitive to the respiratory depressive effects of remifentanil. These patients should be carefully monitored and the remifentanil dose titrated to the individual patient's needs.
Pediatric population
There clearance steady-state mean and volume of distribution of remifentanil were increased in younger children and decreased to values in healthy young adults at 17 years of age. The elimination half-life of remifentanil in neonates is not significantly different from that seen in healthy young people. Changes in the analgesic effect after changes in the remifentanil infusion rate should be rapid and similar to those seen in healthy young people. The pharmacokinetics of the carboxylic acid metabolite in pediatric patients aged 2-17 years are similar to that observed in adults after correction for body weight differences.
Senior citizens
There clearance of remifentanil in elderly patients (over 65 years) is slightly reduced (approximately 25%) compared to that of young patients. The pharmacodynamic activity of remifentanil increases with increasing age. Elderly patients have a remifentanil EC50 for EEG delta wave formation that is 50% lower than that of young people; therefore the starting dose of remifentanil should be reduced by 50% in elderly patients and then carefully titrated according to the patient's individual needs.
05.3 Preclinical safety data
Acute toxicity
Expected signs of mc-opioid intoxication were observed in unventilated mice, rats and dogs after administration of high doses of single-bolus remifentanil intravenously. In these studies, the most sensitive species, the male rat, survived after administration of 5 mg / kg of the drug.
Intracranial haemorrhages in dogs caused by hypoxia were reduced within 14 days of discontinuing remifentanil administration.
Chronic toxicity
Bolus doses of remifentanil, administered to non-ventilated rats and dogs, resulted in respiratory depression in all dose groups and, in dogs, reversible intracranial haemorrhages. Subsequent studies showed that the microhemorrhages were caused by hypoxia and were not specific to remifentanil. In the infusion studies, no cerebral microhemorrhages were observed in non-ventilated rats and dogs as these studies were conducted at doses that did not cause depression. Severe Respiratory: What emerges from preclinical studies is that respiratory depression and associated sequelae are the most likely cause of potentially serious adverse events in humans.
Intrathecal administration of the glycine-only formulation (i.e., without remifentanil) in dogs resulted in agitation, pain, dysfunction and lack of coordination of the hind limbs. These effects are believed to be secondary to the glycine excipient. Due to the improved blood buffering properties, faster dilution and low glycine concentration in the Remifentanil Teva formulation, these observations have no clinical relevance for intravenous administration of Remifentanil Teva. .
Reproductive toxicity studies
Placental transfer studies in rats and rabbits have shown that offspring are exposed to remifentanil and / or its metabolites during the growth and development phase. Remifentanil-related material is excreted in the milk of lactating rats.
Remifentanil reduces fertility in male rats when administered by intravenous injection daily for at least 70 days at a dose of 0.5 mg / kg, or approximately 250 times the maximum recommended human bolus dose of 2 mcg / kg. Fertility of female rats was unaffected at doses up to 1 mg / kg given the drug for at least 15 days prior to mating. No teratogenic effects were observed with remifentanil at doses up to 5 mg / kg in rats and up to 0.8 mg / kg in rabbits. Intravenous administration of remifentanil in late gestational and lactating rats at doses up to 5 mg / kg had no significant effect on the survival, development or reproductive capacity of the F1 generation.
Genotoxicity
Remifentanil did not show positive results in a series of genotoxicity tests in vitro And in vivo, with the exception of the mouse lymphoma tk activity assay in vitro, which gave a positive result with metabolic activation. As the results on mouse lymphoma were not confirmed in further tests in vitro And in vivotreatment with remifentanil is not expected to present a genotoxic risk to patients.
Carcinogenicity
Long-term carcinogenicity studies in animals have not been conducted with remifentanil.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Glycine (E640)
Hydrochloric acid (E507) for pH regulation
Sodium hydroxide (E524) for pH regulation
06.2 Incompatibility
Remifentanil Teva must not be mixed with other medicinal products except those mentioned in section 6.6.
It must not be mixed with Lactated Ringer's for injection or Lactated Ringer's and glucose 50 mg / ml (5%) solution for injection.
Remifentanil Teva must not be mixed with propofol in the same mixed intravenous solution.
For compatibility, when administered into a running intravenous catheter, see section 6.6.
Administration of Remifentanil Teva in the same intravenous line as blood / serum / plasma is not recommended as nonspecific esterase in blood products may result in the hydrolysis of remifentanil to its inactive metabolite.
Remifentanil Teva must not be mixed with other therapeutic agents prior to administration.
06.3 Period of validity
As packaged for sale:
Remifentanil Teva 1 mg: 2 years
Remifentanil Teva 2 mg: 2 years
Remifentanil Teva 5 mg: 2 years
After reconstitution / dilution:
Physico-chemical stability in use has been demonstrated for 24 hours at 25 ° C after initial reconstitution with:
• Water for injections
• Glucose 50 mg / ml (5%) solution for injection
• Glucose 50 mg / ml (5%) solution for injection and sodium chloride 9 mg / ml (0.9%) solution for injection
• Sodium chloride 9 mg / ml (0.9%) solution for injection
• Sodium chloride 4.5 mg / ml (0.45%) solution for injection
• Injectable Lactated Ringer's
• Lactated Ringer's and glucose 50 mg / ml (5%) solution for injection
The chemical-physical stability in use has been demonstrated for 24 hours at 25 ° C after further dilution with:
• Water for injections
• Glucose 50 mg / ml (5%) solution for injection
• Glucose 50 mg / ml (5%) solution for injection and sodium chloride 9 mg / ml (0.9%) solution for injection
• Sodium chloride 9 mg / ml (0.9%) solution for injection
• Sodium chloride 4.5 mg / ml (0.45%) solution for injection.
The chemical-physical stability in use has been demonstrated for 8 hours at 25 ° C after further dilution with:
• Injectable Lactated Ringer's
• Lactated Ringer's and glucose 50 mg / ml (5%) solution for injection
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8 ° C, unless the solution is reconstituted / diluted under aseptic controlled and validated.
Any unused residue must be discarded.
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
For storage conditions of the reconstituted / diluted medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
Remifentanil Teva 1 mg: Type I colorless glass 4 ml vial with bromobutyl rubber stopper and white cap.
Remifentanil Teva 2 mg: 6 ml colorless type I glass vial with bromobutyl rubber stopper and gray cap.
Remifentanil Teva 5 mg: 12.5 ml colorless type I glass vials with bromobutyl rubber stopper and blue cap.
Pack sizes: 1 or 5 vials per pack.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Reconstitution :
Remifentanil Teva must be prepared for intravenous use by adding the appropriate volume (as shown in the table below) of one of the diluents listed below to give a reconstituted solution with a concentration of approximately 1 mg / ml.
Shake until completely dissolved. The reconstituted solution should be clear, colorless and free from visible particles.
Further dilution:
After reconstitution, Remifentanil Teva 1 mg 2 mg 5 mg should not be administered without further dilution at concentrations of 20-250 mcg / ml (50 mcg / ml is the recommended dilution for adults and 20-25 mcg / ml for pediatric population 1 year of age and older) with one of the following intravenous solutions, listed below.
For target-controlled infusion (TCI), the recommended dilution of Remifentanil Teva 20-50 mcg / ml.
The dilution depends on the technical capability of the infusion device and the patient's requirements.
For dilution, one of the following solutions should be used:
• Water for injections
• Glucose 50 mg / ml (5%) solution for injection
• Glucose 50 mg / ml (5%) solution for injection and sodium chloride 9 mg / ml (0.9%) solution for injection
• Sodium chloride 9 mg / ml (0.9%) solution for injection
• Sodium chloride 4.5 mg / ml (0.45%) solution for injection.
When administered via a running intravenous catheter, the following intravenous fluids can be used:
• Injectable Lactated Ringer's
• Lactated Ringer's and glucose 50 mg / ml (5%) solution for injection
Remifentanil Teva is compatible with propofol when administered into a running intravenous catheter.
No other diluents should be used.
The solution should be visually inspected for the presence of particulates prior to administration. The solution should be used if it is clear and free of particles.
Intravenous infusions of remifentanil should preferably be prepared at the time of administration (see section 6.3).
The contents of the vial are for single use only. Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Teva Italia S.r.l. - Piazzale Luigi Cadorna, 4 - 20123 Milan
08.0 MARKETING AUTHORIZATION NUMBER
A.I.C. n. 040266013 - "1 mg powder for concentrate for solution for injection or infusion" 1 glass vial
A.I.C. n. 040266025 - "1 mg powder for concentrate for solution for injection or infusion" 5 glass vials
A.I.C. n. 040266037 - "2 mg powder for concentrate for solution for injection or infusion" 5 glass vials
A.I.C. n. 040266049 - "2 mg powder for concentrate for solution for injection or infusion" 1 glass vial
A.I.C. n. 040266052 - "5 mg powder for concentrate for solution for injection or infusion" 1 glass vial
A.I.C. n. 040266064 - "5 mg powder for concentrate for solution for injection or infusion" 5 glass vials
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
April 27, 2011
10.0 DATE OF REVISION OF THE TEXT
February 2016
