ULTIVA 2 mg POWDER FOR CONCENTRATE FOR INJECTION AND INFUSION SOLUTION

Introduction

Package Leaflet: Information for the User

Ultiva 2 mg powder for concentrate for solution for injection and infusion

Remifentanil

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

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

1. What is Ultiva and what is it used for

Ultiva contains the active substance remifentanil. This belongs to a group of medicines called opioids, which are used to relieve pain. Ultiva differs from other medicines in its group because it has a very rapid onset and very short duration of action.

Ultiva is used for:

• to stop pain before and during an operation
• to stop pain during controlled mechanical ventilation in an Intensive Care Unit (for patients 18 years of age and older).

2. What you need to know before you use Ultiva

Do not use Ultiva

• if you are allergic to remifentanil or any of the other ingredients of this medicine (listed in section 6).
• if you are allergic to fentanyl analogues (pain-relieving medicines similar to fentanyl and belonging to the class of medicines known as opioids)
• as an injection into the spinal canal
• as the only medicine to start anesthesia.

If you are not sure if any of the above applies to you, talk to your doctor, nurse or pharmacist before you are given Ultiva.

Be careful with Ultiva if:

• you are allergic to any other opioid medicine, such as morphine or codeine.
• you have lung problems (you may be more sensitive to having difficulty breathing)
• you are over 65 years old, weak or have a low blood volume and/or low blood pressure (you are more sensitive to suffering cardiac disorders).

If you are not sure if any of the above applies to you, talk to your doctor or nurse before you are given Ultiva.

Talk to your doctor before you start taking remifentanil if:

• You or someone in your family has ever abused or been dependent on alcohol, prescription medicines or illegal drugs ("addiction").
• You are a smoker.
• You have ever had mood problems (depression, anxiety or personality disorder) or have been treated by a psychiatrist for other mental illnesses.

This medicine contains remifentanil which is an opioid. Repeated use of opioids can make the medicine lose its effectiveness (you get used to its effect). It can also cause dependence and abuse, which can lead to a potentially fatal overdose. If you are concerned that you may become dependent on Ultiva, it is important that you talk to your doctor.

Occasionally, withdrawal reactions (e.g. rapid heartbeat, high blood pressure and agitation) have been reported after sudden discontinuation of treatment with this medicine, especially when treatment was administered for more than 3 days (see also section 4. Possible side effects). If you experience these symptoms, your doctor may restart treatment with the medicine and gradually reduce the dose.

Using Ultiva with other medicines

Tell your doctor if you are taking, have recently taken or might take any other medicines. This includes herbal medicines and other medicines that you buy without a prescription. In particular, tell your doctor or pharmacist if you are taking:

• medicines for your heart or blood pressure, such as beta-blockers or calcium channel blockers.
• medicines to treat depression, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs) and monoamine oxidase inhibitors (MAOIs). It is not recommended to use these medicines at the same time as Ultiva, as they may increase the risk of serotonin syndrome, a potentially fatal disease.

Taking Ultiva with sedative medicines, such as benzodiazepines or other related medicines, increases the risk of drowsiness, difficulty breathing (respiratory depression), coma and can put the patient's life at risk. Due to this, concomitant use with these medicines should only be considered when other treatment options are not possible. Concomitant use of opioids and other medicines used to treat epilepsy, nerve pain or anxiety (gabapentin and pregabalin) increases the risk of opioid overdose and respiratory depression, and can be potentially fatal.

However, if your doctor prescribes Ultiva with sedative medicines, they will limit the dose and duration of treatment.

Tell your doctor about all sedative medicines you are taking and closely follow the dose recommendation provided by your doctor. It may be helpful for you to inform a family member or close friend of the signs and symptoms indicated above. Contact your doctor when you experience these symptoms.

Taking Ultiva with alcohol

After receiving Ultiva, you should not drink alcohol until you have fully recovered.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

Your doctor will weigh the benefit for you against the risk to your baby of taking this medicine while pregnant.

If you receive this medicine during childbirth or shortly before delivery, it may affect your baby's breathing. You and your baby will be monitored for signs of excessive sleepiness or difficulty breathing.

You should stop breastfeeding your baby for 24 hours after receiving this medicine. If you express breast milk during this period, you should discard it and not give it to your baby.

Driving and using machines

Do not drive or operate tools or machines after receiving Ultiva, as this medicine may affect your reaction ability. Your doctor will tell you how long you should wait before driving or using machines.

Ultiva contains sodium

This medicine contains less than 1 mmol (23 mg) of sodium per vial; this is essentially "sodium-free".

3. How to use Ultiva

You should never self-administer this medicine. This medicine will always be administered by qualified personnel.

Ultiva can be administered:

• as a single injection into a vein
• as a continuous infusion into a vein. This is when the medicine is administered slowly over a longer period of time.

The way you are given the medicine and the dose you receive will depend on:

• the procedure or treatment you are having in the Intensive Care Unit
• how much pain you have.

The dose varies from patient to patient. No dose adjustment is required in patients with kidney or liver problems.

After your operation

Tell your doctor or nurse if you have pain. If you have pain after your procedure, you may be given other pain-relieving medicines.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Allergic reactions including anaphylaxis: These are rare (may affect up to 1 in 1,000 people who use Ultiva). The signs include:

• blistering rash and itching (hives)
• swelling of the face or mouth (angioedema) causing difficulty breathing
• collapse.

Severe allergic reactions can develop into a life-threatening anaphylactic shock; Frequency not known (cannot be estimated from the available data), which include worsening of allergy symptoms, severe drop in blood pressure, rapid heartbeat or fainting.

If you experience any of these symptoms, contact a doctor urgently.

Very common side effects

May affect more than 1 in 10 people

• muscle stiffness (muscle rigidity)
• low blood pressure (hypotension)
• nausea or vomiting.

Common side effects

May affect up to 1 in 10 people

• slow heart rate (bradycardia)
• shallow breathing (respiratory depression)
• temporary stop in breathing (apnea)
• itching
• coughing.

Uncommon side effects

May affect up to 1 in 100 people

• decrease in the amount of oxygen in the blood (hypoxia)
• constipation.

Rare side effects

May affect up to 1 in 1,000 people

• slow heart rate (bradycardia) followed by a lack of heartbeat (asystole/cardiac arrest) in patients receiving Ultiva with one or more anesthetics.

Side effects with frequency not known

Cannot be estimated from the available data

• physical need for Ultiva (drug dependence) or need to increase the dose over time to achieve the same effect (drug tolerance)
• seizures
• type of irregular heartbeat (atrioventricular block)
• irregular heartbeat (arrhythmia)
• Withdrawal syndrome (may manifest with the appearance of the following side effects: increased heart rate, high blood pressure, feeling of agitation or restlessness, nausea, vomiting, diarrhea, anxiety, chills, tremors and sweating)

Other side effects that you may experience after the procedure

Common side effects

• shivering
• high blood pressure (hypertension).

Uncommon side effects

• pain.

Rare side effects

• feeling very relaxed or drowsy.

If you experience any of these side effects, tell your doctor or nurse if you think they are serious or bothersome, or if you notice any side effects not listed in this leaflet.

Reporting of side effects

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storing Ultiva

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the vial and on the carton after "EXP". The expiry date is the last day of the month shown.

Do not store above 25°C.

Once reconstituted, Ultiva should be used immediately. Any unused diluted solution should be discarded. Medicines should not be disposed of via wastewater or household waste. Your doctor or nurse will dispose of any medicine that you no longer need. This will help protect the environment.

Store in the original package with this leaflet.

6. Contents of the pack and other information

What Ultiva contains per vial

• The active substance is remifentanil (hydrochloride).
• The other ingredients are: glycine, hydrochloric acid* and sodium hydroxide* q.s.
• may be used for pH adjustment if necessary

After reconstitution, each ml contains 1 mg of remifentanil.

Appearance and packaging

White to off-white lyophilized powder, sterile, non-pyrogenic, preservative-free, for concentrate for solution for injection and infusion, in a 3 ml glass vial.

Before administration, the powder must be mixed with a suitable solvent (see information intended for healthcare professionalsfor more details). Once mixed, a clear and colorless solution will be formed. Each pack contains 5 vials.

Marketing authorisation holder and manufacturer

Marketing authorisation holder

Aspen Pharma Trading Limited

3016 Lake Drive,

Citywest Business Campus,

Dublin 24, Ireland

Tel: +34 952 010 137

Local representative:

ASPEN PHARMACARE ESPAÑA, S.L.

Avenida Diagonal, 512,

Planta Interior 1, Oficina 4,

Barcelona, 08006, Spain

Manufacturer

GlaxoSmithKline Manufacturing S.p.A.

Strada Provinciale Asolana 90

43056 - San Polo di Torrile - Parma

Italy

Aspen Pharma Ireland Limited

3016 Lake Drive Citywest Business Campus

Dublin 24

Ireland

Avara Liscate Pharmaceutical Services S.p.A.

Via Fosse Ardeatine, 2

20050 Liscate (MI)

Italy

This medicine is authorised in the Member States of the European Economic Area under the following names:

Ultiva:Austria, Belgium, Denmark, Finland, France, Germany, Greece, Italy, Luxembourg, Netherlands, Portugal and Spain.

Date of last revision of this leaflet:06/2024

Detailed information on this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es-----------------------------------------------------------------------------------------------------------------------

This information is intended only for healthcare professionals:

For detailed information, please refer to the Summary of Product Characteristics of Ultiva.

Posology and method of administration

Ultiva should only be administered in fully equipped facilities for the control and maintenance of respiratory and cardiovascular function, and by personnel specifically trained in the use of anesthetic medicines and in the recognition and management of the expected side effects of potent opioids, including respiratory and cardiac resuscitation. Such training should include the establishment and maintenance of a patent airway and assisted ventilation.

The continuous infusion of Ultiva will be performed using a calibrated infusion device within a rapid intravenous administration route or through an intravenous administration route for effect. This infusion route should be connected to or be near the venous cannula, as well as be primed, to minimize the potential dead space (for more information see Special precautions for disposal and other handlingand section 6.6 of the Summary of Product Characteristics, including tables with examples of infusion rates per body weight to help adjust the dose of Ultiva based on the anesthesia required by the patient).

Ultiva can also be administered through target-controlled infusion (TCI) using an authorized infusion device that incorporates the Minto pharmacokinetic model with covariances based on age and lean body mass (LBM) (Anesthesiology1997; 86: 10 – 23).

It should be ensured that there is no obstruction or disconnection of the infusion routes and that they are properly cleaned to eliminate any residual Ultiva after use (see Special warnings and precautions for use).

Ultiva is administered only by intravenous route, it should not be administered by epidural or intrathecal injection (see Contraindications).

Dilution

Ultiva can be further diluted after reconstitution. For instructions on diluting the medicine before administration, see Special precautions for disposal and other handling.

In the case of manually controlled infusions, it is recommended to dilute Ultiva to concentrations of 20 to 250 micrograms/ml (50 micrograms/ml is the recommended dilution for adults and 20 to 25 micrograms/ml for pediatric population of 1 year of age and older).

The recommended dilution of Ultiva in the case of TCI is 20 to 50 micrograms/ml.

General anesthesia

Administration of Ultiva should be individualized based on the patient's response.

Adults

Administration by manual controlled infusion

Table 1 summarizes the initial injection/infusion rates and dose interval:

Table 1. Dosing Guide for Adults

When Ultiva is administered as a slow bolus injection, administration should not be less than 30 seconds.

At the recommended doses, remifentanil significantly reduces the amount of hypnotic required for anesthesia maintenance. Consequently, the administration of isoflurane and propofol should be as previously recommended to avoid an increase in hemodynamic effects such as hypotension and bradycardia (see Concomitant Medicationin this section).

No data are available on the recommended dosing for concurrent use of other hypnotics different from those indicated in the table with remifentanil.

Anesthesia Induction:Ultiva should be administered with the standard dose of a hypnotic drug such as propofol, thiopental, or isoflurane for anesthesia induction. Ultiva may be administered at an infusion rate of 0.5 to 1 microgram/kg/min with or without an initial slow bolus injection of 1 microgram/kg administered in no less than 30 seconds. If endotracheal intubation is to be performed more than 8 to 10 minutes after the start of Ultiva infusion, a bolus injection is not necessary.

Maintenance of Anesthesia in Ventilated Patients:After endotracheal intubation, the Ultiva infusion rate should be decreased according to the anesthetic technique, as indicated in Table 1. Due to the rapid onset and short duration of action of Ultiva, the infusion rate during anesthesia can be titrated upward in increments of 25% to 100% or downward in decrements of 25% to 50% every 2 to 5 minutes until the desired level of μ-opioid receptor effect is achieved. In response to light anesthesia, supplemental slow bolus injections can be administered every 2 to 5 minutes.

Anesthesia in Patients Undergoing Spontaneous Ventilation with a Secured Airway (e.g., Laryngeal Mask Anesthesia): Respiratory depression may occur in patients undergoing anesthesia with spontaneous ventilation with a secured airway. Special attention is required to adjust the dose according to patient requirements, and supportive ventilation may be necessary. The recommended initial infusion rate for supplemental analgesia in patients undergoing anesthesia with spontaneous ventilation is 0.04 micrograms/kg/min, which can be adjusted to achieve the desired effect. Infusion rates ranging from 0.025 to 0.1 micrograms/kg/min have been studied.

Bolus injections of Ultiva are not recommended for patients undergoing anesthesia with spontaneous ventilation.

Ultiva should not be used as an analgesic in procedures where patients remain conscious or do not receive airway support during the procedure.

Concomitant Medication: Remifentanil decreases the amounts or doses of inhaled anesthetic drugs, hypnotics, and benzodiazepines required for anesthesia (see Interaction with Other Medicinal Products and Other Forms of Interaction).

The doses of the following anesthetic drugs used in anesthesia - isoflurane, thiopental, propofol, and temazepam - have been reduced by up to 75% when used concurrently with remifentanil.

Recommendations for Discontinuation/Continuation in the Immediate Postoperative Period: Due to the very rapid offset of action of Ultiva, within 5 to 10 minutes, there will be no residual opioid activity after discontinuation of administration. In patients undergoing surgical procedures where postoperative pain is anticipated, analgesics should be administered before discontinuing the administration of Ultiva. Sufficient time should be allowed for the maximum effect of the longest-acting analgesic to be attained. The choice of analgesic should be appropriate for the surgical procedure and the level of postoperative care.

In the event that the effect of the longest-acting analgesic has not been established before the end of the surgical procedure, it may be necessary to continue administering Ultiva to maintain analgesia during the immediate postoperative period until the longest-acting analgesic has reached its maximum effect.

In the Intensive Care Unit section of this insert, instructions are provided on how to provide analgesia and sedation to mechanically ventilated patients in Intensive Care Units.

In patients with spontaneous ventilation, the Ultiva infusion rate should be initially reduced to 0.1 micrograms/kg/min. The infusion rate can then be increased or decreased by no more than 0.025 micrograms/kg/min every 5 minutes to balance the level of analgesia and the patient's respiratory rate. Ultiva should only be used in a well-equipped setting for monitoring and maintaining respiratory and cardiovascular function, under the close supervision of personnel trained in the recognition and management of the respiratory effects of potent opioids.

Bolus injections of Ultiva are not recommended for the treatment of pain during the postoperative period in patients with spontaneous ventilation.

Target-Controlled Infusion (TCI)

Induction and Maintenance of Anesthesia in Ventilated Patients: Ultiva TCI should be used in conjunction with intravenous or inhaled hypnotic agents during induction and maintenance of anesthesia in adult patients with ventilation (see Table 1). In conjunction with these agents, adequate analgesia for anesthesia induction can be achieved, and surgical procedures can generally be performed with remifentanil blood concentrations of 3 to 8 nanograms/ml. The adjustment of the Ultiva dose should be based on individual patient response. For surgical procedures involving highly stimulated areas, blood concentrations up to 15 nanograms/ml may be required.

Remifentanil, administered at the doses indicated above, significantly reduces the amount of hypnotic agent necessary to maintain anesthesia. Therefore, it is recommended to administer the indicated amounts of isoflurane and propofol to avoid an increase in hemodynamic effects such as hypotension and bradycardia (see Table 1 and the information on Concomitant Medicationin this section).

Table 11 in section 6.6 of the Summary of Product Characteristics provides information on the remifentanil blood concentrations achieved with manually controlled infusion.

As there are insufficient data, the use of Ultiva via TCI for anesthesia with spontaneous ventilation is not recommended.

Recommendations for Discontinuation/Continuation in the Immediate Postoperative Period: At the end of the surgical procedure, when the TCI infusion is stopped or the achieved concentration is reduced, spontaneous respiration is likely to occur within the range of remifentanil concentrations of 1 to 2 nanograms/ml. As with manually controlled infusion, postoperative analgesia should be administered with longer-acting analgesics before the end of the surgical procedure (see the recommendations for discontinuation in the case of manually controlled infusion in this section).

As there are insufficient data, the use of Ultiva via TCI for postoperative analgesia is not recommended.

Pediatric Population (1 to 12 years)

The concomitant administration of Ultiva with an intravenous anesthetic agent for induction of anesthesia has not been studied in detail, and therefore, its use is not recommended. Ultiva TCI has not been studied in the pediatric population, and therefore, its administration via TCI in these patients is not recommended. The following doses of Ultiva are recommended for the maintenance of anesthesia:

Table 2. Dosing Guidelines for Pediatric Population (1-12 years)

*administered concomitantly with nitrous oxide/oxygen in a 2:1 ratio

When Ultiva is administered as a bolus, it should be given over no less than 30 seconds. The surgical procedure should not begin until at least 5 minutes after the start of the Ultiva infusion, provided that a bolus dose is not administered simultaneously. For the administration of Ultiva with 70% nitrous oxide, usual maintenance infusion rates should range from 0.4 to 3 micrograms/kg/min, and although not specifically studied, data in adults suggest that 0.4 micrograms/kg/min is an appropriate starting rate. Pediatric patients should be monitored, and the dose adjusted based on the depth of analgesia considered appropriate for each surgical procedure.

Concomitant Medication:At the recommended doses, remifentanil significantly reduces the amount of hypnotic required for anesthesia maintenance. Consequently, isoflurane, halothane, and sevoflurane should be administered as recommended in the table to avoid an increase in hemodynamic effects such as hypotension and bradycardia. No data are available on the concurrent use of remifentanil with other hypnotic agents different from those indicated in the table, which would allow for dosing recommendations (see Adults - Concomitant Medicationin this section).

Recommendations for Patient Management in the Immediate Postoperative Period

Establishment of Alternative Analgesia Prior to Discontinuation of Ultiva: Due to the very rapid offset of action of Ultiva, there will be no residual opioid activity within 5 to 10 minutes after discontinuation of administration. In patients undergoing surgical procedures where postoperative pain is anticipated, analgesics should be administered before discontinuing the administration of Ultiva. Sufficient time should be allowed for the maximum effect of the longest-acting analgesic to be attained. The choice, dose, and timing of administration of the agent(s) should be planned in advance and adjusted individually to be suitable for both the surgical procedure and the level of postoperative care (see Special Warnings and Precautions for Use).

Neonates/Infants (less than 1 year of age)

There is limited experience in clinical trials with remifentanil in neonates and infants (children less than 1 year of age; see section 5.1 of the Summary of Product Characteristics). The pharmacokinetic profile of remifentanil in neonates/infants (less than 1 year of age) is comparable to that observed in adults after adjustment for body weight differences (see section 5.2 of the Summary of Product Characteristics). However, as there are insufficient clinical data, the administration of Ultiva is not recommended in this age group.

Use in Total Intravenous Anesthesia (TIVA): There is limited experience in clinical trials with remifentanil in total intravenous anesthesia in infants (see section 5.1 of the Summary of Product Characteristics), but there are insufficient clinical data to make dosing recommendations.

Cardiac Anesthesia

Administration via manually controlled infusion

Table 3. Dosage guidelines for cardiac anesthesia

Induction period of anesthesia: After administration of the hypnotic to achieve loss of consciousness, Ultiva should be administered with an initial infusion rate of 1 microgram/kg/min. In patients undergoing cardiac surgery, the use of bolus injections of Ultiva during induction is not recommended. Endotracheal intubation should not occur until at least 5 minutes after the start of infusion.

Maintenance period of anesthesia: After endotracheal intubation, the infusion rate of Ultiva should be adjusted according to the patient's needs. If necessary, supplemental bolus doses can also be administered. High-risk cardiac patients, such as those with poor ventricular function or those undergoing valvular surgery, should receive a maximum bolus dose of 0.5 micrograms/kg. These dosage recommendations are also applicable during hypothermic cardiopulmonary bypass (see section 5.2 of the Technical Sheet).

Concomitant medication: At the previously recommended doses, remifentanil significantly reduces the amount of hypnotic drug needed to maintain anesthesia. Therefore, isoflurane and propofol should be administered at the previously recommended doses to avoid an increase in hemodynamic effects such as hypotension and bradycardia. There is no data to make recommendations on the simultaneous use of remifentanil and other hypnotic drugs different from those indicated in the table (see Adults - Concomitant medicationin this section).

Recommendations for postoperative patient management

Continuation of Ultiva administration in the postoperative period to achieve analgesia prior to extubation: It is recommended that the infusion of Ultiva be maintained at the final intraoperative rate during the transfer of patients to the postoperative care area. After arrival in this area, the patient's level of analgesia and sedation should be closely monitored, and the infusion rate of Ultiva should be adjusted according to the patient's requirements (see the Use in Intensive Care Unitssection of this section for more information on patient management in Intensive Care Units).

Establishment of alternative analgesia prior to interruption of Ultiva: Due to the very rapid offset of action of Ultiva, there will be no residual opioid activity within 5 to 10 minutes after the end of administration. Prior to the interruption of Ultiva, patients should be administered alternative analgesic and sedative agents, with sufficient time to allow for the establishment of the therapeutic effects of these agents. It is recommended that the choice, dose, and time of administration of the drug(s) be planned before weaning the patient off the ventilator.

Recommendations for the interruption of Ultiva: Due to the very rapid offset of action of Ultiva, cases of hypertension, shivering, and pain have been reported in patients after cardiac surgery immediately after the interruption of Ultiva (see section 4 Possible adverse effectsof the prospectus). To minimize the risk of their appearance, adequate alternative analgesia should be established (as previously indicated) before the interruption of the Ultiva infusion. The infusion rate should be reduced by 25% at intervals of at least 10 minutes until the infusion of Ultiva is interrupted.

During weaning from the ventilator, the infusion of Ultiva should not be increased, and only downward adjustments of the dose should be made, complemented if necessary with alternative analgesics. Hemodynamic changes such as hypertension and tachycardia should be treated, if necessary, with alternative agents.

When other opioid agents are administered as part of the regimen for transitioning to alternative analgesia, the patient should be carefully monitored. The benefit of achieving adequate postoperative analgesia should be weighed against the potential risk of respiratory depression due to these drugs.

Administration via target-controlled infusion (TCI)

Induction and maintenance of anesthesia: Ultiva TCI should be used in association with an intravenous or inhalational hypnotic agent during the induction and maintenance of anesthesia in adult patients with ventilation (see Table 3). In association with these agents, a level of analgesia adequate for cardiac surgery is generally achieved at the upper limit of the range of proposed remifentanil blood concentrations for general surgery procedures. After titration of remifentanil according to the individual response of each patient, blood concentrations as high as 20 nanograms/ml have been used in clinical studies. At the recommended doses, remifentanil significantly reduces the amount of hypnotic agent needed to maintain anesthesia. Therefore, isoflurane and propofol should be administered as previously indicated to avoid an increase in hemodynamic effects such as hypotension and bradycardia (see Table 3 and Concomitant medicationin this section).

In the Table 11 of section 6.6 of the Technical Sheet, the remifentanil blood concentrations achieved by manually controlled infusions are provided for information.

Recommendations for interruption/continuation in the immediate postoperative period: at the end of the procedure, when the TCI infusion is stopped or the achieved concentration is reduced, spontaneous breathing is likely to occur within the range of remifentanil concentrations of around 2 nanograms/ml. As with manually controlled infusion, postoperative analgesia should be administered with longer-acting analgesics before the end of the procedure (see the recommendations for interruption in the case of administration by manually controlled infusion in this section).

It is not recommended to use Ultiva via TCI for postoperative analgesia, as there is insufficient data.

Pediatric patients (1 to 12 years old)

There is insufficient data to make a dosage recommendation for use during cardiac surgery.

Use in Intensive Care Units

Adults

Ultiva can be used to provide analgesia to patients with mechanical ventilation who are admitted to Intensive Care Units. Sedative substances should be administered when necessary.

The efficacy and safety of Ultiva in Intensive Care Unit patients with mechanical ventilation have been established in well-controlled clinical trials of up to three days in duration (see Patients with renal insufficiency in Intensive Care Unitsin this section and section 5.2 of the Technical Sheet). Therefore, it is not recommended to use Ultiva for more than 3 days of treatment.

The use of Ultiva via TCI has not been studied in Intensive Care Unit patients, so it is not recommended to administer Ultiva via TCI in these patients.

In adults, it is recommended that the administration of Ultiva be started at an infusion rate of 0.1 micrograms/kg/min (6 micrograms/kg/h) to 0.15 micrograms/kg/min (9 micrograms/kg/h). The infusion rate should be adjusted with increments of 0.025 micrograms/kg/min (1.5 micrograms/kg/h) to achieve the desired level of analgesia. A period of at least 5 minutes should be allowed between dose adjustments. The patient should be regularly evaluated, and the infusion rate of Ultiva should be adjusted according to the needs. If an infusion rate of 0.2 micrograms/kg/min (12 micrograms/kg/h) is reached and sedation is required, it is recommended that the administration of a suitable sedative drug be started (see the information included below). The dose of the sedative should be adjusted to achieve the desired level of sedation. Additional increments of 0.025 micrograms/kg/min (1.5 micrograms/kg/h) can be made in the infusion rate of Ultiva if additional analgesia is required.

Table 4 summarizes the initial infusion rates and usual dose ranges for providing analgesia to patients in Intensive Care Units.

Table 4 Dosage guidelines for Ultiva in Intensive Care Units

In Intensive Care Units, it is not recommended to administer Ultiva in bolus.

The use of Ultiva will reduce the dose of any sedative drug administered concomitantly. Table 5 provides the usual initial doses for sedative drugs, if their administration is necessary.

Table 5 Recommended initial dose for sedative drugs, if necessary:

To allow for separate adjustment of the doses of the different drugs, sedatives should not be prepared as a mixture in the same infusion bag.

Additional analgesia for ventilated patients undergoing stimulation procedures: It may be necessary to increase the existing infusion rate of Ultiva to provide additional analgesic coverage to ventilated patients who are undergoing stimulation and/or painful procedures such as endotracheal aspiration, wound care, and physiotherapy. It is recommended that, for at least 5 minutes before starting the stimulation procedure, the infusion rate of Ultiva be maintained at a rate of at least 0.1 micrograms/kg/min (6 micrograms/kg/h). The dose can be adjusted thereafter, every 2 to 5 minutes, in increments of 25% to 50%, anticipating or in response to requirements for additional analgesia. During stimulation procedures, a mean infusion rate of 0.25 micrograms/kg/min (15 micrograms/kg/h) has been used, and up to 0.74 micrograms/kg/min (45 micrograms/kg/h) to provide additional anesthesia.

Establishment of alternative analgesia before interruption of Ultiva: Due to the very rapid offset of action of Ultiva, there will be no residual opioid activity within 5 to 10 minutes after the end of administration, regardless of the duration of infusion. After administration of Ultiva, the possibility of tolerance, hyperalgesia, and hemodynamic changes associated with its use in the intensive care unit should be considered (see section 4.4 Special warnings and precautions for use). Therefore, before interrupting the administration of Ultiva, patients should receive alternative analgesic and sedative agents to prevent hyperalgesia and associated hemodynamic changes. These drugs should be administered with sufficient time to allow for the establishment of their therapeutic effects. Among the existing analgesic options are long-acting analgesic drugs for oral, intravenous, or regional administration, controlled by nurses or patients. These techniques should always be adjusted to the individual needs of the patients as the infusion of Ultiva is reduced. It is recommended that the choice, dose, and time of administration of the drug(s) be planned before interrupting the administration of Ultiva.

There is a possibility that tolerance may develop over time during prolonged administration of μ-opioid receptor agonists.

Recommendations for extubation and interruption of Ultiva administration: To ensure a gradual transition from the Ultiva regimen, it is recommended that the infusion rate of Ultiva be gradually adjusted to 0.1 micrograms/kg/min (6 micrograms/kg/h) over a period of up to 1 hour before extubation.

After extubation, the infusion rate should be reduced by 25% at intervals of at least 10 minutes until the infusion of Ultiva is stopped. During weaning from the ventilator, the infusion of Ultiva should not be increased, and only downward adjustments of the dose should be made, complemented if necessary with alternative analgesics.

After interruption of Ultiva administration, the IV cannula should be flushed or removed to avoid subsequent inadvertent administration of the drug.

When opioid drugs are administered as part of the regimen for transitioning to alternative analgesia, the patient should be carefully monitored. The benefit of providing adequate analgesia should always be weighed against the potential risk of respiratory depression after administration of these agents.

Pediatric patients in Intensive Care Units

There is no data on the use in the pediatric population.

Patients with renal insufficiency in Intensive Care Units

No dose adjustments are necessary when administering Ultiva to patients with renal insufficiency, including those undergoing dialysis. However, the clearance of the carboxylic acid metabolite is reduced in patients with renal insufficiency (see section 5.2 of the Technical Sheet).

Special populations

Elderly patients (over 65 years old)

General anesthesia: The initial dose of remifentanil administered to patients over 65 years old should be half the recommended dose for adults, and subsequent dosing should be based on the individual needs of the patient, as this population of patients has shown increased sensitivity to the pharmacological 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 Ultiva, the initial concentration to be achieved when administering Ultiva via TCI to this population should be 1.5 to 4 nanograms/ml, with subsequent titration based on the response.

Cardiac anesthesia: No reduction in the initial dose is necessary (see Cardiac anesthesiasection).

Intensive Care: No reduction in the initial dose is necessary (see Use in Intensive Care Unitsin this section).

Obese patients

It is recommended that the dosage of Ultiva administered via manually controlled infusion in obese patients be reduced and based on the ideal body weight, as the clearance and volume of distribution of remifentanil are better correlated with the ideal body weight than with the actual body weight.

Using the lean body mass calculation in the Minto model, it is possible that the lean body mass is being underestimated in female patients with a body mass index (BMI) greater than 35 kg/m2 and in male patients with a BMI greater than 40 kg/m2. To avoid underdosing in these patients, it is recommended to carefully titrate remifentanil administered via TCI based on the individual response of each patient.

Renal insufficiency

Based on the investigations carried out to date, no dose adjustment is necessary in patients with renal function impairment, including patients in Intensive Care Units.

Hepatic insufficiency

Studies conducted with a limited number of patients with hepatic function impairment do not justify special dosage recommendations. However, patients with severe hepatic insufficiency may be slightly more sensitive to the respiratory depressant effects of remifentanil (see Special warnings and precautions for use). These patients should be closely monitored, and the dose of remifentanil should be graduated according to the individual needs of the patient.

Neurosurgery

Limited clinical experience with patients undergoing neurosurgery has shown that no special dosage recommendations are required.

Patients in ASA groups III/IV

General anesthesia: As the hemodynamic effects of potent opioids are expected to be more pronounced in patients in ASA groups III/IV, caution should be exercised when administering Ultiva to these patients. It is recommended that the initial dose be reduced and subsequent adjustments be made. There is insufficient data in the pediatric population to establish dosage recommendations.

In the case of administration via TCI, a lower initial concentration of 1.5 to 4 nanograms/ml should be used in patients belonging to ASA groups III and IV, and subsequent titration should be based on the response.

Cardiac anesthesia: No reduction in the initial dose is necessary (see Cardiac anesthesiasection).

Contraindications

As Ultiva contains glycine, its administration via epidural or intrathecal injection is contraindicated (see section 5.3 of the Technical Sheet).

Ultiva is contraindicated in patients with hypersensitivity to the active substance or to other opioids.

Rapid reversal of action/Transition to alternative analgesia

Due to the very rapid reversal of action of Ultiva, there will be no residual opioid activity within 5-10 minutes after discontinuation of Ultiva administration. In those patients undergoing surgical interventions where postoperative pain is anticipated, analgesics should be administered before discontinuing Ultiva administration. When used in Intensive Care Units (see section 4.2 Posology and method of administration), the possibility of tolerance, hyperalgesia, and hemodynamic changes associated with it should be taken into account. Before discontinuing treatment with Ultiva, alternative sedative and analgesic substances should be administered to patients. Sufficient time should be allowed to elapse for the therapeutic effect of the longer-acting analgesic to be attained. The choice, dose, and time of administration of the agent(s) should be planned in advance and adjusted individually to be suitable for both the surgical procedure to which the patient will be subjected and the level of postoperative care anticipated. When other opioid agents are administered as part of the transition regimen to alternative analgesia, the benefit of providing adequate postoperative analgesia should be weighed against the potential risk of respiratory depression due to these drugs.

Risk of concomitant use of sedative medications such as benzodiazepines or other related medications

The concomitant use of Ultiva and sedative medications, such as benzodiazepines or other related medications, may cause sedation, respiratory depression, coma, and death. Due to these risks, concomitant prescription with these medications should be reserved for patients without alternative treatment options. If the decision is made to prescribe Ultiva concomitantly with these medications, the effective lowest dose should be used, for the shortest possible time.

Patients should be closely monitored to detect signs and symptoms of respiratory depression and sedation. In this regard, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see Interaction with other medicinal products and other forms of interaction)

Discontinuation of treatment and withdrawal syndrome

Repeated administration at short intervals during prolonged periods may lead to the development of a withdrawal syndrome after discontinuation of treatment. After withdrawal of remifentanil treatment, it has been reported with low frequency of symptoms such as tachycardia, hypertension, and agitation, particularly after abrupt withdrawal after prolonged administration of more than 3 days. When they occur, reintroduction and gradual reduction of perfusion have been beneficial. The use of Ultiva is not recommended in patients with intensive care with mechanical ventilation for treatment lasting more than 3 days.

Muscle rigidity - prevention and management

At recommended doses, muscle rigidity may occur. As with other opioids, the incidence of muscle rigidity is related to the dose and speed of administration. Therefore, slow bolus injections should be administered in no less than 30 seconds.

Remifentanil-induced muscle rigidity should be treated in the context of the patient's clinical condition with adequate supportive measures. Excessive muscle rigidity that occurs during the induction of anesthesia should be treated by administering a neuromuscular blocking agent and/or additional hypnotics. Muscle rigidity observed during the use of remifentanil as an analgesic may be treated by interrupting or decreasing the rate of remifentanil administration. The resolution of muscle rigidity after discontinuation of remifentanil perfusion occurs within minutes. Alternatively, an opioid antagonist may be administered, however, this may cancel or attenuate the analgesic effect of remifentanil.

Respiratory depression - prevention and management

As with all potent opioid analgesics, profound analgesia is accompanied by significant respiratory depression. Consequently, remifentanil should only be used in areas equipped with facilities for monitoring and treating respiratory depression. Special attention should be paid to patients with respiratory dysfunction. The onset of respiratory depression should be treated appropriately, including a reduction of up to 50% of the perfusion rate or temporary interruption of perfusion. Unlike other fentanyl analogs, remifentanil has not been shown to cause recurrent respiratory depression, even after prolonged administration. However, since many factors can affect postoperative recovery, it is essential to ensure that a state of full consciousness and adequate spontaneous ventilation is achieved before the patient leaves the recovery area.

Cardiovascular effects

The risk of cardiovascular effects such as hypotension and bradycardia, which very rarely lead to asystole/cardiac arrest (see section 4 of the prospectus and Interaction with other medicinal products and other forms of interaction), can be reduced by slowing the rate of Ultiva perfusion or the doses of anesthetics administered concurrently, or by administering intravenous fluids, vasopressor drugs, or anticholinergics, as convenient.

Debilitated patients, those with hypovolemia, hypotensive patients, and the elderly may be more sensitive to the cardiovascular effects of remifentanil.

Inadvertent administration

In the dead space of the intravenous administration route and/or in the cannula, there may be sufficient amounts of Ultiva to cause respiratory depression, apnea, and/or muscle rigidity if the line is flushed with intravenous fluids or other medications. This can be avoided by administering Ultiva in a rapid intravenous administration route or through an intravenous administration route that is removed when Ultiva administration is discontinued.

Newborns/infants

There are limited data available on the use in newborns/infants under 1 year of age (see Posology and method of administration- Newborns/infants (under 1 year of age)and section 5.1 of the Summary of Product Characteristics).

Tolerance and opioid use disorder (abuse and dependence)

Repeated administration of opioids may induce tolerance, physical and psychological dependence, and opioid use disorder. The intentional abuse or misuse of opioids may cause overdose and/or death. The risk of developing opioid use disorder is greater in patients with personal or family history (parents or siblings) of substance use disorders (including alcohol use disorder), in smokers, or in patients with a personal history of other mental health disorders (e.g., major depression, anxiety, or personality disorders).

Ultiva contains sodium

This medicinal product contains less than 1 mmol of sodium (23 mg) per vial; i.e., it is essentially “sodium-free”.

Interaction with other medicinal products and other forms of interaction

Remifentanil is not metabolized by plasma cholinesterase, so interactions with drugs that are metabolized by this enzyme are not anticipated.

As with other opioid drugs, remifentanil, administered by manually controlled infusion or by Target-Controlled Infusion (TCI), reduces the doses of inhaled or intravenous anesthetics as well as benzodiazepines required for anesthesia (see Posology and method of administration). If the doses of centrally acting depressant drugs administered concomitantly are not reduced, patients may experience an increased incidence of adverse reactions associated with the use of these drugs.

Sedative medications such as benzodiazepines or other related medications: the concomitant use of opioids with sedative medications such as benzodiazepines or other related medications increases the risk of sedation, respiratory depression, coma, and death due to the additive central nervous system depressant effect. The dose and duration of concomitant treatment with Ultiva and these medications should be limited (see Special warnings and precautions for use). The concomitant use of opioids and gabapentinoids (gabapentin and pregabalin) increases the risk of opioid overdose, respiratory depression, and death.

The concomitant administration of remifentanil with a serotonergic medication, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or monoamine oxidase inhibitors (MAOIs), may increase the risk of a potentially life-threatening condition called serotonin syndrome. Caution should be exercised when administering MAOIs concomitantly. Treatment with irreversible MAOIs should be discontinued at least 2 weeks before using remifentanil.

The cardiovascular effects of Ultiva (hypotension and bradycardia - see section 4 of the prospectus and Special warnings and precautions for use) may be exacerbated in patients receiving concomitant treatment with cardiac depressant drugs, such as beta-blockers and calcium channel blockers.

After receiving Ultiva, it is recommended to avoid consuming alcoholic beverages.

Fertility, pregnancy, and lactation

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Ultiva should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether remifentanil is excreted in breast milk. However, since fentanyl analogs are excreted in breast milk and since remifentanil-related material has been detected in rat milk after administration of remifentanil, nursing mothers should be advised to discontinue breast-feeding for 24 hours after administration of remifentanil.

Labour and delivery

There are insufficient data to recommend the use of remifentanil during labour or caesarean section. It is known that remifentanil crosses the placental barrier and that fentanyl analogs may cause respiratory depression in the newborn. If remifentanil is administered, the patient and newborn should be monitored for signs of excessive sedation or respiratory depression (see Special warnings and precautions for use).

Overdose

As with all potent opioid analgesics, an overdose would manifest as an increase in the predictable pharmacological effects of remifentanil. Due to the very short duration of action of Ultiva, the potential for adverse effects due to an overdose is limited to the immediate period following administration. The response to discontinuation of the drug is rapid, returning to baseline within 10 minutes.

In case of overdose or suspected overdose, the following should be done: discontinue Ultiva administration, maintain an open airway, start assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function. If respiratory depression is associated with muscle rigidity, a neuromuscular blocker may be required to facilitate assisted or controlled ventilation. For the treatment of hypotension, intravenous fluids and vasopressor drugs may be used, as well as other supportive measures.

An opioid antagonist, such as naloxone, may be administered intravenously as a specific antidote to treat severe respiratory depression and muscle rigidity. It is unlikely that the duration of respiratory depression after an overdose with Ultiva will be longer than the action of the opioid antagonist.

Incompatibilities

Ultiva should only be reconstituted and diluted with the recommended infusion solutions (see Special precautions for disposal and other handling).

Ultiva should not be reconstituted, diluted, or mixed with Ringer's lactate injection solution or Ringer's lactate and 5% glucose injection solution.

Ultiva should not be mixed with propofol in the same infusion bag before administration.

Ultiva should not be administered through the same intravenous line as blood/saline/plasma, as the presence of non-specific esterases in blood products may lead to the hydrolysis of remifentanil, resulting in its inactive metabolite.

Ultiva should not be mixed with other medicinal products before administration.

Shelf-life

Vials:

1 mg vials: 18 months

2 mg vials: 2 years

5 mg vials: 3 years

Reconstituted solution:

Chemical and physical stability has been demonstrated for the reconstituted solution for 24 hours at 25°C. From a microbiological point of view, the product should be used immediately. If not used immediately, the in-use storage times and conditions of the reconstituted solution are the responsibility of the user and normally should not exceed 24 hours at 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Diluted solution:

All diluted solutions of Ultiva injection solution for infusion should be used immediately. Any unused diluted solution should be discarded.

Special precautions for disposal and other handling

To prepare Ultiva for intravenous administration, 1, 2, or 5 ml of the diluent should be added, as convenient, to obtain a reconstituted solution with a concentration of 1 mg/ml of remifentanil. The reconstituted solution is clear, colorless, and practically free of particles. After reconstitution, the product should be inspected visually (if the container allows) for particles, color changes, or container damage. Any solution with such defects should be discarded. The reconstituted product is for single use. Disposal of unused medicinal products and all materials that have come into contact with them should be in accordance with local regulations.

Ultiva should not be administered by manually controlled infusion without subsequent dilution to concentrations of 20 to 250 micrograms/ml (50 micrograms/ml is the recommended dilution in adults and 20 to 25 micrograms/ml in children over 1 year of age).

Ultiva should not be administered by Target-Controlled Infusion (TCI) without prior dilution (20 to 50 micrograms/ml is the recommended dilution for administration by TCI).

The dilution depends on the technical capability of the infusion device and the patient's anticipated requirements.

Dilution should be performed with one of the following intravenous fluids:

After dilution, the product should be inspected visually to ensure it is clear, colorless, and practically free of particles, and that the container is not damaged. Any solution with such defects should be discarded.

Ultiva is compatible with the following intravenous fluids when administered through an intravenous line:

Ultiva has been shown to be compatible with propofol when administered through an intravenous line.