ULTIVA 5 mg POWDER FOR CONCENTRATE FOR INJECTION AND INFUSION SOLUTION

Introduction

Package Leaflet: Information for the User

Ultiva 5 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. Storage of 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 due to its 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 sole medicine to initiate anesthesia.

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

Be cautious 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, consult your doctor or nurse before you are given Ultiva.

Consult your doctor before starting to take 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 essential that you consult 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 resume 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, inform your doctor or pharmacist if you take:

• medicines for the heart or blood pressure, such as beta-blockers or calcium channel blockers.
• medicines for treating 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.

The concomitant use of Ultiva and 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. The 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 along with sedative medicines, they should limit the dose and duration of treatment.

Tell your doctor about all sedative medicines you are taking and closely follow the recommended dosage 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 plan to become pregnant, consult your doctor before using this medicine.

Your doctor will weigh the benefit to you against the risk to your baby of receiving 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.

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 and 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 potentially fatal anaphylactic shock; Frequency not known (cannot be estimated from the available data), which includes 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 cessation of 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

• chills
• high blood pressure (hypertension).

Uncommon side effects

• pains.

Rare side effects

• feeling very relaxed or drowsy.

If you consider any of these side effects serious or bothersome, or if you notice any side effects not mentioned in this leaflet, tell your doctor or nurse.

Reporting of side effects

If you experience 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 through 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. Storage of 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 outer packaging 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.

Keep in the original packaging with this leaflet.

6. Contents of the pack and other information

Composition of Ultiva 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, pyrogen-free, preservative-free, for concentrate for solution for injection and infusion, in a 3 ml glass vial.

Before administration, the powder should 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

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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 this purpose. This administration route for infusion should be connected to or be near the venous cannula and should 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 by 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 and 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 the pediatric population aged 1 year and older).

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

General anesthesia

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

Adults

Administration through manually controlled infusion

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

Table 1. Dosage 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 dosage in the simultaneous 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 after more than 8 to 10 minutes 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 or downward in increments of 25% to 100% or decrements of 25% to 50% every 2 to 5 minutes to achieve the desired level of response in the μ opioid receptors. 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 under 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 under 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 administration of Ultiva is not recommended in patients under 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, hypnotic, and benzodiazepine drugs required for anesthesia (see Interaction with Other Medicinal Products and Other Forms of Interaction).

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

Recommendations for Interruption/Continuation in the Immediate Postoperative Period: 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 Ultiva administration. 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 longer-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 center 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 for pain treatment during the postoperative period are not recommended in patients with spontaneous ventilation.

Target-Controlled Infusion (TCI)

Induction and Maintenance of Anesthesia in Ventilated Patients: Ultiva TCI should be used in association with intravenous or inhaled hypnotic agents during induction and maintenance of anesthesia in adult patients with ventilation (see Table 1). In association 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. In the case of surgery in highly stimulated areas, blood concentrations of up to 15 nanograms/ml may be required.

Remifentanil, administered at the doses indicated above, significantly reduces the amount of hypnotic agent necessary for anesthesia maintenance. 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 Interruption/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 interruption in the case of manual 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 induction agent 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 anesthesia maintenance:

Table 2. Dosage 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, administration should be 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 nitrous oxide (70%) alone, usual maintenance 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 according to 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 simultaneous use of remifentanil with other hypnotic agents different from those indicated in the table, which would allow dosage recommendations to be made (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 Ultiva administration. Sufficient time should be allowed for the maximum effect of the longest-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 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 under 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 correction for differences in body weight (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.

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 dosage 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 Ultiva bolus injections 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 are no data to make dosage recommendations for 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 for pre-extubation analgesia: It is recommended that the infusion of Ultiva be maintained at the final intraoperative rate during patient transfer 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 discontinuation of administration. Prior to discontinuation of Ultiva, patients should receive 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 discontinuing Ultiva.

Recommendations for 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 discontinuation 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 discontinuation of Ultiva infusion. The infusion rate should be reduced by 25% at intervals of at least 10 minutes until Ultiva infusion is discontinued.

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 transition regimen 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 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 remifentanilo according to individual patient response, 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 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 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 are insufficient data.

Pediatric patients (1 to 12 years old)

There are 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 mechanically ventilated patients in Intensive Care Units. Sedative substances should be administered when necessary.

The efficacy and safety of Ultiva in mechanically ventilated patients in Intensive Care Units have been established in well-controlled clinical trials of up to three days' 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 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 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 dosage ranges for providing analgesia to patients in Intensive Care Units.

Table 4 Dosage guidelines for Ultiva in Intensive Care Units

In Intensive Care Units, bolus administration of Ultiva is not recommended.

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 required.

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

To allow 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 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, a Ultiva infusion rate of at least 0.1 micrograms/kg/min (6 micrograms/kg/h) be maintained. 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 discontinuation 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 available 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 of developing tolerance 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 is discontinued. 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 transition regimen 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 are 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 individual patient needs, 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 response.

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

Intensive Care: No reduction in 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 ideal body weight, as the clearance and volume of distribution of remifentanil correlate better with ideal body weight than with 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 individual patient response.

Renal insufficiency

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

Hepatic insufficiency

Studies conducted with a limited number of patients with impaired hepatic function 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 individual patient needs.

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 are 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, with subsequent titration based on response.

Cardiac anesthesia: No reduction in 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.

Rápida neutralización de la acción/Transición a analgesia alternativa

Debido a la muy rápida neutralización de acción de Ultiva, no quedará actividad opioidea residual en los 5-10 minutos siguientes a la interrupción de la administración de Ultiva. En aquellos pacientes sometidos a intervenciones quirúrgicas en las que se anticipa la existencia de dolor postoperatorio, deberán administrarse analgésicos antes de interrumpir la administración de Ultiva. Cuando se utilice en Unidades de Cuidados Intensivos (ver sección 4.2 Posología y forma de administración)se debe tener en cuenta la posibilidad de que aparezca tolerancia, hiperalgesia y cambios hemodinámicos asociados. Antes de interrumpir el tratamiento con Ultiva se deben administrar sustancias sedantes y analgésicas alternativas a los pacientes. Se dejará transcurrir el tiempo suficiente para alcanzar el efecto terapéutico del analgésico de duración de acción más prolongada. La elección, dosis y tiempo de administración del agente(s) deberán estar planeados previamente y ajustados individualmente para que sean adecuados tanto para el proceso quirúrgico al que será sometido el paciente como al nivel de cuidados postoperatorios previstos. Cuando se administren otros agentes opiáceos como parte del régimen de transición a la analgesia alternativa, se deberá evaluar el beneficio de aportar una analgesia adecuada postoperatoria frente al potencial riesgo de depresión respiratoria debida a estos fármacos.

Riesgo por el uso concomitante de medicamentos sedantes como benzodiazepinas u otros medicamentos relacionados

El uso concomitante de Ultiva y medicamentos sedantes, como benzodiazepinas u otros medicamentos relacionados, puede provocar sedación, depresión respiratoria, coma y muerte. Debido a estos riesgos, la prescripción concomitante con estos medicamentos, se debe reservar para pacientes sin opción a tratamientos alternativos. Si se toma la decisión de prescribir Ultiva concomitantemente con éstos medicamentos, se debe usar la dosis efectiva más baja, durante el menor tiempo posible.

Los pacientes deben ser estrechamente monitorizados para detectar los signos y síntomas de depresión respiratoria y sedación. A este respecto, se recomienda encarecidamente informar a los pacientes y a sus cuidadores para que estén atentos a estos síntomas (ver Interacción con otros medicamentos y otras formas de interacción)

Interrupción del tratamiento y síndrome de abstinencia

La administración repetida a intervalos cortos durante períodos prolongados puede dar lugar al desarrollo del síndrome de abstinencia tras la interrupción del tratamiento. Tras la retirada del tratamiento de remifentanilo se ha informado con poca frecuencia de síntomas como taquicardia, hipertensión y agitación, particularmente tras su retirada abrupta después de una administración prolongada de más de 3 días. Cuando aparecen, la reintroducción y disminución paulatina de la perfusión han sido beneficiosas. No se recomienda el uso de Ultiva en pacientes con cuidados intensivos con ventilación mecánica para un tratamiento que dure más de 3 días.

Rigidez muscular - prevención y manejo

A las dosis recomendadas, puede aparecer rigidez muscular. Como con otros opiáceos, la incidencia de rigidez muscular está relacionada con la dosis y la velocidad de administración. Por tanto, las inyecciones en bolo lentas se administrarán en no menos de 30 segundos.

La rigidez muscular inducida por remifentanilo debe tratarse en el contexto del estado clínico del paciente con medidas de apoyo adecuadas. La excesiva rigidez muscular que aparece durante la inducción de la anestesia deberá tratarse administrando un fármaco bloqueante neuromuscular y/o hipnóticos adicionales. La rigidez muscular observada durante el uso de remifentanilo como analgésico puede ser tratada interrumpiendo o disminuyendo la velocidad de administración de remifentanilo. La resolución de la rigidez muscular tras interrumpir la perfusión de remifentanilo tiene lugar en minutos. Alternativamente, puede administrarse un antagonista opiáceo, no obstante, esto puede anular o atenuar el efecto analgésico de remifentanilo.

Depresión respiratoria - prevención y manejo

Como con todos los opiáceos potentes, la analgesia profunda está acompañada por una notable depresión respiratoria. Por consiguiente, sólo se utilizará remifentanilo en áreas provistas de instalaciones para el seguimiento y tratamiento de la depresión respiratoria. Deberá prestarse una atención especial en pacientes con disfunción respiratoria. La aparición de una depresión respiratoria se tratará convenientemente, incluyendo una disminución de hasta un 50 % de la velocidad de perfusión o interrumpiendo temporalmente la perfusión. A diferencia de otros análogos de fentanilo, remifentanilo no ha mostrado ser causante de depresión respiratoria recurrente, aún después de una administración prolongada. No obstante, dado que son muchos los factores que pueden afectar a la recuperación postoperatoria, es importante asegurarse de que se alcance un estado de consciencia total y una ventilación espontánea adecuada antes de que el paciente salga del área de recuperación.

Efectos cardiovasculares

El riesgo de aparición de efectos cardiovasculares tales como hipotensión y bradicardia, que muy raramente conducen a asistolia/parada cardiaca (ver sección 4 del prospecto e Interacción con otros medicamentos y otras formas de interacción) puede reducirse enlenteciendo la velocidad de perfusión de Ultiva o las dosis de anestésicos administrados concurrentemente, o mediante administración por vía intravenosa de fluidos, fármacos vasopresores o anticolinérgicos, a conveniencia.

Los pacientes debilitados, con hipovolemia, hipotensos y ancianos pueden ser más sensibles a los efectos cardiovasculares de remifentanilo.

Administración inadvertida

En el espacio muerto de la vía para la administración intravenosa y/o en la cánula puede haber suficiente cantidad de Ultiva como para causar depresión respiratoria, apnea y/o rigidez muscular si se drena el conducto con fluidos intravenosos u otros fármacos. Esto puede evitarse administrando Ultiva en una vía para administración intravenosa rápida o mediante una vía para administración intravenosa al efecto, que se retirase cuando se interrumpiera la administración de Ultiva.

Recién nacidos/lactantes

Se dispone de datos limitados acerca del uso en recién nacidos/lactantes con menos de 1 año de edad (ver

Posología y método de la administración- Recién nacidos/lactantes (con menos de 1 año de edad)y sección 5.1 de la Ficha Técnica).

Tolerancia y trastorno por consumo de opioides (abuso y dependencia)

La administración repetida de opioides puede inducir tolerancia, dependencia física y psicológica y trastorno por consumo de opioides (TCO). El abuso o uso indebido intencionado de opioides puede provocar una sobredosis y/o la muerte. El riesgo de presentar TCO es mayor en pacientes con antecedentes personales o familiares (progenitores o hermanos) de trastornos por consumo de sustancias (incluido el trastorno por consumo de alcohol), en fumadores o en pacientes con antecedentes personales de otros trastornos de salud mental (p. ej., depresión mayor, ansiedad o trastornos de la personalidad).

Ultiva contiene sodio

Este medicamento contiene menos de 1 mmol de sodio (23 mg) por vial; esto es, esencialmente “exento de sodio”.

Interacción con otros medicamentos y otras formas de interacción

Remifentanilo no se metaboliza por la colinesterasa plasmática, por lo que no se anticipa la existencia de interacciones con fármacos que sean metabolizados por esta enzima.

Como con otros fármacos opiáceos, el remifentanilo, administrado mediante perfusión controlada manualmente o mediante TCI, reduce las dosis de anestésicos por vía inhalatoria o intravenosa así como de las benzodiazepinas que se requieren en anestesia (ver Posología y método de la administración). Si no se reducen las dosis de los fármacos depresores del SNC administrados concomitantemente, los pacientes pueden experimentar un aumento en la incidencia de reacciones adversas asociadas al uso de estos fármacos.

Medicamentos sedantes como benzodiazepinas u otros medicamentos relacionados: el uso concomitante de opiáceos con medicamentos sedantes como benzodiazepinas u otros medicamentos relacionados aumenta el riesgo de sedación, depresión respiratoria, coma y muerte, debido a la suma del efecto depresor del SNC. La dosis y la duración del tratamiento concomitante de Ultiva con estos medicamentos deben ser limitadas (ver Advertencias y precauciones especiales de empleo). El uso concomitante de opiáceos y gabapentinoides (gabapentina y pregabalina) aumenta al riesgo de sobredosis por opiáceos, depresión respiratoria y muerte.

La administración concomitante de remifentanilo con un fármaco serotoninérgico como, por ejemplo, los inhibidores selectivos de la recaptación de la serotonina (ISRS), los inhibidores de la recaptación de serotonina y norepinefrina (IRSN) o los inhibidores de la monoaminoxidasa (IMAO) puede aumentar el riesgo de una enfermedad potencialmente mortal denominada síndrome serotoninérgico. Se debe tener precaución al administrar IMAO de forma concomitante. Se debe interrumpir el tratamiento con IMAO irreversibles al menos 2 semanas antes de utilizar remifentanilo.

Los efectos cardiovasculares de Ultiva (hipotensión y bradicardia – ver sección 4 del prospecto y Advertencias y precauciones especiales de empleo) pueden estar exacerbados en pacientes que reciban tratamiento concomitante con fármacos depresores del sistema cardiaco, tales como beta-bloqueantes y bloqueantes de los canales del calcio.

Tras recibir Ultiva, se recomienda evitar el consumo de bebidas alcohólicas.

Fertilidad, embarazo y lactancia

Embarazo

No hay estudios adecuados y bien controlados con mujeres embarazadas. Ultiva deberá utilizarse durante el embarazo solamente si el potencial beneficio justifica el potencial riesgo para el feto.

Lactancia

Se desconoce si remifentanilo se excreta en leche materna. No obstante, como los análogos de fentanilo se excretan en leche materna y como se ha detectado la presencia de material relacionado con remifentanilo en leche de rata tras administración de remifentanilo, se advertirá a las madres en periodo de lactancia que dejen de dar el pecho durante las 24 horas siguientes a la administración de remifentanilo.

Parto y alumbramiento

No se dispone de un número de datos suficiente para recomendar el uso de remifentanilo durante un parto o cesárea. Se sabe que remifentanilo cruza la barrera placentaria y los análogos de fentanilo pueden causar depresión respiratoria en el niño. Si, pese a todo, se acaba administrando remifentanilo, se debe controlar al paciente y recién nacido por si presentaran signos de sedación excesiva o depresión respiratoria (ver Advertencias y precauciones especiales de empleo).

Sobredosis

Como con todos los potentes analgésicos opiáceos, una sobredosis se manifestaría por un incremento de las acciones farmacológicamente previsibles de remifentanilo. Debido a la muy corta duración de acción de Ultiva, el potencial de aparición de efectos perjudiciales debidos a una sobredosis está limitado al periodo de tiempo inmediato siguiente a la administración. La respuesta a la interrupción de la administración del fármaco es rápida, regresándose al estado inicial a los 10 minutos.

En caso de sobredosis o de sospecha de sobredosis, realizar lo siguiente: interrumpir la administración de Ultiva, mantener una vía respiratoria abierta, comenzar a instaurar ventilación asistida o controlada con oxígeno y mantener adecuadamente la función cardiovascular. Si la depresión respiratoria se asocia con rigidez muscular, puede requerirse un bloqueante neuromuscular para facilitar una respiración asistida o controlada. Para el tratamiento de la hipotensión pueden emplearse fluidos intravenosos y fármacos vasopresores así como otras medidas de soporte.

Puede administrarse por vía intravenosa un antagonista opiáceo tal como la naloxona como antídoto específico para tratar la depresión respiratoria grave y la rigidez muscular. Es improbable que la duración de la depresión respiratoria tras sobredosis con Ultiva sea más prolongada que la acción del antagonista opiáceo.

Incompatibilidades

Ultiva sólo debe reconstituirse y diluirse con aquellas soluciones para perfusión recomendadas (ver Precauciones especiales de eliminacióny otras manipulaciones).

Ultiva no debe reconstituirse, diluirse o mezclarse con solución inyectable Ringer lactato o con solución inyectable Ringer lactato y glucosa al 5 %.

No debe mezclarse Ultiva con propofol en la misma bolsa de perfusión antes de la administración.

No se recomienda administrar Ultiva dentro de la misma vía de administración intravenosa de sangre/suero/plasma, ya que la presencia de esterasas inespecíficas en productos sanguíneos puede conducir a la hidrólisis de remifentanilo dando lugar a su metabolito inactivo.

Ultiva no debe mezclarse con otros medicamentos antes de la administración.

Periodo de validez

Viales:

Viales de 1 mg: 18 meses

Viales de 2 mg: 2 años

Viales de 5 mg: 3 años

Solución reconstituida:

Se ha demostrado la estabilidad química y física durante el uso de la solución reconstituida durante 24 horas a 25ºC. Desde el punto de vista microbiológico, el producto debe usarse inmediatamente. Si no se usa de forma inmediata, los tiempos y condiciones de almacenamiento de la solución reconstituida previa a la utilización, son responsabilidad de la persona que lo vaya a usar y normalmente no deben ser superiores a 24 horas a 2-8ºC, a menos que la reconstitución se haya producido en condiciones asépticas controladas y validadas.

Solución diluida:

Todas las soluciones diluidas de Ultiva solución inyectable y perfusión deben usarse inmediatamente. Cualquier solución diluida no utilizada se debe desechar.

Precauciones especiales de eliminación y otras manipulaciones

Para preparar la administración de Ultiva por vía intravenosa, se añadirán a conveniencia 1, 2 ó 5 ml del diluyente, a fin de obtener una solución reconstituida con una concentración de 1 mg/ml de remifentanilo. La solución reconstituida es transparente, incolora y prácticamente está libre de partículas. Tras la reconstitución, inspeccionar visualmente el producto (si el recipiente lo permite) para ver si hay partículas, si presenta alteraciones del color o si el recipiente está dañado. Desechar cualquier solución donde se observen tales defectos. El producto reconstituido es para un solo uso. La eliminación del medicamento no utilizado y de todos los materiales que hayan estado en contacto con él, se realizará de acuerdo con la normativa local.

Ultiva no deberá administrarse mediante perfusión controlada manualmente sin diluirse posteriormente hasta obtener concentraciones de 20 a 250 microgramos/ml (50 microgramos/ml es la dilución recomendada en adultos y 20 a 25 microgramos/ml en niños con 1 o más años de edad).

Ultiva no deberá administrarse mediante TCI sin diluirse previamente (20 a 50 microgramos/ml es la dilución recomendada para la administración mediante TCI).

La dilución depende de la capacidad técnica del dispositivo para perfusión y de los requerimientos previstos del paciente.

La dilución debe realizarse con alguno de los siguientes fluidos para administración intravenosa:

Tras la dilución, inspeccionar visualmente el producto para asegurarse de que es transparente, incoloro, está prácticamente libre de partículas y que el recipiente no está dañado. Desechar cualquier solución donde se observen tales defectos.

Ultiva resulta compatible con los siguientes fluidos para administración intravenosa cuando se administra en catéter intravenoso de:

Ultiva ha mostrado ser compatible con propofol cuando se administra en un catéter intravenoso.