Prospect: information for the user

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

Remifentanil

Read this prospect carefully before starting to use this medication,because it contains important information for you.

• Keep this prospect, as you may need to read it again.
• If you have any doubts, consult your doctor or pharmacist.
• Ifyou experience adverse effects, consult your doctor or pharmacist,even if they are not listed in this prospect. See section 4.

1.What Ultiva is and for what it is used

2.What you need to knowbeforestarting touse Ultiva

3.How to use Ultiva

4.Possible adverse effects

5.Storage of Ultiva

6.Contents of the package and additional information

Ultiva contains an active ingredient called 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 surgery

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

Do not use Ultiva

• if you are allergic to remifentanilo or any of the other components of this medication (listed in section 6).
• if you are allergic to fentanilo analogues (similar pain-relieving medications that belong to the class of medications known as opiates)
• as a spinal canal injection
• as the only medication to initiate anesthesia.

?If you are unsure whether any of the above applies to you, consult your doctor, nurse or pharmacist before Ultiva is administered to you.

Be especially careful with Ultiva if:

• you are allergic to any other opioid medication, such as morphine or codeine.
• you have respiratory problems (you may be more sensitive to difficulty breathing)
• you are over 65 years old, weak, or have a low blood volume and/or hypotension (you are more sensitive to cardiac changes).

?If you are unsure whether any of the above applies to you, consult your doctor or nurse before Ultiva is administered to you.

Consult your doctor before starting to take remifentanilo if:

- You or a family member have ever abused or been dependent on alcohol, prescription medications, or illegal drugs (“addiction”).

- You are a smoker.

- You have ever had mood disorders (depression, anxiety, or personality disorders) or have been treated by a psychiatrist for other mental illnesses.

This medication contains remifentanilo, which is an opioid. Repeated use of opioids can make the medication less effective (you become accustomed 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 to consult your doctor.

Occasionally, withdrawal reactions (e.g., rapid heartbeats, high blood pressure, and agitation) have been reported after sudden discontinuation of treatment with this medication, 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 medication and gradually reduce the dose.

Use of Ultiva with other medications

Inform your doctor if you aretaking, havetakenrecentlyor may need to take any other medication. This includes herbal medications and other medications obtained without a prescription. In particular, inform your doctor or pharmacist if you take:

• heart or blood pressure medications, such as beta-blockers or calcium channel blockers.
• depression medications, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs). These medications should not be used at the same time as Ultiva, as they may increase the risk of serotonin syndrome, a potentially fatal condition.

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

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

Inform your doctor about all sedatives you are taking and follow the recommended dose provided by your doctor. It may be helpful to inform a family member or close friend of the signs and symptoms mentioned above. Contact your doctor when you experience these symptoms.

Ultiva use with alcohol

Do not drink alcohol after receiving Ultiva until you have fully recovered.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, or think you may be pregnant, consult your doctor before using this medication.

Your doctor will weigh the benefits for you against the risk to your baby of receiving this medication while pregnant.

If you receive this medication during delivery 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 medication. If you express milk during this period, discard it and do not give it to your baby.

Driving and operating machinery

Do not drive or operate tools or machinery after receiving Ultiva, as this medication may affect your reaction time. Your doctor will indicate how long you should wait before driving or operating machinery.

Ultiva contains sodium

This medication contains less than 1 mmol (23 mg) of sodium per vial; it is essentially “sodium-free”.

You should never self-administer this medication. This medication will always be administered by qualified individuals.

Ultiva can be administered:

-as a single intravenous injection

-as a continuous intravenous infusion. This is when the medication is administered slowly over a longer period of time.

The way the medication is administered to you and the dose you receive will depend on:

-the intervention or treatment you are receiving in the Intensive Care Unit

-the amount of pain you are experiencing.

The dose may vary from one patient to another. No dose adjustment is required in patients with kidney or liver problems.

After your operation

?Inform your doctor or nurse if you are experiencing pain. If you are experiencing pain after your procedure, you may be given other pain medications.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

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

• eruption with blisters and itching (hives)
• swelling of the face or mouth (angioedema) causing difficulty breathing
• collapse.

Severe allergic reactions can evolve into potentially fatal anaphylactic shock; Frequency unknown (cannot be estimated from the available data), which include worsening of allergy symptoms, a strong drop in blood pressure, rapid heartbeats or fainting.

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

Very common side effects

Can affectmore than 1 in 10 people

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

Common side effects

Can affectup to1 in 10 people

• slow heart rate (bradycardia)
• shallow breathing (respiratory depression)
• temporary cessation of breathing (apnea)
• itching
• cough.

Rare side effects

Can affectup to1 in 100 people

• decreased oxygen levels in the blood (hypoxia)
• constipation.

Very rare side effects

Can affectup to1 in 1,000 people

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

Side effects of unknown frequency

Cannot be estimated from the available data

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

Other side effects that may occur after the procedure

Common side effects

• chills
• high blood pressure (hypertension).

Rare side effects

• pain.

Very rare side effects

• feeling very relaxed or drowsy.

?Inform your doctor or nurseif you consider any of the side effects serious or bothersome, or if you noticeany side effect not mentioned in this leaflet.

Reporting side effects

If you experience any type of side effect, consult your doctor or nurse, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through theSpanish System for the Pharmacovigilance of Medicines for Human Use:www.notificaRAM.es. By reporting side effects, you can contribute to providing more information on the safety of this medicine.

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

Do not use this medication after the expiration date that appears on the vial and on the packaging after “CAD”. The expiration date is the last day of the month indicated.

Do not store above 25°C.

Once Ultiva is reconstituted, it must be used immediately. Any diluted solution not used must be discarded. Medications should not be thrown down the drain or in the trash. Your doctor or nurse will dispose of any medication that is no longer needed. This will help protect the environment.

Store in the original packaging with this leaflet.

Composition of Ultiva by vial

-The active ingredient is remifentanil (hydrochloride).

-The other components are: glycine, hydrochloric acid* and sodium hydroxide* c.s.

* may be used to adjust the pH if necessary

After reconstituting as indicated, each ml contains 1 mg of remifentanil.

Appearance of the product and contents of the container

Lyophilized powder of white to off-white color, sterile, without pyrogenic inducers, preservative-free, for injectable solution concentrate and perfusion, in a 3 ml glass vial.

Before administration, the powder must be mixed with an appropriate solvent (see the information for healthcare professionals or medical professionals for more details). Once mixed, a clear and colorless solution will be formed. Each container contains 5 vials.

Holder of the marketing authorization and responsible for manufacturing

Holder of the marketing authorization

Aspen Pharma Trading Limited

3016Lake Drive,

Citywest Business Campus,

Dublín 24, Ireland

Tel: +34 952 010 137

Local Representative:

ASPEN PHARMACARE ESPAÑA, S.L.

Avenida Diagonal, 512,

Planta Interior 1, Office 4,

Barcelona, 08006, Spain

Responsible for manufacturing

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

Dublín 24

Irlanda

Avara Liscate Pharmaceutical Services S.p.A.

Via Fosse Ardeatine, 2

20050 Liscate (MI)

Italy

This medicinal product is authorized in the Member States of the European Economic Area with the following names:

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

Last revision date of this leaflet:06/2024

The detailed information of this medicinal product is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es
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This information is intended only for healthcare professionals or medical professionals:

Please refer to the Ultiva Technical Dossier for more detailed information.

Dosage 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 persons specifically trained in the use of anesthetic drugs and in the recognition and management of the expected adverse reactions of potent opioids, including respiratory and cardiac resuscitation.

The continuous infusion of Ultiva will be performed through a calibrated infusion device inside a rapid intravenous administration line or a line for intravenous effect. This administration line should be connected with or near the venous cannula, and primed, to minimize the potential dead space (seeSpecial precautions for disposal and other manipulationsand section 6.6 of the Technical Dossier, including tables with examples of infusion rates per body weight to help adjust the Ultiva dose according to the required anesthesia by the patient).

Ultiva may also be administered by controlled infusion according to a target plasma concentration (target-controlled infusion -TCI) through an authorized infusion device that incorporates the Minto pharmacokinetic model with covariances according to age and non-fat body mass (LBM) (Anesthesiology1997; 86: 10 – 23).

Care should be taken to ensure that there is no obstruction or disconnection of the administration lines, and that they are properly cleaned to eliminate any residual Ultiva that may remain after use (seeWarnings and precautions for use).

Ultiva is administered only by intravenous route, and should not be administered by epidural or intrathecal injection (seeContraindications).

Dilution

Ultiva may be rediluted after reconstitution. For instructions on diluting the medication before administration, seeSpecial precautions for disposaland other manipulations.

In the case of manually controlled infusions, it is recommended to dilute Ultiva to obtain concentrations of20 to250 micrograms/ml (50 micrograms/ml is the recommended dilution for adults and20 to25 micrograms/ml for children aged 1 year or older).

The recommended dilution forTCIis20 to50 micrograms/ml.

General anesthesia

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

Adults

Administration by manually controlled infusion

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

Table 1. Guidelines for adult dosing

When the Ultiva injection is slow, the administration will not be performed in less than 30 seconds.

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

No data are available on recommended dosing for the simultaneous use of other hypnotics different from those indicated in the table, which would allow making dosing recommendations (seeAdults - Concomitant medicationin this section).

Induction of anesthesia:Ultiva should be administered with the standard dose of a hypnotic such as propofol, thiopental, or isoflurane, for the induction of anesthesia. Ultiva may be administered at an infusion rate of0.5 to1 micrograms/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 than8 to10 minutes of Ultiva infusion, the slow bolus injection is not necessary.

Maintenance of anesthesia in ventilated patients:After endotracheal intubation, the Ultiva infusion rate should be adjusted according to the patient's needs, as indicated in Table 1. If necessary, additional slow bolus injections may be administered. Patients with high-risk cardiac disease, such as those with poor ventricular function or those undergoing valve surgery, should receive a maximum slow bolus dose of 0.5 micrograms/kg. These dosing recommendations also apply during cardiopulmonary bypass hypothermic anastomosis (see section 5.2 of the Technical Dossier).

Concomitant medication:At the previously recommended doses, remifentanil significantly reduces the amount of hypnotic required for maintenance of anesthesia. Therefore, isoflurane and propofol should be administered as previously recommended to avoid an increase in hemodynamic effects such as hypotension and bradycardia. No data are available for making dosing recommendations for the simultaneous use of remifentanil and other hypnotics different from those indicated in the table (seeAdults - Concomitant medicationin this section).

Recommendations for managing patients in the immediate postoperative period

Establishing alternative analgesia before interrupting Ultiva:Due to the very rapid neutralization of Ultiva's action, there will be no residual opioid activity in the 5-10 minutes following the interruption of Ultiva administration. In patients undergoing surgical procedures where postoperative pain is anticipated, analgesics should be administered before interrupting Ultiva administration. Sufficient time should be allowed for the analgesic with the longest duration of action to take effect. The choice, dose, and timing of the agent(s) should be planned in advance and adjusted individually to be appropriate for the surgical procedure to be performed and the level of postoperative care planned (seeWarnings and precautions for use).

Pediatric patients (1 to 12 years)

No data are available for making dosing recommendations for pediatric patients.

Newborns/infants (less than 1 year old)

There is limited experience in clinical trials with remifentanil in newborns and infants (children less than 1 year old; see section 5.1 of the Technical Dossier). The pharmacokinetic profile of remifentanil in newborns/infants (less than 1 year old) is comparable to that observed in adults after corresponding adjustments for differences in body weight (see section 5.2 of the Technical Dossier). However, due to the lack of sufficient clinical data, the administration of Ultiva in this age group is not recommended.

Cardiopulmonary Bypass

Administration by manually controlled infusion

Table 3.Guidelines for cardiopulmonary bypass dosing

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

Maintenance period of anesthesia:After endotracheal intubation, the Ultiva infusion rate should be adjusted according to the patient's needs. If necessary, additional slow bolus injections may be administered. Patients with high-risk cardiac disease, such as those with poor ventricular function or those undergoing valve surgery, should receive a maximum slow bolus dose of 0.5 micrograms/kg. These dosing recommendations also apply during cardiopulmonary bypass hypothermic anastomosis (see section 5.2 of the Technical Dossier).

Concomitant medication:At the previously recommended doses, remifentanil significantly reduces the amount of hypnotic required for maintenance of anesthesia. Therefore, isoflurane and propofol should be administered as previously recommended to avoid an increase in hemodynamic effects such as hypotension and bradycardia. No data are available for making dosing recommendations for the simultaneous use of remifentanil and other hypnotics different from those indicated in the table (seeAdults - Concomitant medicationin this section).

Recommendations for managing postoperative patients

Continuation of Ultiva administration in the postoperative period to achieve analgesia before extubation:The Ultiva infusion should be maintained at the final intraoperative infusion rate during transfer of the patient to the postoperative care area. After arrival in this area, the patient's level of analgesia and sedation should be closely monitored, and the Ultiva infusion rate should be adjusted according to the patient's needs (see theIntensive Care Unitssection for more information on managing patients in Intensive Care Units).

Establishing alternative analgesia before interrupting Ultiva:Due to the very rapid neutralization of Ultiva's action, there will be no residual opioid activity in the 5-10 minutes following the interruption of Ultiva administration. Before interrupting Ultiva administration, patients should receive alternative analgesics and sedatives to prevent hyperalgesia and hemodynamic changes associated with its use (seeWarnings and precautions for use).

Recommendations for interrupting Ultiva:Due to the very rapid neutralization of Ultiva's action, cases of hypertension, tremors, and pain have been reported in patients after cardiac surgery immediately after interrupting Ultiva (see section 4Adverse reactionsof the Technical Dossier). To minimize the risk of their occurrence, alternative analgesia should be established (as indicated above), before interrupting the Ultiva infusion. The infusion rate should be reduced by 25% at intervals of at least 10 minutes, until the infusion is interrupted.

During extubation, the Ultiva infusion rate should not be increased, and only downward adjustments should be made, supplemented if necessary with alternative analgésics. 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 benefits of providing adequate postoperative analgesia should be weighed against the potential risk of respiratory depression due to these drugs.

Administration by target-controlled infusion (TCI)

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

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

Recommendations for interrupting/continuing in the immediate postoperative period:At the end of the intervention, when the perfusion byTCIis stopped or the achieved concentration is reduced, it is likely that spontaneous respiration will appear in the range of remifentanil concentrations of about 2 nanograms/ml. As with manually controlled infusion, alternative postoperative analgesia with analgesics of longer duration should be administered before the end of the intervention (see the recommendations for interrupting in the case of administration by manually controlled infusion in this section).

No data are available for making dosing recommendations for the use of Ultiva byTCIfor postoperative analgesia.

Pediatric patients (1 to 12 years)

No data are available for making dosing recommendations for pediatric patients.

Intensive Care Units

Adults

Ultiva may be used to provide analgesia to mechanically ventilated patients admitted to Intensive Care Units. Sedatives 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 (seePatients with renal insufficiency in Intensive Care Unitsin this section and section 5.2 of the Technical Dossier). Therefore, the use of Ultiva for more than 3 days of treatment is not recommended.

No data are available for making dosing recommendations for the use of Ultiva byTCIin patients in Intensive Care Units.

In adults, it is recommended that the administration of Ultiva be initiated 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 adjustments. The patient should be regularly evaluated and the Ultiva infusion rate adjusted according to the patient's 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 a suitable sedative be initiated (see the information below). The dose of sedative should be adjusted to achieve the desired level of sedation. Additional increments of 0.025 micrograms/kg/min (1.5 micrograms/kg/h) in the Ultiva infusion rate may be made if additional analgesia is required.

Table 4 summarizes the initial infusion rates and dose intervals for providing analgesia to patients.

Table 4. Guidelines for Ultiva dosing in Intensive Care Units

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

The use of Ultiva will reduce the dose of any concomitantly administered sedative. Table 5 provides the recommended initial doses for sedatives, if necessary:

Table 5. Recommended initial dose for sedatives, if necessary:

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

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

Establishing alternative analgesia before interrupting Ultiva:Due to the very rapid neutralization of Ultiva's action, there will be no residual opioid activity in the 5-10 minutes following the interruption of Ultiva administration. Before interrupting Ultiva administration, patients should receive alternative analgesics and sedatives to prevent hyperalgesia and hemodynamic changes associated with its use (seeWarnings and precautions for use).

The time required to establish alternative analgesia should be planned in advance and adjusted individually to be appropriate for the procedure to be performed and the level of postoperative care planned.

Recommendations for extubation and interrupting Ultiva administration:To ensure a gradual transition from the Ultiva dosing regimen, it is recommended that the Ultiva infusion rate 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 stopped. During extubation, the Ultiva infusion rate should not be increased, and only downward adjustments should be made, supplemented if necessary with alternative analgésics. Hemodynamic changes such as hypertension and tachycardia should be treated, if necessary, with alternative agents.

After interrupting Ultiva administration, the IV cannula should be flushed or removed to prevent accidental administration of the drug.

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

Pediatric patients in Intensive Care Units

No data are available for making dosing recommendations for pediatric patients.

Patients with renal insufficiency in Intensive Care Units

No adjustment to the recommended doses is necessary when administering Ultiva to patients with renal insufficiency, including those undergoing dialysis, however, the clearance of the acidic carboxylic acid metabolite is reduced in patients with renal insufficiency (see section 5.2 of the Technical Dossier).

Special populations

Geriatric patients (over 65 years)

General anesthesia:The initial dose of remifentanil administered to patients over 65 years should be half of the recommended dose for adults, and subsequent dosing should be adjusted according to the individual needs of the patient, as this population has been observed to have an 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 byTCIto this population should be1.5 to4 nanograms/ml, and subsequent titration should be based on the patient's response.

Cardiopulmonary Bypass:No dose reduction is required (see section onCardiopulmonary Bypass).

Intensive Care Units:No dose reduction is required (seeIntensive Care Unitssection).

Obese patients

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

Using the Minto model, it is possible that the lean body mass may be underestimated in female patients with a body mass index (IMC) greater than 35 kg/m2and in male patients with aIMCgreater than 40 kg/m2. To avoid underdosing in these patients, it is recommended that the remifentanil administered byTCIbe carefully titrated according to the individual response of each patient.

Renal insufficiency

No adjustment to the recommended doses is necessary in patients with renal insufficiency, including those undergoing dialysis (see section 5.2 of the Technical Dossier).

Hepatic insufficiency

No adjustment to the recommended doses is necessary in patients with hepatic insufficiency, however, patients with severe hepatic insufficiency may be slightly more sensitive to the respiratory depressive effects of remifentanil (seeWarnings and precautions for use).

Neurosurgery

No adjustment to the recommended doses is necessary in patients undergoing neurosurgery (see section 5.2 of the Technical Dossier).

American Society of Anesthesiologists (ASA) classification III/IV

General anesthesia:As expected, the hemodynamic effects of potent opioids may be more pronounced in patients classified as ASA III/IV. Therefore, caution should be exercised when administering Ultiva to these patients, and the initial dose should be reduced, with subsequent adjustment according to the individual needs of the patient. No data are available for making dosing recommendations for pediatric patients.

In the case ofTCI, a lower initial concentration, of1.5 to4 nanograms/ml, should be used in patients classified as ASA III/IV, and subsequent titration should be based on the patient's response.

Cardiopulmonary Bypass:No dose reduction is required (see section onCardiopulmonary Bypass).

Contraindications

Due to the presence of glycine in Ultiva, it is contraindicated to