Ultiva 1 mg powder for concentrate for solution for injection and infusion: detailed information

Package leaflet: Information for the user

Introduction

Package leaflet: information for the user

Ultiva 1 mg powder for concentrate for solution for 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 questions, ask your doctor or pharmacist.
If you experience any side effects, talk to your doctor or pharmacist, even if they are not listed in this leaflet. See section 4.

Contents of the leaflet

What Ultiva is and what it is used for
What you need to know before you use Ultiva
How to use Ultiva
Possible side effects
How to store Ultiva
Contents of the pack and other information

1. What Ultiva is and what it is used for

Ultiva contains an active substance called remifentanil. It belongs to a group of medicines known as opioids, which are used to relieve pain. Ultiva differs from other medicines in its class by its very rapid onset and very short duration of action.

Ultiva is used for:

relieving pain before and during surgery
relieving 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 using Ultiva

Do not use Ultiva

if you are allergic to remifentanil or to any of the other ingredients of this medicine (listed in section 6).
if you are allergic to fentanyl analogs (analgesic medicines similar to fentanyl that belong 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 unsure whether any of the above applies to you, consult your doctor, nurse, or pharmacist before receiving Ultiva.

Take special care with Ultiva if:

you are allergic to any other opioid medicines, such as morphine or codeine.
you have lung problems (you may be more sensitive to experiencing difficulty breathing).
you are over 65 years of age, are frail, or have low blood volume and/or hypotension (you are more sensitive to experiencing cardiac disturbances).

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

Talk to your doctor before starting remifentanil if:

you or a family member have ever abused or been dependent on alcohol, prescription medicines, or illegal drugs (“addiction”).
you are a smoker.
you have ever had mood disorders (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 may cause the medicine to lose effectiveness (you become accustomed to its effect). It may also lead to dependence and abuse, which in turn could result in potentially fatal overdose. If you are concerned about becoming dependent on Ultiva, it is important to speak with your doctor.

Occasionally, withdrawal reactions (e.g., rapid heartbeat, high blood pressure, and agitation) have been reported after abrupt discontinuation of treatment with this medicine, especially when treatment has been 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.

Use of Ultiva with other medicines

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

medicines for the heart or blood pressure, such as beta-blockers or calcium channel blockers.
medicines to treat depression, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or monoamine oxidase inhibitors (MAOIs). The use of these medicines together with Ultiva is not recommended, as they may increase the risk of serotonin syndrome, a potentially life-threatening condition.

Concomitant use of Ultiva and sedative medicines, such as benzodiazepines or other related drugs, increases the risk of drowsiness, breathing difficulties (respiratory depression), coma, and may be life-threatening. For this reason, concomitant use with these medicines should only be considered when no other treatment options are 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 may be potentially fatal.

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

Inform your doctor about all sedative medicines you are taking and closely follow the dosing recommendations provided by your doctor. It may be helpful for you to inform a close family member or friend about the signs and symptoms mentioned above. Contact your doctor if you experience these symptoms.

Taking Ultiva with alcohol

After receiving Ultiva, you must 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 during pregnancy.

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

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

Driving and using machines

Do not drive or operate tools or machinery after receiving Ultiva, as this medicine may affect your reaction ability. Your doctor will advise 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 must never self-administer this medicine. This medicine will always be administered by qualified personnel.

Ultiva may be administered:

as a single intravenous injection
as a continuous intravenous infusion. This is when the drug is given slowly over a longer period of time.

The way in which the medicine is administered to you and the dose you receive will depend on:

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

The dose varies from patient to patient. Dose adjustment is not required in patients with kidney or liver problems.

After your operation

?Inform your doctor or nurse if you have pain. If you have pain after your procedure, you may be given other analgesics.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone experiences them.

Allergic reactions including anaphylaxis: These are rare (may affect up to 1 in 1,000 people using Ultiva). Signs include:

rash with blisters and itching (wheals)
swelling of the face or mouth (angioedema) causing difficulty breathing
collapse.

Severe allergic reactions may progress to potentially life-threatening anaphylactic shock; Frequency unknown (cannot be estimated from available data), which may include worsening of allergy symptoms, a severe drop in blood pressure, rapid heartbeat, or fainting.

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

Very common adverse effects

May affect more than 1 in 10 people

stiffness (muscle rigidity) of the muscles
low blood pressure (hypotension)
nausea or vomiting.

Common adverse effects

May affect up to 1 in 10 people

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

Uncommon adverse effects

May affect up to 1 in 100 people

decreased oxygen levels in the blood (hypoxia)
constipation.

Rare adverse effects

May affect up to 1 in 1,000 people

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

Adverse effects with unknown frequency

Cannot be estimated from available data

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

Other adverse effects you may experience after the procedure

Common adverse effects

chills
high blood pressure (hypertension).

Uncommon adverse effects

pain.

Rare adverse effects

feeling very relaxed or drowsy.

? Inform your doctor or nurse if you consider any of the adverse effects to be severe or bothersome, or if you notice any adverse effects not mentioned in this leaflet.

Reporting of adverse effects

If you experience any type of adverse effect, consult your doctor or nurse, even if it is a possible adverse effect not listed in this leaflet. You may also report them directly via the Spanish Pharmacovigilance System for Human Medicinal Products: www.notificaRAM.es. By reporting adverse 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 stated on the vial and packaging following “EXP”. The expiry date refers to the last day of the month indicated.

Do not store above 25°C.

Once reconstituted, Ultiva must be used immediately. Any unused diluted solution must be discarded. Medicines must not be disposed of via wastewater or household waste. Your doctor or nurse will dispose of any unused medicine. This helps protect the environment.

Store in the original packaging with this leaflet.

6. Contents of the container and other information

Composition of Ultiva per vial

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

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

Appearance of the product and contents of the pack

White to off-white sterile lyophilized powder, free of pyrogens and preservatives, for concentrate for solution for injection and infusion, in a 3 ml glass vial.

Prior to administration, the powder must be mixed with an appropriate solvent (see information intended for physicians or healthcare professionals for further details). Once mixed, a clear, colourless solution is formed. Each pack contains 5 vials.

Marketing Authorization Holder and Manufacturer

Marketing Authorization 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

Manufacturers

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 medicinal product is authorized in the European Economic Area member states under the following names:

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

Date of the most recent review of this leaflet: 06/2024

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

This information is intended exclusively for physicians or healthcare professionals:

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

Dosage and method of administration

Ultiva must only be administered in facilities fully equipped for monitoring and maintaining respiratory and cardiovascular function, and by personnel specifically trained in the use of anesthetic drugs and in the recognition and management of expected adverse effects of potent opioids, including respiratory and cardiac resuscitation. Such training must include establishing and maintaining a patent airway and providing assisted ventilation.

Continuous infusion of Ultiva should be administered using a calibrated infusion device into a rapid intravenous administration line or a dedicated intravenous line. This infusion line should be connected close to or at the venous cannula and should be primed to minimize potential dead space (for further information, see Special precautions for disposal and other handling and section 6.6 of the SmPC, including tables with examples of weight-based infusion rates to assist in adjusting the Ultiva dose according to the patient's anesthetic requirements).

Ultiva may also be administered via target-controlled infusion (TCI), using an authorized infusion device incorporating the Minto pharmacokinetic model with covariates based on age and lean body mass (LBM) (Anesthesiology 1997; 86: 10 – 23).

Care must be taken to ensure there is no obstruction or disconnection of the infusion lines, and they must be properly flushed to remove any residual Ultiva after use (see Warnings and special precautions for use).

Ultiva is administered exclusively by intravenous route and must not be administered via epidural or intrathecal injection (see Contraindications).

Dilution

Ultiva may be further diluted after reconstitution. For instructions on dilution prior to administration, see Special precautions for disposal and other handling.

For manually controlled infusions, it is recommended to dilute Ultiva to concentrations between 20 and 250 micrograms/ml (a concentration of 50 micrograms/ml is recommended for adults, and 20 to 25 micrograms/ml for pediatric patients aged one year and older).

The recommended dilution for TCI is 20 to 50 micrograms/ml.

General anesthesia

The administration of Ultiva should be individualized according to the patient's response.

Adults

Administration via manually controlled infusion

Table 1 summarizes the initial infusion rates and dosage range:

Table 1. Dosing guidelines in adults

INDICATION	BOLUS INJECTION (micrograms/kg)	CONTINUOUS INFUSION (micrograms/kg/min)
		Initial rate	Range

Anesthesia induction	1 (over no less than 30 seconds)	0.5 to 1	--

Anesthesia maintenance in ventilated patients
Nitrous oxide (66%)	0.5 to 1	0.4	0.1 to 2
Isoflurane (initial dose 0.5 MAC)	0.5 to 1	0.25	0.05 to 2
Propofol (initial dose 100 micrograms/kg/min)	0.5 to 1	0.25	0.05 to 2

When administering Ultiva by slow bolus injection, the administration must not be performed in less than 30 seconds.

At the previously recommended doses, remifentanil significantly reduces the amount of hypnotic agent required to maintain anesthesia. Therefore, administration of isoflurane and propofol should be carried out as previously recommended to avoid an increase in hemodynamic effects such as hypotension and bradycardia (see Concomitant Medication in this section).

There are no data available on recommended dosing when using other hypnotic agents simultaneously with remifentanil, apart from those indicated in the table.

Induction of anesthesia: Ultiva should be administered with the standard dose of a hypnotic agent such as propofol, thiopental, or isoflurane for induction of anesthesia. 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 given over no less than 30 seconds. If endotracheal intubation is performed more than 8 to 10 minutes after starting Ultiva infusion, a bolus injection is not necessary.

Maintenance of anesthesia in ventilated patients: After endotracheal intubation, the Ultiva infusion rate should be reduced according to the anesthetic technique, as indicated in Table 1. Due to the rapid onset and short duration of action of Ultiva, the administration rate during anesthesia may be adjusted upward by increments of 25% to 100%, or downward by reductions of 25% to 50%, every 2 to 5 minutes until the desired level of μ-opioid receptor response is achieved. In response to light anesthesia, supplemental slow bolus injections may be administered every 2 to 5 minutes.

Anesthesia in anesthetized patients breathing spontaneously with a secured airway (e.g., laryngeal mask anesthesia): Respiratory depression may occur in patients under anesthesia who are breathing spontaneously with a secured airway. Special attention is required to adjust the dose according to individual patient needs, and supportive ventilation may be necessary. The recommended initial infusion rate for supplemental analgesia in spontaneously breathing anesthetized patients is 0.04 microgram/kg/min, titrated to effect. A range of infusion rates between 0.025 and 0.1 microgram/kg/min has been studied.

Bolus administration is not recommended in patients under anesthesia who are breathing spontaneously.

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

Concomitant medication: Remifentanil reduces the amounts or doses of inhaled anesthetic agents, hypnotics, and benzodiazepines required during anesthesia (see Interaction with Other Medicines and Other Forms of Interaction).

Doses of the following anesthetic agents: isoflurane, thiopentone, 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, there will be no residual opioid activity within 5 to 10 minutes after stopping the infusion. In patients undergoing surgical procedures where postoperative pain is anticipated, analgesics should be administered before discontinuing Ultiva. Sufficient time should be allowed for the longer-acting analgesic to reach its maximum effect. The choice of analgesic should be appropriate based on the surgical procedure performed and the level of postoperative care.

If the effect of the longer-acting analgesic has not been established before the end of surgery, 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.

Instructions on providing analgesia and sedation to mechanically ventilated patients in Intensive Care Units are provided in the section Use in Intensive Care Units.

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

Bolus injections of Ultiva are not recommended for the treatment of postoperative pain in patients breathing spontaneously.

Administration by Target-Controlled Infusion (TCI)

Induction and maintenance of anesthesia in ventilated patients: TCI of Ultiva must be used in combination with intravenous or inhaled hypnotic agents during the induction and maintenance of anesthesia in ventilated adult patients (see Table 1). Adequate analgesia for anesthesia induction can be achieved when combined with these agents, and surgery can generally be performed with remifentanil blood concentrations of 3 to 8 nanograms/ml. The dose of Ultiva should be adjusted according to the individual patient's response. For surgery involving particularly stimulating procedures, blood concentrations of remifentanil up to 15 nanograms/ml may be required.

When administered at the doses indicated above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anesthesia. Therefore, it is recommended to administer the doses of isoflurane and propofol indicated above to avoid increased hemodynamic effects such as hypotension and bradycardia (see Table 1 and the information on Concomitant Medication in this section).

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

Due to insufficient data, the use of Ultiva by TCI for anesthesia with spontaneous ventilation is not recommended.

Recommendations for discontinuation/continuation in the immediate postoperative period: at the end of surgery, when the TCI infusion is stopped or the target concentration is reduced, spontaneous respiration is likely to return within remifentanil blood concentrations of 1 to 2 nanograms/ml. As with manually controlled infusion, postoperative analgesia with longer-acting analgesics should be administered before the end of surgery (see recommendations for discontinuation in the case of manually controlled infusion in this section).

Due to insufficient data, the use of Ultiva by TCI for postoperative analgesia is not recommended.

Paediatric population (1 to 12 years of age)

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

Table 2. Dosage guidelines for paediatric population (1–12 years)

CONCOMITANT ANESTHETIC AGENT*	BOLUS INJECTION (micrograms/kg)	CONTINUOUS INFUSION (micrograms/kg/min)
		Initial rate	Usual maintenance rate
Halothane (initial dose 0.3 MAC)	1	0.25	0.05 to 1.3
Sevoflurane (initial dose 0.3 MAC)	1	0.25	0.05 to 0.9
Isoflurane (initial dose 0.5 MAC)	1	0.25	0.06 to 0.9

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

When Ultiva injection 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 Ultiva infusion, if a bolus dose is not simultaneously administered. For the sole administration of nitrous oxide (70%) with Ultiva, the usual maintenance rates should range between 0.4 and 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 closely, with dose adjustments made according to the depth of analgesia considered appropriate for each surgical procedure.

Concomitant medication: At the recommended doses above, remifentanil significantly reduces the amount of hypnotic agent required to maintain anesthesia. Therefore, isoflurane, halothane, and sevoflurane should be administered as recommended in the table in order to avoid an increase in hemodynamic effects such as hypotension and bradycardia. There are no data on the simultaneous use of remifentanil with other hypnotic agents not listed in the table to allow for dosage recommendations (see Adults - Concomitant Medication in this section).

Recommendations for managing patients in the immediate postoperative period

Establishing 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 5–10 minutes after stopping administration. In patients undergoing surgical procedures where postoperative pain is anticipated, analgesics should be administered before discontinuing Ultiva. Sufficient time should be allowed for the therapeutic effect of the longer-acting analgesic to be achieved. The choice, dose, and timing of administration of the agent(s) should be planned in advance and individually adjusted to be appropriate for both the surgical procedure the patient has undergone and the anticipated level of postoperative care (see Warnings and special precautions for use).

Neonates/infants (less than 1 year of age)

There is limited clinical trial experience 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 appropriate adjustments for body weight differences (see section 5.2. of the Summary of Product Characteristics). However, as sufficient clinical data are not available, administration of Ultiva is not recommended in this age group.

Use in Total Intravenous Anesthesia (TIVA): There is limited clinical trial experience with remifentanil for total intravenous anesthesia in infants (see section 5.1 of the Summary of Product Characteristics); however, there are insufficient clinical data to provide dosage recommendations.

Cardiac anesthesia

Manual controlled infusion administration

Table 3. Dosing guidelines for cardiac anesthesia

INDICATION	BOLUS INJECTION (micrograms/kg)	CONTINUOUS INFUSION (micrograms/kg/min)	Initial Infusion Rate	Usual Infusion Rate

Intubation	Not recommended	1	--

Maintenance of anesthesia

? Isoflurane (initial dose 0.4 MAC)	0.5 to 1	1	0.003 to 4
? Propofol (initial dose 50 micrograms/kg/min)	0.5 to 1	1	0.01 to 4.3

Continuation of pre-extubation postoperative analgesia	Not recommended	1	0 to 1

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

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

Concomitant medication: At the previously recommended doses, remifentanil significantly reduces the amount of hypnotic agent required 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. Data are not available to provide dosage recommendations for the simultaneous use of remifentanil with other hypnotic agents not listed in the table (see - Adults - Concomitant Medication in this section).

Recommendations for postoperative patient management

Continuation of Ultiva administration postoperatively to provide analgesia prior to extubation: It is recommended that Ultiva infusion be maintained at the final intraoperative rate during patient transfer to the post-anesthesia care unit. Upon arrival in this unit, the patient's level of analgesia and sedation should be closely monitored, and the Ultiva infusion rate adjusted according to patient requirements (see the section Use in Intensive Care Units in this section for further information on managing patients in intensive care units).

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 stopping the infusion. Prior to discontinuing Ultiva, alternative analgesic and sedative agents should be administered with sufficient lead time to allow establishment of their therapeutic effects. It is therefore recommended that the choice, dosage, and timing of administration of such drug(s) be planned in advance of weaning the patient from mechanical ventilation.

Recommendations for discontinuation of Ultiva: Due to the very rapid offset of action of Ultiva, cases of hypertension, tremors, and pain have been reported in patients after cardiac surgery immediately following discontinuation of Ultiva (see section 4 Possible adverse effects in the package leaflet). To minimize the risk of these events, appropriate alternative analgesia (as indicated above) should be established before stopping the Ultiva infusion. The infusion rate should be reduced in steps of approximately 25%, at intervals of at least 10 minutes, until Ultiva infusion is discontinued.

During weaning from mechanical ventilation, Ultiva infusion should not be increased; only downward adjustments should be made, supplemented if necessary with administration of alternative analgesics. Hemodynamic changes such as hypertension and tachycardia should be treated, when needed, with alternative agents.

When other opioid agents are administered as part of the transition 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 caused by these drugs.

Administration by target-controlled infusion (TCI)

Induction and maintenance of anesthesia: Ultiva TCI should be used in combination with an intravenous or inhaled hypnotic agent during induction and maintenance of anesthesia in ventilated adult patients (see Table 3). In combination with these agents, an adequate level of analgesia for cardiac surgery is generally achieved at the upper end of the remifentanil blood concentration range recommended for general surgical procedures. After titrating remifentanil according to individual patient response, blood 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 agent required 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 Medication in this section).

Remifentanil blood concentrations achieved with manually controlled infusions are provided in Table 11 of section 6.6. of the Summary of Product Characteristics for reference.

Recommendations for discontinuation/continuation in the immediate postoperative period: At the end of surgery, when TCI infusion is stopped or the target concentration reduced, spontaneous respiration is likely to occur at remifentanil concentrations around 2 nanograms/ml. As with manually controlled infusion, postoperative analgesia with longer-acting analgesics should be administered before the end of surgery (see discontinuation recommendations for manually controlled infusion in this section).

Due to insufficient data, the use of Ultiva via TCI for postoperative analgesia is not recommended.

Pediatric patients (1 to 12 years of age)

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

Use in Intensive Care Units

Adults

Ultiva may be used to provide analgesia in mechanically ventilated patients admitted to Intensive Care Units. Sedative agents should be administered when necessary.

The efficacy and safety of Ultiva in mechanically ventilated intensive care patients have been established in well-controlled clinical trials of up to three days' duration (see Renal Impairment in Intensive Care Patients in this section and section 5.2 of the Summary of Product Characteristics). Therefore, use of Ultiva for longer than 3 days of treatment is not recommended.

The use of Ultiva via TCI has not been studied in intensive care patients, and therefore administration of Ultiva via TCI in these patients is not recommended.

In adults, Ultiva administration should be initiated at an infusion rate of 0.1 microgram/kg/min (6 micrograms/kg/h) to 0.15 microgram/kg/min (9 micrograms/kg/h). The infusion rate should be adjusted in increments of 0.025 microgram/kg/min (1.5 micrograms/kg/h) until the desired level of analgesia is achieved. A minimum interval of at least 5 minutes should be allowed between dose adjustments. The patient should be regularly assessed, and the Ultiva infusion rate adjusted according to individual needs. If an infusion rate of 0.2 microgram/kg/min (12 micrograms/kg/h) is reached and sedation is required, administration of an appropriate sedative agent is recommended (see information below). The sedative dose should be adjusted to achieve the desired level of sedation. Additional increments of approximately 0.025 microgram/kg/min (1.5 micrograms/kg/h) may be made in the Ultiva infusion rate if additional analgesia is needed.

Table 4 summarizes the recommended initial infusion rates and usual dosage ranges for providing analgesia in patients.

Table 4 Dosing guidelines for Ultiva in Intensive Care Units

CONTINUOUS INFUSION

Micrograms/kg/min (micrograms/kg/h)

Initial rate

Range

0.1 (6) to 0.15 (9)

0.006 (0.38) to 0.74 (44.6)

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

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

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

Sedative drugs

Bolus (mg/kg)

Infusion (mg/kg/h)

Propofol

Midazolam

Up to 0.5

Up to 0.03

0.5

0.03

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 stimulating procedures: It may be necessary to increase the existing infusion rate of Ultiva to provide additional analgesic coverage for ventilated patients undergoing stimulating and/or painful procedures such as endotracheal suctioning, wound care, and physiotherapy. It is recommended that, for at least 5 minutes prior to initiating the stimulating procedure, an Ultiva infusion rate of at least 0.1 microgram/kg/min (6 micrograms/kg/h) be maintained. The dose may subsequently be adjusted every 2 to 5 minutes in increments of approximately 25% to 50%, either anticipating or in response to the need for additional analgesia. During stimulating procedures, a mean infusion rate of 0.25 microgram/kg/min (15 micrograms/kg/h) has been used, with a maximum of 0.74 microgram/kg/min (45 micrograms/kg/h) to provide additional analgesia.

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 5 to 10 minutes after stopping the infusion, regardless of the duration of infusion. After Ultiva administration, the potential for development of tolerance, hyperalgesia, and associated hemodynamic changes should be considered when used in the intensive care unit (see section 4.4 Warnings and special precautions for use). Therefore, before discontinuing Ultiva, patients should receive alternative analgesics and sedatives to prevent hyperalgesia and associated hemodynamic changes. These drugs should be administered with sufficient lead time to allow establishment of their therapeutic effects. Available analgesic options include long-acting analgesics administered orally, intravenously, or regionally, delivered via nurse- or patient-controlled techniques. These methods should always be tailored to individual patient needs as Ultiva infusion is tapered. It is recommended that the choice, dose, and timing of administration of such drug(s) be planned in advance of discontinuing Ultiva.

Tolerance may develop over time during prolonged administration of -opioid receptor agonists.

Recommendations for extubation and discontinuation of Ultiva: To ensure a gradual transition out of Ultiva therapy, it is recommended that the Ultiva infusion rate be gradually reduced to 0.1 microgram/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, Ultiva infusion should not be increased, and only dose reductions should occur, supplemented if necessary with alternative analgesics.

After discontinuation of Ultiva, the intravenous cannula should be flushed or removed to prevent inadvertent subsequent administration of the drug.

When opioid drugs are administered as part of the transition to alternative analgesia, patients must be carefully monitored. The benefit of providing appropriate analgesia must always be weighed against the potential risk of respiratory depression following administration of these agents.

Paediatric patients in Intensive Care Units

No data are available on use in the paediatric population.

Renal impairment in Intensive Care Units

No dose adjustments to the recommended doses above are necessary when administering Ultiva to patients with renal impairment, including those undergoing dialysis; however, clearance of the carboxylic acid metabolite is reduced in patients with renal impairment (see section 5.2 of the Summary of Product Characteristics).

Special populations

Elderly patients (over 65 years)

General anaesthesia: The initial dose of remifentanil administered to patients over 65 years should be half the recommended dose for adults, with subsequent dosing adjusted according to individual patient need, as increased sensitivity to the pharmacological effects of remifentanil has been observed in this patient population. This dose adjustment applies to all phases of anaesthesia, including induction, maintenance, and immediate postoperative analgesia.

Due to increased sensitivity of elderly patients to Ultiva, the initial target concentration when administering Ultiva via TCI in this population should be 1.5 to 4 nanogram/ml, with subsequent titration according to response.

Cardiac anaesthesia: No reduction in initial dose is required (see Cardiac anaesthesia section).

Intensive Care: No reduction in initial dose is required (see Use in Intensive Care Units in this section).

Obese patients

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

With the lean body mass calculation used in the Minto model, lean body mass may be underestimated in female patients with a body mass index (BMI) above 35 kg/m² and in male patients with a BMI above 40 kg/m². To avoid underdosing in these patients, careful titration of remifentanil administered via TCI according to individual patient response is recommended.

Renal impairment

Based on investigations conducted to date, dose adjustment is not necessary in patients with impaired renal function, including patients in intensive care.

Hepatic impairment

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

Neurosurgery

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

ASA class III/IV patients

General anaesthesia: As the haemodynamic effects of potent opioids are expected to be more pronounced in ASA class III/IV patients, appropriate caution should be exercised when administering Ultiva to these patients. Therefore, it is recommended that the initial dose be reduced and subsequently adjusted. There are insufficient data in the paediatric population to establish dosage recommendations.

When administering via TCI, a lower initial concentration of 1.5 to 4 nanogram/ml should be used in patients belonging to ASA classes III and IV, with subsequent titration according to response.

Cardiac anaesthesia: No reduction in initial dose is required (see Cardiac anaesthesia section).

Contraindications

As Ultiva contains glycine, administration of Ultiva via epidural or intrathecal injection is contraindicated (see section 5.3 of the Summary of Product Characteristics).

Ultiva is contraindicated in patients with hypersensitivity to the active substance, to other fentanyl analogues, or to any of the excipients listed in section 6.1 of the Summary of Product Characteristics.

The use of Ultiva as the sole medication for induction of anaesthesia is contraindicated.

Warnings and special precautions for use

Ultiva should only be administered in a well-equipped facility capable of monitoring and maintaining respiratory and cardiovascular function, and by personnel specifically trained in the use of anaesthetic drugs and in the recognition and management of expected adverse reactions to potent opioids, including respiratory and cardiac resuscitation. Such training must include establishment and maintenance of an airway and assisted ventilation. The use of Ultiva is not recommended in mechanically ventilated patients admitted to Intensive Care Units for treatment durations exceeding 3 days.

Patients with known hypersensitivity to another class of opioids may experience a hypersensitivity reaction following administration of Ultiva. Caution should be exercised before using Ultiva in these patients (see Contraindications).

Rapid reversal of action/Transition to alternative analgesia

Due to the very rapid offset of action of Ultiva, there will be no residual opioid activity within 5–10 minutes after discontinuation of Ultiva administration. In patients undergoing surgical procedures where postoperative pain is anticipated, analgesics should be administered before stopping Ultiva. When used in Intensive Care Units (see section 4.2 Dosage and method of administration), the possibility of tolerance, hyperalgesia, and associated hemodynamic changes should be considered. Prior to discontinuing Ultiva treatment, alternative sedative and analgesic agents should be administered to patients. Sufficient time should elapse to achieve the therapeutic effect of the longer-acting analgesic. The choice, dose, and timing of administration of the agent(s) should be planned in advance and individually adjusted to suit both the surgical procedure and the anticipated level of postoperative care. When other opioid agents are administered as part of the transition to alternative analgesia, the benefit of providing adequate postoperative analgesia must be weighed against the potential risk of respiratory depression associated with these drugs.

Risk associated with concomitant use of sedative medicines such as benzodiazepines or related drugs

The concomitant use of Ultiva and sedative medicines, such as benzodiazepines or other related drugs, may result in sedation, respiratory depression, coma, and death. Because of these risks, concomitant prescribing with these drugs should be reserved for patients for whom no alternative treatment options are available. If a decision is made to prescribe Ultiva concomitantly with these medicines, the lowest effective dose should be used for the shortest possible duration.

Patients must be closely monitored for signs and symptoms of respiratory depression and sedation. In this regard, patients and caregivers should be strongly advised to remain vigilant for these symptoms (see Interaction with other medicines and other forms of interaction).

Discontinuation of treatment and withdrawal syndrome

Repeated administration at short intervals over prolonged periods may lead to the development of a withdrawal syndrome following discontinuation of treatment. After discontinuation of remifentanil treatment, symptoms such as tachycardia, hypertension, and agitation have been infrequently reported, particularly after abrupt withdrawal following prolonged administration of more than 3 days. When such symptoms occur, reintroduction and gradual tapering of the infusion have been beneficial. The use of Ultiva in mechanically ventilated intensive care patients is not recommended for treatment durations exceeding 3 days.

Muscle rigidity – prevention and management

Muscle rigidity may occur at recommended doses. As with other opioids, the incidence of muscle rigidity is related to dose and rate of administration. Therefore, bolus injections should be administered slowly over no less than 30 seconds.

Remifentanil-induced muscle rigidity should be managed according to the patient's clinical condition with appropriate supportive measures. Excessive muscle rigidity occurring during 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 managed by interrupting or reducing the infusion rate of remifentanil. Resolution of muscle rigidity after stopping the remifentanil infusion occurs within minutes. Alternatively, an opioid antagonist may be administered; however, this may reverse or attenuate the analgesic effect of remifentanil.

Respiratory depression – prevention and management

As with all potent opioids, profound analgesia is accompanied by significant respiratory depression. Therefore, remifentanil should only be used in areas equipped with facilities for monitoring and managing respiratory depression. Particular attention should be paid to patients with respiratory dysfunction. The occurrence of respiratory depression should be appropriately managed, including reducing the infusion rate by up to 50% or temporarily interrupting the infusion. Unlike other fentanyl analogs, remifentanil has not been shown to cause recurrent respiratory depression, even after prolonged administration. Nevertheless, since many factors may influence postoperative recovery, it is important to ensure that full consciousness and adequate spontaneous ventilation are 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 package leaflet and Interaction with other medicines and other forms of interaction), can be reduced by slowing the infusion rate of Ultiva or the doses of concurrently administered anesthetics, or by intravenous administration of fluids, vasopressors, or anticholinergics as appropriate.

Elderly, debilitated, hypovolemic, and hypotensive patients may be more sensitive to the cardiovascular effects of remifentanil.

Unintentional administration

Sufficient amounts of Ultiva may remain in the dead space of the intravenous administration line and/or cannula to cause respiratory depression, apnea, and/or muscle rigidity if the line is flushed with intravenous fluids or other drugs. This can be avoided by administering Ultiva via a dedicated rapid intravenous access line or by using a separate intravenous line that is removed when Ultiva infusion is discontinued.

Neonates/infants

Limited data are available regarding use in neonates/infants under 1 year of age (see Dosage and method of administration – Neonates/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 lead to tolerance, physical and psychological dependence, and opioid use disorder (OUD). Intentional abuse or misuse of opioids may result in overdose and/or death. The risk of developing OUD is higher in patients with personal or family history (parents or siblings) of substance use disorders (including alcohol use disorder), smokers, or patients with personal history of other mental health disorders (e.g., major depression, anxiety, or personality disorders).

Ultiva contains sodium

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

Interaction with other medicines and other forms of interaction

Remifentanil is not metabolized by plasma cholinesterase; therefore, interactions with drugs metabolized by this enzyme are not expected.

As with other opioid drugs, remifentanil, administered via manually controlled infusion or target-controlled infusion (TCI), reduces the required doses of inhaled or intravenous anesthetics as well as benzodiazepines used during anesthesia (see Dosage and method of administration). If doses of concomitantly administered CNS depressants are not reduced, patients may experience an increased incidence of adverse reactions associated with these drugs.

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

Concomitant administration of remifentanil with a serotonergic drug, 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 known as serotonin syndrome. Caution should be exercised when administering MAOIs concomitantly. 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 package leaflet and Special warnings and precautions for use) may be exacerbated in patients receiving concomitant treatment with drugs that depress cardiac function, such as beta-blockers and calcium channel blockers.

Alcohol consumption should be avoided after receiving Ultiva.

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.

Lactation

It is unknown whether remifentanil is excreted in human breast milk. However, since fentanyl analogs are excreted in breast milk and remifentanil-related material has been detected in rat milk after administration of remifentanil, breastfeeding women should be advised to discontinue breastfeeding for 24 hours following administration of remifentanil.

Labour and delivery

There are insufficient data to recommend the use of remifentanil during labour or cesarean section. Remifentanil is known to cross the placental barrier, and fentanyl analogs may cause respiratory depression in the newborn. If remifentanil is administered, both mother 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, overdose would manifest as an exaggeration of the pharmacologically predictable effects of remifentanil. Due to the very short duration of action of Ultiva, the potential for harmful effects following overdose is limited to the immediate period after administration. Response to discontinuation of the drug is rapid, with return to baseline status within 10 minutes.

In case of overdose or suspected overdose, the following actions should be taken: discontinue administration of Ultiva, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function. If respiratory depression is associated with muscle rigidity, a neuromuscular blocking agent may be required to facilitate assisted or controlled ventilation. Intravenous fluids and vasopressors, as well as other supportive measures, may be used to treat hypotension.

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 following an overdose of Ultiva will exceed the duration of 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 must not be reconstituted, diluted, or mixed with Ringer's lactate injection solution or Ringer's lactate and 5% glucose injection solution.

Ultiva must not be mixed with propofol in the same infusion bag prior to administration.

It is not recommended to administer Ultiva through the same intravenous line used for blood/serum/plasma, as the presence of nonspecific esterases in blood products may lead to hydrolysis of remifentanil, resulting in its inactive metabolite.

Ultiva must not be mixed with other medicines prior to 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 24 hours at 25°C. From a microbiological standpoint, the product should be used immediately. If not used immediately, storage conditions and times prior to use are the responsibility of the user and normally should not exceed 24 hours at 2–8°C, unless reconstitution was carried out under controlled and validated aseptic conditions.

Diluted solution:

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

Special precautions for disposal and other handling

To prepare Ultiva for intravenous administration, 1, 2, or 5 ml of diluent should be added as appropriate 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 visually inspected (if the container permits) for particles, discoloration, or container damage. Any solution showing such defects should be discarded. The reconstituted product is for single use only. Disposal of unused medicine and all materials that have come into contact with it should be carried out in accordance with local regulations.

Ultiva must not be administered via manually controlled infusion without further 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 aged 1 year or older).

Ultiva must not be administered via TCI without prior dilution (20 to 50 micrograms/ml is the recommended dilution for TCI administration).

The dilution depends on the technical capacity of the infusion device and the anticipated requirements of the patient.

Dilution must be performed using one of the following intravenous fluids:

-	Water for injections
-	5 % glucose injection solution
-	5 % glucose and 0.9 % sodium chloride injection solution
-	0.9 % sodium chloride injection solution
-	0.45 % sodium chloride injection solution.

After dilution, visually inspect the product to ensure it is clear, colorless, practically free of particles, and that the container is undamaged. Discard any solution in which such defects are observed.

Ultiva is compatible with the following intravenous fluids when administered via an intravenous catheter:

-	Injectable solution Ringer lactate
-	Injectable solution Ringer lactate and 5 % glucose

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