Ultiva

Leaflet accompanying the packaging: patient information

Ultiva, 1 mg, powder for solution for injection and infusion

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

Ultiva, 5 mg, powder for solution for injection and infusion

Remifentanil

You should carefully read the contents of this leaflet before taking this medicine, as it contains important information for you.

• You should keep this leaflet, so you can read it again if you need to.
• If you have any doubts, you should consult your doctor.
• If the patient experiences any side effects, including any side effects not listed in this leaflet, they should inform their doctor or pharmacist. See section 4.

Table of contents of the leaflet

• 1. What is Ultiva and what is it used for
• 2. Important information before taking Ultiva
• 3. How to take Ultiva
• 4. Possible side effects
• 5. How to store Ultiva
• 6. Contents of the packaging and other information

1. What is Ultiva and what is it used for

Ultiva contains the active substance remifentanil. Remifentanil belongs to a group of medicines called opioids, which are used to relieve pain. Ultiva differs from other medicines in this group due to its very rapid onset and very short duration of action. Ultiva is used to:

• relieve pain before or during surgery
• relieve pain in patients aged 18 and over who are mechanically ventilated in intensive care units (ICU).

2. Important information before taking Ultiva

When not to take Ultiva

• if the patient is allergic (hypersensitive) to remifentanil or any of the other ingredients of this medicine (listed in section 6) or to fentanyl derivatives (such as alfentanil, fentanyl, sufentanil)
• for spinal injections
• as the only medicine for induction of anesthesia.

In case of doubt whether any of the above situations apply to the patient, they should consult their doctor, nurse, or pharmacist before taking Ultiva.

Warnings and precautions

Before starting treatment with Ultiva, the patient should discuss the following with their doctor:

• if the patient has impaired lung function (the patient may be more susceptible to respiratory depression)
• if the patient is allergic to other opioids (e.g., morphine, codeine, pethidine)
• if the patient is over 65, is emaciated, has reduced blood volume, and/or low blood pressure (the patient may be more susceptible to cardiac disorders)

In case of doubt whether any of the above situations apply to the patient, they should consult their doctor or nurse before taking Ultiva. Before starting treatment with remifentanil, the patient should discuss the following with their doctor:

• if the patient or a family member has ever abused alcohol, prescription drugs, or illegal substances or has been dependent on them ("addiction").
• if the patient smokes.
• if the patient has ever had mood problems (depression, anxiety, or personality disorders) or has been treated by a psychiatrist for other mental illnesses.

This medicine contains remifentanil, which is an opioid medicine. Repeated use of opioid painkillers may lead to a decrease in the effectiveness of the medicine (the patient getting used to it) and may also lead to dependence and abuse, which can be life-threatening. If the patient is concerned about becoming dependent on Ultiva, it is essential to consult their doctor. In the event of sudden discontinuation of this medicine, especially if treatment has lasted longer than 3 days, withdrawal reactions have sometimes occurred, including rapid heartbeat, high blood pressure, and anxiety (see also section 4, "Possible side effects"). If the patient experiences these symptoms, their doctor may recommend resuming the medicine and gradually reducing the dose.

Ultiva and other medicines

The patient should tell their doctor about all medicines they are currently taking or have recently taken, as well as any medicines they plan to take. This includes herbal medicines or medicines available without a prescription. In particular, the patient should inform their doctor if they are taking any of the following medicines:

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

Taking Ultiva and sedative medicines (such as benzodiazepine derivatives or benzodiazepine-like medicines) at the same time increases the risk of drowsiness, breathing difficulties (respiratory depression), coma, and can be life-threatening. Therefore, taking such medicines at the same time should only be considered when there are no other treatment options available. Taking opioids and medicines used to treat epilepsy, nerve pain, or anxiety (gabapentin and pregabalin) at the same time increases the risk of opioid overdose, respiratory depression, and can be life-threatening. However, if the doctor prescribes Ultiva to the patient along with sedative medicines, they should limit the dose and duration of such concurrent treatment. The patient should inform their doctor about all sedative medicines they are taking and strictly follow their doctor's instructions. It may be helpful to inform friends and family to watch for the above symptoms. If such symptoms occur, the patient should contact their doctor.

Ultiva and alcohol

After taking Ultiva, the patient should not consume alcohol until the effects of the medicine have fully worn off.

Pregnancy and breastfeeding

If the patient is pregnant or breastfeeding, thinks they may be pregnant, or plans to have a child, they should consult their doctor before taking this medicine. If the patient receives this medicine during childbirth, it may have a negative effect on the baby's breathing. The patient and the newborn will be monitored for signs of excessive drowsiness and breathing difficulties.

Driving and using machines

If the patient is in the hospital for only one day, their doctor will inform them when they can leave the hospital or drive a car. Driving too soon after surgery can be dangerous.

Ultiva contains sodium

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

3. How to take Ultiva

The patient will never take this medicine by themselves. It will always be administered to them by a qualified person. Ultiva can be given:

• as a single intravenous injection
• as a continuous intravenous infusion (the medicine is given slowly over a long period).

The method of administration and the dose the patient receives will depend on:

• the type of surgery or treatment the patient will undergo in the intensive care unit
• the severity of the pain experienced.

The dose of the medicine may vary from patient to patient. There is no need to adjust the dose in patients with kidney or liver function disorders.

After surgery

If the patient experiences pain after the operation, they should inform their doctor or nurse. They will then be able to administer other pain-relieving medicines.

4. Possible side effects

Like all medicines, Ultiva can cause side effects, although not everybody gets them. Allergic reactions, including anaphylactic reactions:these are rare side effects (may occur in less than 1 in 1,000 patients) after taking Ultiva. Symptoms include:

• raised and itchy skin rash (hives)
• swelling of the face, lips, mouth, or tongue (angioedema), which can cause breathing difficulties
• collapse

Severe allergic reactions can lead to life-threatening anaphylactic shock;

Frequency not known (cannot be estimated from the available data), including exacerbation of allergic symptoms, significant drop in blood pressure, rapid heartbeat, and/or fainting.

Very common side effects (may occur in more than 1 in 10 patients)

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

Common side effects (may occur in less than 1 in 10 patients)

• slow heartbeat (bradycardia)
• shallow breathing (respiratory depression)
• periodic cessation of breathing (apnea)
• itching
• coughing

Uncommon side effects (may occur in less than 1 in 100 patients)

• oxygen deficiency (hypoxia)
• constipation

Rare side effects (may occur in less than 1 in 1,000 patients)

• slow heartbeat (bradycardia), followed by cardiac arrest (asystole and cardiac arrest) in patients taking Ultiva at the same time as one or more anesthetic medicines

Frequency not known (cannot be estimated from the available data)

• physical need to take Ultiva (drug dependence) or the need to take increasingly larger doses to achieve the same effect (drug tolerance)
• seizures
• uneven heartbeat (atrioventricular block)
• irregular heartbeat (arrhythmia)
• withdrawal syndrome (the following side effects may occur: increased heart rate, high blood pressure, anxiety or agitation, nausea, vomiting, diarrhea, anxiety, shivering, and sweating)

Side effects that may occur after surgery

Common side effects (may occur in less than 1 in 10 patients)

• shivering
• high blood pressure (hypertension)

Uncommon side effects (may occur in less than 1 in 100 patients)

• pain

Rare side effects (may occur in less than 1 in 1,000 patients)

• feeling of calmness and drowsiness

Reporting side effects

If side effects occur, including any side effects not listed in this leaflet, the patient should inform their doctor or pharmacist. Side effects can be reported directly to the Department of Monitoring of Adverse Reactions to Medicinal Products, Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw, phone: +48 22 49 21 301, fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl. Side effects can also be reported to the marketing authorization holder. By reporting side effects, more information can be gathered on the safety of this medicine.

5. How to store Ultiva

The medicine should be stored out of sight and reach of children. Do not use this medicine after the expiry date stated on the packaging. The expiry date refers to the last day of the month stated. Store at a temperature not exceeding 25°C. The solution of Ultiva should be used immediately after preparation. For information on the storage conditions of Ultiva after reconstitution and further dilution, see "Information intended for healthcare professionals only". Medicines should not be disposed of via wastewater or household waste. The patient should ask their pharmacist how to dispose of medicines that are no longer needed. This will help protect the environment.

6. Contents of the packaging and other information

What Ultiva contains

• The active substance of Ultiva is remifentanil (as remifentanil hydrochloride).

Ultiva, 1 mg: one vial contains 1 mg of remifentanil (Remifentanilum) as remifentanil hydrochloride. After reconstitution as recommended, one ml of the solution contains 1 mg of remifentanil (1 mg in 1 ml). Ultiva, 2 mg: one vial contains 2 mg of remifentanil (Remifentanilum) as remifentanil hydrochloride. After reconstitution as recommended, one ml of the solution contains 1 mg of remifentanil (2 mg in 2 ml). Ultiva, 5 mg: one vial contains 5 mg of remifentanil (Remifentanilum) as remifentanil hydrochloride. After reconstitution as recommended, one ml of the solution contains 1 mg of remifentanil (5 mg in 5 ml).

• The other ingredients are glycine, diluted hydrochloric acid (for pH adjustment), and sodium hydroxide (for pH adjustment).

What Ultiva looks like and contents of the pack

Ultiva is a lyophilized, white to off-white, sterile, apyrogenic powder without preservatives for solution for injection and infusion. It is supplied in vials of 3 ml, 5 ml, or 10 ml of clear glass, closed with a bromobutyl rubber stopper and an aluminum cap with a plastic cover in a cardboard box. Pack sizes: Ultiva, 1 mg: 5 vials of 3 ml. Ultiva, 2 mg: 5 vials of 5 ml. Ultiva, 5 mg: 5 vials of 10 ml. Before injection, the powder will be mixed with a suitable liquid (for further information, see "Information intended for healthcare professionals only"). The solution after dissolution of the powder is clear and colorless.

Marketing authorization holder

Aspen Pharma Trading Limited, 3016 Lake Drive, Citywest Business Campus, Dublin 24, Ireland, Tel: 00 48 22 104 21 00

Manufacturer

Avara Liscate Pharmaceutical Services S.p.A., Via Fosse Ardeatine, 2, 20050 Liscate (MI), Italy

Date of last revision of the leaflet: 08/2024 ((logo Aspen))

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Information intended for healthcare professionals only:

To obtain more detailed information, please refer to the Summary of Product Characteristics.

Ultiva, 1 mg, powder for solution for injection and infusion

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

Ultiva, 5 mg, powder for solution for injection and infusion

Remifentanil

Dosage and administration

Ultiva may only be used in departments equipped with equipment that allows for monitoring and supporting respiratory and circulatory functions and may only be administered by persons trained in the use of anesthetic medicines, in recognizing and treating expected side effects of potent opioids (including conducting respiratory and circulatory resuscitation), ensuring and maintaining airway patency, and providing assisted ventilation.

Ultiva should be administered via a calibrated infusion pump into an intravenous line with a high flow rate or through a dedicated intravenous line for this medicinal product only.This line should be connected directly to or close to the intravenous cannula and checked before use to minimize potential dead space (see section "Special precautions for disposal and preparation of the medicinal product for administration" and section 6.6 of the Summary of Product Characteristics, which includes tables with example infusion rates based on body weight to facilitate gradual dose adjustment of Ultiva to individual patient needs). Care should be taken to avoid clogging or disconnection of the line. After completion of the infusion, the line should be flushed appropriately to remove any remaining Ultiva (see section "Special warnings and precautions for use"). Ultiva is intended for intravenous use only. The product should not be administered via epidural or intrathecal injection (see section "Contraindications").

Preparation of the solution

After reconstitution, Ultiva may be further diluted [see section "Shelf life and storage" and "Special precautions for disposal and preparation of the medicinal product for administration" for information on the storage conditions of the reconstituted and/or diluted solution and recommended diluents]. For manual infusion, Ultiva can be diluted to concentrations between 20 and 250 micrograms/ml (recommended dilution for adults is 50 micrograms/ml, for children aged 1 year and over is 20-25 micrograms/ml).

Anesthesia

Dosing of remifentanil should be individualized and titrated to the desired clinical effect. The following table provides recommended initial infusion rates and dose ranges for adults:

Table 1: Recommended dosing for adults

Administration of remifentanil in a single injection during induction of anesthesia should not be less than 30 seconds. Isoflurane and propofol should be administered according to the above recommendations to avoid potentiation of hemodynamic effects such as hypotension and bradycardia (see section "Concomitant use with other medicines" and Table 1). Due to the rapid onset and short duration of action of remifentanil, the infusion rate can be gradually increased by 25-100% or decreased by 25-50% every 2-5 minutes until the desired opioid receptor effect is achieved. In case of inadequate anesthesia, remifentanil can be administered in additional single injections every 2-5 minutes.

Children and adolescents (1-12 years)

Induction of anesthesia

Due to the lack of detailed studies on the concomitant administration of remifentanil and intravenous anesthetic medicines during induction of anesthesia, such a combination is not recommended.

Maintenance of anesthesia

For maintenance of anesthesia, the following doses of Ultiva are recommended:

Table 2: Guidelines for dosing for maintenance of anesthesia in children and adolescents (1-12 years)

* in a mixture of oxygen with nitrous oxide and/or oxygen in a 1:2 ratio Administration of remifentanil in a single injection should not be less than 30 seconds. The procedure can be started no earlier than 5 minutes after the start of the remifentanil infusion if no single injection is given. When nitrous oxide (70%) is used alone in combination with Ultiva, the typical infusion rate during maintenance of general anesthesia should be between 0.4 and 3 micrograms/kg/min, and although detailed studies have not been conducted, data from adult patients suggest that 0.4 micrograms/kg/min is an appropriate initial rate. The patient's condition should be monitored, and the dose adjusted according to the depth of anesthesia required for the surgical procedure.

Concomitant use with other medicines

In the recommended doses above, remifentanil significantly reduces the dose of anesthetic medicines required for maintenance of anesthesia. Therefore, isoflurane, halothane, and sevoflurane should be administered according to the above recommendations to avoid potentiation of hemodynamic effects such as hypotension and bradycardia. Due to the lack of data, no recommendations can be made regarding dosing during general anesthesia with remifentanil and other anesthetic medicines than those mentioned above (see section "General anesthesia - Adults - Concomitant use with other medicines").

Guidelines for postoperative management

Establishing alternative analgesia before discontinuing Ultiva

Due to the very rapid offset of action of Ultiva, residual opioid activity disappears within 5-10 minutes after discontinuation of the medicine. In patients undergoing surgical procedures where postoperative pain is expected, analgesic medicines should be administered before discontinuation of Ultiva. The time required to achieve therapeutic effects with long-acting analgesic medicines should be taken into account. The choice of medicine, dose, and time of administration should be planned in advance and individualized according to the type of surgical procedure and the expected scope of postoperative care (see section "Special warnings and precautions for use").

Infants and toddlers (under 1 year)

Experience with remifentanil in clinical studies is limited in infants and toddlers under 1 year of age (see section 5.1 of the Summary of Product Characteristics). The pharmacokinetic profile of remifentanil in infants and toddlers (under 1 year) is similar to that observed in adults (after adjusting for body weight differences) (see section 5.2 of the Summary of Product Characteristics). However, due to the lack of sufficient clinical data, Ultiva should not be used in this age group.

Cardioanesthesia

Table 3: Recommended dosing for cardioanesthesia

Induction of anesthesia

After administration of the anesthetic medicine to achieve a state of reduced consciousness, the remifentanil infusion should be started at an initial rate of 1 microgram/kg/min. Remifentanil should not be administered in a single injection during induction of anesthesia in patients undergoing cardiothoracic surgery. Intubation should not be performed before 5 minutes after the start of the remifentanil infusion.

Maintenance of anesthesia

After intubation, the remifentanil infusion rate should be adjusted according to the patient's needs. If necessary, additional single injections can be administered. Patients at high risk of cardiac complications (e.g., those with impaired ventricular function or undergoing valve surgery) should receive a maximum dose of 0.5 micrograms/kg in a single injection. These recommendations also apply to patients undergoing surgery under hypothermic conditions with cardiopulmonary bypass (see section 5.2 of the Summary of Product Characteristics).

Concomitant use with other medicines

In the recommended doses above, remifentanil significantly reduces the dose of anesthetic medicines required for maintenance of anesthesia. Therefore, isoflurane and propofol should be administered according to the above recommendations to avoid potentiation of hemodynamic effects such as hypotension and bradycardia. There are no available data to provide recommendations for dosing with remifentanil and other anesthetic medicines than those mentioned above (see section "General anesthesia - Adults - Concomitant use with other medicines").

Guidelines for postoperative management

Continuation of anesthesia in the postoperative period before extubation

During transportation of the patient to the postoperative care unit, the remifentanil infusion should be continued at the same rate as at the end of surgery. After arrival at the postoperative care unit, the level of analgesia and sedation should be closely monitored, and the remifentanil infusion rate adjusted according to individual patient needs (see section "Use in intensive care units" for further information on treatment of patients in intensive care units). The remifentanil infusion rate should be gradually decreased by 25% at intervals of at least 10 minutes before discontinuation. The infusion rate should not be increased during extubation. Only gradual reduction of the infusion rate and, if necessary, administration of other analgesic medicines are permitted. Hemodynamic changes such as hypertension and tachycardia should be treated with other appropriate medicines.

If other opioid medicines are administered as part of the postoperative management, the patient should be closely monitored.

The benefits of providing adequate postoperative pain management must always be weighed against the potential risk of respiratory depression.

Use in intensive care units

Ultiva can be used to provide analgesia in mechanically ventilated patients in intensive care units. If necessary, sedative medicines should also be administered. Remifentanil has been evaluated in clinical studies lasting up to 3 days in mechanically ventilated patients in intensive care units (see section 5.2 of the Summary of Product Characteristics). Therefore, Ultiva should not be used for treatment lasting longer than 3 days. In adult patients, the remifentanil infusion should be started at a 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 increased by 0.025 micrograms/kg/min (1.5 micrograms/kg/h) to achieve the desired level of sedation and analgesia. Dose adjustments should not be made more frequently than every 5 minutes. The level of sedation and analgesia should be closely monitored and regularly assessed to adjust the remifentanil infusion rate accordingly. If a satisfactory level of sedation is not achieved at an infusion rate of 0.2 micrograms/kg/min (12 micrograms/kg/h), administration of a suitable sedative medicine should be started. The dose of the sedative medicine should be adjusted according to the desired level of sedation. The remifentanil infusion rate can be increased again by 0.025 micrograms/kg/min (1.5 micrograms/kg/h) if additional analgesia is required.

Table 4: Recommendations for use in intensive care units

Continuous infusion micrograms/kg/min (micrograms/kg/h)

Initial infusion rate Range

0.1 (6) to 0.15 (9) 0.006 (0.38) to 0.74 (44.6) Ultiva should not be administered in single injections in intensive care units. The use of Ultiva reduces the need for concomitantly administered sedative medicines. Standard initial doses of sedative medicines (if their administration is necessary) are presented in the following table.

Table 5. Recommended Initial Doses of Sedative Medicinal Products (if necessary)

In order to enable separate dose adjustment of individual medicinal products, sedative medicinal products should not be added to the solution containing remifentanil.
Additional anesthesia for mechanically ventilated patients undergoing procedures related to painful stimulation
such as tracheal suction, dressing changes, and physiotherapy
Increasing the infusion rate of Ultiva may be necessary to provide additional anesthesia to ventilated patients during procedures related to painful stimulation, such as tracheal suction, dressing changes, and physiotherapy. The infusion rate should be maintained at least 0.1 micrograms/kg body weight/min (6 micrograms/kg body weight/h) for at least 5 minutes before the start of the painful stimulation procedure. In case of anticipated or existing need for additional anesthesia, the dose can be further adjusted at intervals of 2 to 5 minutes by 25 - 50%. To achieve additional anesthesia during painful stimulation, the average infusion rate of remifentanil is 0.25 micrograms/kg body weight/min (15 micrograms/kg body weight/h), up to a maximum of 0.75 micrograms/kg body weight/min (45 micrograms/kg body weight/h).
Establishing alternative anesthesia before discontinuing Ultiva administration
Due to the very rapid offset of action of Ultiva, residual opioid activity disappears within 5 - 10 minutes after discontinuation of the medicinal product, regardless of the duration of infusion. The possibility of tolerance, hyperalgesia, and associated hemodynamic changes should be considered after administration of Ultiva in the intensive care unit (see section 4.2 “Special warnings and precautions for use”).
Therefore, before discontinuing Ultiva, other analgesic and sedative medicinal products should be administered to prevent hyperalgesia and associated hemodynamic changes.
These products should be administered with sufficient lead time to allow for the full therapeutic effect. Optional analgesic treatment includes long-acting oral, intravenous, or regional anesthesia medicinal products, whose administration is controlled by a nurse or patient. Treatment should always be adjusted to the individual patient's needs as the dose of Ultiva is reduced. The choice of medicinal product, dose, and time of administration should be planned in advance and adjusted according to the type of surgical procedure and anticipated postoperative care. If other opioid medicinal products are administered as part of the treatment during the transition to alternative analgesic treatment, the benefits of ensuring adequate analgesic treatment must always take into account the potential risk of respiratory depression.

Use in Children and Adolescents in Intensive Care Units

There are no available data on the use of Ultiva in children and adolescents in intensive care units.

Patients with Renal Impairment Treated in Intensive Care Units

In patients with impaired function, including those undergoing renal replacement therapy, adjustment of the recommended doses is not necessary. However, the clearance of the carboxylic metabolite is reduced in patients with renal impairment (see section 5.2 Pharmaceutical Product Characteristics).

Special Populations

Elderly Patients (over 65 years)

General Anesthesia
In patients over 65 years of age, increased sensitivity to the pharmacological effects of remifentanil has been observed. Therefore, the initial dose of remifentanil in this patient population should be half of the recommended dose for adults. Subsequent dosing should be adjusted to individual patient needs, both during the induction and maintenance of anesthesia and during postoperative pain treatment.
Cardiovascular Anesthesia
Reduction of the initial dose is not necessary.
Intensive Care
Reduction of the initial dose is not necessary.

Obese Patients

In obese patients, the dosing of remifentanil should be reduced and adjusted to their ideal body weight, as in this population, the clearance and volume of distribution of remifentanil are better correlated with ideal than with actual body weight.

Patients with Renal Impairment

Based on the studies conducted to date, dose adjustment is not necessary in patients with renal impairment, including those in intensive care units.

Patients with Hepatic Impairment

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

Neurosurgery

Limited clinical experience in patients undergoing neurosurgical procedures indicates that there are no special dosage recommendations for this patient population.

Dosing in Patients with ASA III/IV Physical Status

General Anesthesia
Since the hemodynamic effects of potent opioids may be enhanced in patients with ASA III/IV physical status, caution should be exercised when administering Ultiva to these patients. The initial dose should be reduced, and subsequent dosing adjusted according to the therapeutic response.
There are insufficient data to determine dosage recommendations in the pediatric population.
Cardiovascular Anesthesia
Reduction of the initial dose is not necessary.

Contraindications

Hypersensitivity to the active substance or other fentanyl derivatives or to any of the excipients listed in section 6.1.
Due to the presence of glycine, Ultiva is contraindicated for epidural or spinal use (see section 5.2 Pharmaceutical Product Characteristics).
Ultiva is contraindicated for use as the sole medicinal product for the induction of anesthesia.

Special Warnings and Precautions for Use

Ultiva should only be used in units equipped with facilities for monitoring and supporting respiratory and cardiovascular function and only administered by persons trained in the use of anesthetic medicinal products, in the recognition and management of overdose, and in the resuscitation of patients, including the maintenance of a patent airway, ventilation, and circulatory support. Ultiva should not be used in mechanically ventilated patients in intensive care units for longer than 3 days.
In patients with known hypersensitivity to opioids of other classes, a hypersensitivity reaction may occur after administration of remifentanil. Therefore, caution should be exercised when using Ultiva in these patients.
Rapid Offset/Transition to Alternative Analgesia
Due to the very rapid offset of action of Ultiva, residual opioid activity disappears within 5 - 10 minutes after discontinuation of the medicinal product. In patients undergoing surgical procedures where postoperative pain is expected, analgesic medicinal products should be administered before discontinuation of Ultiva. During use in intensive care units, the possibility of tolerance, hyperalgesia, and associated hemodynamic changes should be considered (see section 4.2 “Special warnings and precautions for use”).
Before discontinuation of Ultiva, alternative analgesic and sedative medicinal products should be administered to prevent hyperalgesia and associated hemodynamic changes. The time necessary to achieve the therapeutic effect of long-acting analgesic medicinal products should be taken into account. The choice of medicinal product, dose, and time of administration should be planned in advance and adjusted according to the type of surgical procedure and anticipated postoperative care. If other opioid medicinal products are administered as part of the treatment during the transition to alternative analgesic treatment, the benefits of ensuring adequate analgesic treatment must always take into account the potential risk of respiratory depression.

Interaction with Other Medicinal Products and Other Forms of Interaction

Remifentanil is not metabolized by plasma cholinesterase, and therefore, no interactions with medicinal products metabolized by this enzyme are expected.
Like other opioids, remifentanil allows the use of smaller doses of inhalational or intravenous anesthetic medicinal products and benzodiazepines required for anesthesia (see section “Dosage and Administration”). If the doses of concomitantly administered medicinal products with a depressant effect on the central nervous system are not reduced, the frequency of adverse reactions caused by these medicinal products may be higher.
The effect of Ultiva on the cardiovascular system (hypotension and bradycardia, see section 4 of the Package Leaflet and “Special warnings and precautions for use”) may be enhanced in patients receiving beta-blockers and calcium channel blockers.
Concomitant use of opioids with sedative medicinal products, such as benzodiazepine derivatives or benzodiazepine-like medicinal products, increases the risk of excessive sedation, respiratory depression, coma, and death due to their additive depressant effect on the central nervous system. The dose and duration of concomitant use of these sedative medicinal products should be limited (see section “Special warnings and precautions for use”).
Concomitant use of opioids and gabapentinoids (gabapentin and pregabalin) increases the risk of overdose, respiratory depression, and death.
Concomitant administration of remifentanil with a serotonergic medicinal product, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or monoamine oxidase inhibitors (MAOIs), may increase the risk of serotonin syndrome, a potentially life-threatening condition. Caution should be exercised when concomitantly using MAOIs. Irreversible MAOIs should be discontinued at least 2 weeks before starting remifentanil treatment.
After administration of Ultiva, the patient should not consume alcohol.

Pregnancy, Breast-feeding, and Fertility

Pregnancy
There have been no adequate, well-controlled studies of remifentanil in pregnant women. Ultiva should only be used during pregnancy if the potential benefits justify the potential risk to the fetus.
Breast-feeding
It is not known whether remifentanil is excreted in human milk. However, since fentanyl analogs are excreted in human milk, and remifentanil derivatives have been detected in the milk of lactating rats, breast-feeding women should be advised to discontinue breast-feeding for 24 hours after administration of remifentanil.
Childbirth
There are insufficient data to recommend the use of remifentanil during childbirth or cesarean section. Remifentanil crosses the placental barrier, and fentanyl derivatives may cause respiratory depression in the newborn. If remifentanil is administered, the mother and newborn should be monitored for signs of excessive sedation or respiratory depression (see section “Special warnings and precautions for use”).

Overdose

Objective and Subjective Symptoms
As with all potent opioid analgesics, the symptom of overdose of Ultiva is an increase in the pharmacological effects of remifentanil.
Due to the very short duration of action of remifentanil, the risk of overdose only occurs immediately after administration. The response to discontinuation of the medicinal product is rapid, and recovery occurs within 10 minutes.
Treatment
In case of overdose or suspected overdose, the following actions should be taken:
discontinue administration of Ultiva, ensure a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate circulatory function. If respiratory depression is associated with muscle rigidity, administration of a neuromuscular blocking medicinal product may be necessary to facilitate assisted or controlled respiration. In the treatment of hypotension, intravenous fluids, vasoconstrictor medicinal products, and other supportive treatment may be used.
In case of severe respiratory depression and muscle rigidity, a specific opioid receptor antagonist, such as naloxone, can be administered intravenously as an antidote. It is unlikely that the duration of respiratory depression after overdose of Ultiva will be longer than the duration of action of the opioid receptor antagonist.

Incompatibilities

Ultiva should only be reconstituted and diluted using the infusion solutions listed in section “Special precautions for disposal and other handling”.
Ultiva should not be reconstituted, diluted, or mixed with:

• Ringer’s solution with lactate, solution for injection
• Ringer’s solution with lactate and glucose, 50 mg/ml (5%), solution for injection.

Ultiva should not be mixed with propofol in the same infusion bag.
Ultiva should not be administered through the same intravenous line as blood, plasma, or serum, as non-specific esterases present in blood products may cause hydrolysis of remifentanil to its inactive metabolite.
Ultiva should not be mixed with other medicinal products before administration.

Shelf Life and Storage

Medicinal Product in Powder Form:
Ultiva, 1 mg: 18 months.
Ultiva, 2 mg: 2 years.
Ultiva, 5 mg: 3 years.
Store at a temperature not exceeding 25°C.
Reconstituted and/or Diluted Solution
Chemical and physical stability of the solution has been demonstrated for 24 hours at 25°C. Ultiva should not be used without further dilution (see section 6.6). From a microbiological point of view, the product should be used immediately after reconstitution and dilution. If not used immediately, the in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution and dilution have been carried out in controlled and validated aseptic conditions. After this period, any unused solution should be discarded.

Special Precautions for Disposal and Other Handling

Ultiva should be prepared for intravenous administration by adding 1, 2, or 5 ml of solvent to obtain a remifentanil solution with a concentration of 1 mg/ml. The reconstituted solution is clear, colorless, and practically free from particulate matter. After reconstitution, Ultiva can only be administered after further dilution to a concentration of 20 to 250 micrograms/ml (recommended dilution for adults is 50 micrograms/ml, for children aged ≥1 year 20 to 25 micrograms/ml) using one of the following intravenous infusion solutions:
Dilution depends on the technical capabilities of the infusion device and the anticipated needs of the patient.

• Water for injections
• Glucose, 50 mg/ml (5%), solution for injection,
• Glucose, 50 mg/ml (5%) solution for injection and sodium chloride 9 mg/ml (0.9%) solution for injection,
• Sodium chloride, 9 mg/ml (0.9%), solution for injection,
• Sodium chloride, 4.5 mg/ml (0.45%), solution for injection.

Compatibility of Ultiva with the following infusion solutions has been demonstrated when administered through a Y-connector:

• Ringer’s solution with lactate, solution for injection,
• Ringer’s solution with lactate and glucose, 50 mg/ml (5%), solution for injection.

It has been demonstrated that Ultiva can be administered through a Y-connector with propofol.
The reconstituted product is for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
In section 6.6 of the Pharmaceutical Product Characteristics, tables are provided with recommendations for the infusion rates of Ultiva based on body weight to facilitate the gradual adjustment of the dose of Ultiva in patients requiring anesthetic medicinal products.