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 the leaflet before using the medicine, as it contains important information for the patient.

• You should keep this leaflet, so that you can read it again if you need to.
• If you have any doubts, you should consult a 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 using Ultiva
• 3. How to use 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 of action 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 using Ultiva

When not to use 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 doubts whether any of the above situations apply to the patient, they should consult a doctor, nurse, or pharmacist before using 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 doubts whether any of the above situations apply to the patient, they should consult a doctor or nurse before using Ultiva.
Before starting treatment with remifentanil, the patient should discuss the following with their doctor:

• if the patient or anyone in their family 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 can lead to reduced effectiveness of the medicine (the patient becoming accustomed to it) and may 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 a 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, the doctor may recommend resuming the medicine and gradually reducing the dose.

Ultiva and other medicines

The patient should inform 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.

Concomitant use of Ultiva and sedative medicines, such as benzodiazepine derivatives or benzodiazepine-like medicines, increases the risk of drowsiness, breathing difficulties (respiratory depression), and coma, and may be life-threatening. Therefore, concomitant use of such medicines should only be considered when there are no other treatment options available.
Concomitant use of opioids and medicines used to treat epilepsy, nerve pain, or anxiety (gabapentin and pregabalin) increases the risk of opioid overdose, respiratory depression, and may 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 concomitant treatment.
The patient should inform their doctor about all sedative medicines they are taking and strictly follow the 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 using 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 using this medicine.
If the patient receives this medicine during childbirth, it may have an adverse effect on the baby's breathing. The patient and newborn will be monitored for signs of excessive drowsiness and breathing difficulties.

Driving and operating machinery

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

Ultiva contains sodium

The medicine contains less than 1 mmol (23 mg) of sodium per vial, which means the medicine is considered "sodium-free".

3. How to use Ultiva

The patient will never use this medicine on their own. The medicine will always be administered to the patient by a qualified person.
Ultiva can be administered:

• as a single intravenous injection
• as a continuous intravenous infusion (the medicine is administered 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 impaired kidney and liver function.

After surgery

If the patient experiences pain after the procedure, they should inform their doctor or nurse. They will then be able to administer other painkillers to the patient.

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 using 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), includes 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 concomitantly with 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 use increasingly larger doses to achieve the same effect (drug tolerance),
• seizures
• irregular 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 the 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. Reporting side effects will help to gather more information on the safety of the 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.
Store at a temperature not exceeding 25°C.
The Ultiva solution should be used immediately after preparation.
For information on the storage conditions for 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 overlay 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
Phone: 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 for monitoring and supporting respiratory and circulatory functions and may only be administered by persons trained in the use of anesthetic medicines

who are skilled in recognizing and treating the expected side effects of potent opioids (including conducting respiratory and circulatory resuscitation), ensuring and maintaining airway patency, and providing assisted ventilation.
Ultiva for continuous infusion should only be administered using a calibrated infusion pump through an intravenous line with a high flow rate or through a dedicated catheter specifically designed for the administration of this medicinal product. The catheter 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 patient body weight to facilitate gradual dose adjustment of Ultiva to individual patient needs).
Caution should be exercised to avoid catheter occlusion or disconnection. After completion of the infusion, the catheter should be thoroughly flushed 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 storage conditions for the reconstituted and/or diluted solution and recommended diluents].
For manual infusion control, 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 above is 20 to 25 micrograms/ml).

Anesthesia

Dosing of remifentanil should be individualized and based on the patient's response.
Adults
The following table provides initial infusion rates and recommended 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.
The procedure can be started no earlier than 5 minutes after the start of the remifentanil infusion, unless a single injection is administered concurrently. In cases where only nitrous oxide (70%) is used 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 no specific studies have 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 specific surgical procedure.
Combined therapy
In the recommended doses above, remifentanil significantly reduces the dose of anesthetic medicine required to maintain anesthesia. Therefore, isoflurane and propofol should be administered according to the above recommendations to avoid enhancing the hemodynamic effects of remifentanil, such as hypotension and bradycardia (see "Anesthesia - Adults - Combined therapy" and Table 1).
Guidelines for postoperative treatment
Establishing alternative anesthesia before discontinuing Ultiva
Due to the very rapid offset of action of Ultiva, residual opioid activity disappears within 5 to 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 the therapeutic effect of long-acting analgesic medicines should be taken into account. The choice of medicine, dose, and time of administration should be planned in advance and individually tailored to the type of surgical procedure and the expected scope of postoperative care (see section "Special warnings and precautions for use").

Children and adolescents (aged 1 to 12 years)

Induction of anesthesia
Due to the lack of detailed studies on the concomitant administration of remifentanil with 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 (aged 1 to 12 years)

* in a mixture of oxygen with nitrous oxide and/or oxygen in a 1:2 ratio
Administration of Ultiva 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, unless a single injection is administered concurrently. In cases where only nitrous oxide (70%) is used 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 no specific studies have 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 specific surgical procedure.
Combined therapy
In the recommended doses above, remifentanil significantly reduces the dose of anesthetic medicine required to maintain anesthesia. Therefore, isoflurane, halothane, and sevoflurane should be administered according to the above recommendations to avoid enhancing the hemodynamic effects, such as hypotension and bradycardia (see "Anesthesia - Adults - Combined therapy" and Table 1).
Guidelines for postoperative treatment
Establishing alternative anesthesia before discontinuing Ultiva
Due to the very rapid offset of action of Ultiva, residual opioid activity disappears within 5 to 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 the therapeutic effect of long-acting analgesic medicines should be taken into account. The choice of medicine, dose, and time of administration should be planned in advance and individually tailored to the type of surgical procedure and the expected scope of postoperative care (see section "Special warnings and precautions for use").

Infants and neonates (under 1 year of age)

Experience with remifentanil in clinical studies in infants and neonates under 1 year of age is limited (see section 5.1 of the Summary of Product Characteristics). The pharmacokinetic profile of remifentanil in infants and neonates (under 1 year of age) 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.

• Ultiva should not be used in this age group.

Use during total intravenous anesthesia (TIVA)
Experience with remifentanil in clinical studies in infants undergoing total intravenous anesthesia is limited (see section 5.1 of the Summary of Product Characteristics). Clinical data are insufficient to establish dosing recommendations 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 cardiochirurgical procedures. Intubation should not be performed before 5 minutes have elapsed 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 doses can be administered in single injections.
Patients at high risk of cardiac complications (e.g., those with impaired ventricular function or undergoing valve replacement 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).
Combined therapy (concomitantly administered medicines)
In the recommended doses above, remifentanil significantly reduces the dose of anesthetic medicine required to maintain anesthesia. Therefore, isoflurane and propofol should be administered according to the above recommendations to avoid enhancing the hemodynamic effects, such as hypotension and bradycardia (see "Anesthesia - Adults - Combined therapy").
Guidelines for postoperative treatment
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 rate used at the end of the surgical procedure.
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 the individual needs of the patient (for further information on treatment of patients in intensive care units, see section "Use in intensive care units").
Establishing alternative anesthesia before discontinuing Ultiva
Due to the very rapid offset of action of Ultiva, residual opioid activity disappears within 5 to 10 minutes after discontinuation of the medicine. Before discontinuing Ultiva, the patient should receive other analgesic and sedative medicines. These medicines should be administered with sufficient lead time to achieve a stable therapeutic effect. Therefore, the choice of medicine, dose, and time of administration should be planned in advance.
Guidelines for discontinuing Ultiva
Due to the very rapid offset of action of Ultiva, patients undergoing cardiochirurgical procedures have reported hypertension, shivering, and pain immediately after discontinuation of the remifentanil infusion (see section 4 of the patient leaflet). To minimize the risk of these side effects, another suitable analgesic medicine should be administered before discontinuing remifentanil (as described above). The remifentanil infusion rate should be decreased by 25% at intervals of at least 10 minutes until discontinued.
The remifentanil 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 treatment regimen, the patient's condition 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 can 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 "Renal impairment" and 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 Ultiva 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 Ultiva infusion rate accordingly. If a rate of 0.2 micrograms/kg/min (12 micrograms/kg/h) is reached and the level of sedation is not satisfactory, 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 Ultiva infusion rate can be increased again by 0.025 micrograms/kg/min (1.5 micrograms/kg/h) if additional analgesia is required.
The following table summarizes the recommended initial infusion rates and typical dose ranges for providing analgesia and sedation in individual patients.

Table 4. Recommended use of Ultiva 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 allow for separate adjustment of the dose of individual medicinal products, sedative medicinal products should not be added to the solution containing remifentanil.
Additional anesthesia in mechanically ventilated patients undergoing procedures related to painful stimulation
related to painful stimulation
Increase in the infusion rate of Ultiva may be necessary to ensure 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 a rate of 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 procedure related to painful stimulation. 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).
Determination of alternative anesthesia before the end of administration of Ultiva
Due to the very rapid termination of action of Ultiva, residual opioid activity disappears within 5 - 10 minutes after discontinuation of administration of the medicinal product, regardless of the duration of infusion. It should be considered the possibility of tolerance, hyperalgesia, and related hemodynamic changes after administration of Ultiva in the intensive care unit (see section 4.2 "Special warnings and precautions for use"). Therefore, before the end of administration of Ultiva, other analgesic and sedative medicinal products should be administered to prevent hyperalgesia and related 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, the administration of which 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 procedure during the change 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 renal 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 impaired renal function (see section 5.2 Characteristic of the Medicinal Product).

• 5.2 Characteristic of the Medicinal Product.

Special patient groups

Elderly patients (over 65 years)

General anesthesia
In patients over 65 years of age, increased sensitivity to the pharmacological effect 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 the individual patient's needs, both during the induction and maintenance of anesthesia and during postoperative pain treatment.
Cardioanesthesia
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 so far, it is not necessary to adjust the dosing in patients with renal impairment, including those in intensive care units.

Patients with hepatic impairment

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

Neurosurgery

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

Dosing in patients with ASA III/IV physical status

General anesthesia
Since the hemodynamic effect 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 dosing recommendations in the pediatric population.
Cardioanesthesia
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 content of glycine, Ultiva is contraindicated for epidural or spinal use (see section 5.2 Characteristic of the Medicinal Product).
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 the patient's respiratory and cardiovascular function and only administered by persons trained in the use of anesthetic medicinal products, in the recognition and treatment of the adverse effects of potent opioids, including the management of respiratory and cardiovascular support, securing the airway, and providing ventilatory 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 another class, a hypersensitivity reaction may occur after administration of remifentanil. Therefore, caution should be exercised when using Ultiva in these patients.
Rapid offset of action/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 administration of the medicinal product. In patients undergoing surgical procedures, where postoperative pain is expected, analgesic medicinal products should be administered before the end of administration of Ultiva. During use in intensive care units, the possibility of tolerance, hyperalgesia, and related hemodynamic changes should be considered (see section 4.2 "Special warnings and precautions for use"). Therefore, before the end of administration of Ultiva, alternative analgesic and sedative medicinal products should be administered to prevent hyperalgesia and related hemodynamic changes. The benefits of ensuring adequate analgesic treatment must always take into account the potential risk of respiratory depression associated with the administration of these medicinal products.

Ultiva contains sodium

The medicinal product contains less than 1 mmol (23 mg) of sodium per vial, i.e., the medicinal product is considered "sodium-free".

Interactions 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 for the use of smaller doses of inhalational or intravenous anesthetic medicinal products and benzodiazepines required for anesthesia (see section "Dosing and method of 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 taking beta-blockers and calcium channel blockers.
Concomitant use of opioids with sedative medicinal products, such as benzodiazepine derivatives or medicinal products similar to benzodiazepines, increases the risk of excessive sedation, respiratory depression, coma, and death due to the additive depressant effect on the central nervous system. The dose and duration of concomitant use of these sedative medicinal products and Ultiva should be limited (see section "Special warnings and precautions for use"). Patients should be closely monitored for signs of respiratory depression and excessive sedation. It is important to inform patients and their caregivers about the need to pay attention to these signs (see section "Interactions with other medicinal products and other forms of interaction").
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 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.
After administration of Ultiva, the patient should not consume alcohol.

Pregnancy, breastfeeding, and fertility

Pregnancy
There have been no adequate, well-controlled studies of remifentanil in pregnant women. Ultiva should only be used in pregnant women when the potential benefits outweigh the potential risks to the fetus.
Breastfeeding
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, breastfeeding women should be advised to discontinue breastfeeding 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 placenta, 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 effect of remifentanil. Due to the very short duration of action of remifentanil, the risk associated with overdose only occurs immediately after administration. The response to discontinuation is rapid, and the return to baseline 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 ventilatory support or controlled ventilation with oxygen, and maintain adequate cardiovascular function. If respiratory depression is associated with muscle rigidity, it may be necessary to administer a medicinal product that blocks neuromuscular conduction 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 preparation of the medicinal product for administration".
The medicinal product 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.

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

Shelf life and storage conditions

Medicinal product in the form of powder:
Ultiva, 1 mg: 18 months.
Ultiva, 2 mg: 2 years.
Ultiva, 5 mg: 3 years.
Store at a temperature not exceeding 25°C.
Solution after reconstitution and/or dilution
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 2-8°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 preparation of the medicinal product for administration

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 of 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 is 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 has been demonstrated with the following infusion solutions administered through a common intravenous line:

• 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 common intravenous line 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 Characteristic of the Medicinal Product, tables are presented with recommendations for the infusion rate of Ultiva based on body weight to facilitate gradual adjustment of the dose of Ultiva in patients requiring administration of anesthetic medicinal products.