Rocuronium bromide kalcekz

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROCCURONIUM BROMIDE KALCEKS (ROCURONIUM BROMIDE KALCEKS)

Composition:

Active substance: rocuronium bromide;

1 ml of solution contains 10 mg of rocuronium bromide;

5 ml of solution (1 vial) contains 50 mg of rocuronium bromide;

Excipients: sodium chloride, sodium acetate trihydrate, glacial acetic acid, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colourless or slightly yellow solution.

Pharmacotherapeutic group. Peripheral-acting muscle relaxants. Other quaternary ammonium compounds. Rocuronium bromide. ATC code M03AC09.

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Rocuronium bromide is a rapid-onset, intermediate-duration non-depolarizing neuromuscular blocking agent possessing all the pharmacological properties typical of this class of drugs (curare-like). It acts by competing for nicotinic cholinergic receptors at the motor end plate of the neuromuscular junction. Its effects can be antagonized by acetylcholinesterase inhibitors such as neostigmine, edrophonium, and pyridostigmine.

Pharmacodynamic effects

The ED90 (the dose required to suppress 90% of the twitch response of the adductor pollicis muscle upon ulnar nerve stimulation) during intravenous anesthesia is approximately 0.3 mg/kg of rocuronium bromide. The ED95 in infants is lower than in adults and older children (0.25, 0.35, and 0.40 mg/kg, respectively). The clinical duration of action (time from administration to spontaneous recovery of muscle twitch to 25% of control) following a dose of 0.6 mg/kg rocuronium bromide is 30–40 minutes. The total duration of action (time to spontaneous recovery to 90% of control twitch response) is approximately 50 minutes. The mean time for spontaneous recovery from 25% to 75% of control twitch (recovery index) after a bolus dose of 0.6 mg/kg rocuronium bromide is 14 minutes. With lower doses (0.3–0.45 mg/kg, or 1½ × ED90), onset is slower and duration of action is shorter. At higher doses (2 mg/kg), the clinical duration extends to 110 minutes.

Intubation under standard anesthesia. Within 60 seconds after intravenous administration of 0.6 mg/kg rocuronium bromide (2 × ED90 under intravenous anesthesia), adequate intubation conditions are achieved in nearly all patients, with 80% of patients having excellent intubation conditions. Complete muscle relaxation suitable for any procedure is achieved within 2 minutes. After administration of 0.45 mg/kg rocuronium bromide, acceptable intubation conditions are achieved within 90 seconds.

Rapid sequence induction. During rapid sequence induction under propofol or fentanyl/thiopental anesthesia, adequate intubation conditions are achieved within 60 seconds in 93% and 96% of patients, respectively, after administration of 1.0 mg/kg rocuronium bromide, with excellent conditions in 70% of patients. The clinical duration of action at this dose approaches 1 hour, after which neuromuscular blockade may safely reverse spontaneously. After administration of 0.6 mg/kg rocuronium bromide, adequate intubation conditions are achieved within 60 seconds in 81% and 75% of patients when using rapid sequence induction with propofol or fentanyl/thiopental, respectively. Doses exceeding 0.1 mg/kg of rocuronium bromide do not significantly improve intubation conditions but do prolong the duration of action. Doses exceeding 4 × ED90 have not been studied.

Pediatric patients. The mean onset time in neonates, infants, and children following a 0.6 mg/kg intubating dose is slightly shorter than in adults. Comparisons across pediatric age groups show that the mean onset time in neonates and adolescents (1.0 min) is slightly longer than in infants, young children, and older children (0.4, 0.6, and 0.8 min, respectively). Duration of muscle relaxation and recovery time are generally shorter in children compared to infants and adults. Comparisons across pediatric age groups show that the mean time to T3 recovery (first twitch response) is prolonged in neonates and infants (56.7 and 60.7 min, respectively) compared to young children, children, and adolescents (45.4, 37.6, and 42.9 min, respectively).

Table 1

Mean (SD) time to onset and clinical duration of action after 0.6 mg/kg rocuronium as the initial intubating dose* under sevoflurane/nitrous oxide and isoflurane/nitrous oxide (maintenance) anesthesia in the PP group (children)

* Rocuronium dose is administered over 5 seconds.

** Calculated from the end of administration of the intubating dose of rocuronium.

Geriatric patients and patients with hepatic and/or biliary tract disorders and/or renal impairment. The duration of action of rocuronium bromide at a maintenance dose of 0.15 mg/kg during intravenous anesthesia may be slightly longer when enflurane and isoflurane anesthesia are used in geriatric patients and in patients with hepatic and/or renal disease (approximately 20 minutes), compared to patients without organ excretory dysfunction (approximately 13 minutes) (see section "Posology and method of administration"). No cumulative effect (progressive prolongation of duration of action) has been observed with repeated administration of maintenance doses at the recommended level.

Use in intensive care units. After continuous infusion in intensive care units, the time to recovery of muscle contractility following tetanic stimulation (train of four - TOF) to a ratio of 0.7 depends on the degree of blockade at the end of the infusion. After continuous infusion for 20 hours or more, the mean time (range) between return of T2 response to tetanic stimulation and recovery of the TOF ratio to 0.7 is approximately 1.5 (1–5) hours in patients without multi-organ failure and 4 (1–25) hours in patients with multi-organ failure.

Cardiovascular surgery. In patients scheduled for cardiovascular surgical procedures, the most common cardiovascular changes observed during maximal blockade after administration of 0.6–0.9 mg/kg rocuronium bromide are a slight and clinically insignificant increase in heart rate (up to 9%) and an increase in mean arterial pressure (up to 16%) compared to baseline values.

Reversal of muscle relaxation. Administration of acetylcholinesterase inhibitors (neostigmine, pyridostigmine, or edrophonium) upon reappearance of T2 or at the first signs of clinical recovery antagonizes the effects of rocuronium bromide.

Pharmacokinetics.

Distribution and elimination. After single intravenous bolus administration of rocuronium bromide, plasma concentrations exhibit a triphasic exponential decline. In healthy adult volunteers, the mean elimination half-life (t_1/2) (95% CI) is 73 (66–80) minutes, the (steady-state) volume of distribution is 203 (193–214) mL/kg, and plasma clearance is 3.7 (3.5–3.9) mL/kg/min.

Rocuronium is excreted in urine and bile. Urinary excretion approaches 40% within 12–24 hours. After administration of radiolabeled rocuronium bromide, excretion of radioactivity averages 47% in urine and 43% in feces over 9 days. Approximately 50% of the drug is excreted unchanged.

Biotransformation. No metabolites have been detected in plasma.

Children. The pharmacokinetics of rocuronium bromide in children (n=146) aged 0 to 17 years were evaluated using population analysis of pooled pharmacokinetic data from two anesthesia clinical trials: sevoflurane (induction) and isoflurane/nitrous oxide (maintenance anesthesia). All pharmacokinetic parameters were found to be linearly proportional to body weight, as indicated by similar clearance (L·hr⁻¹·kg⁻¹).

Volume of distribution (L·kg⁻¹) and t_1/2 (hours) decrease with age (years). Pharmacokinetic parameters in typical pediatric patients in each age group are shown below.

Table 2

Estimated PK parameters (mean [SD]) of rocuronium bromide in typical pediatric patients during administration of sevoflurane and nitrous oxide (induction) and isoflurane/nitrous oxide (maintenance anesthesia)

Geriatric patients and patients with hepatic and/or biliary tract disorders and/or renal impairment. Controlled studies have shown that plasma clearance was reduced in geriatric patients and in younger patients with renal dysfunction; however, in most studies, this reduction did not reach statistical significance. In patients with hepatic disease, the mean t1/2 increases by 30 minutes, and the mean plasma clearance decreases by 1 ml/kg/min (see section "Dosage and administration").

Use in intensive care units. When administered as a continuous infusion over 20 hours or more to facilitate mechanical ventilation, the mean t1/2 and the mean (apparent) volume of distribution at steady state increase. Controlled clinical studies have shown considerable inter-patient variability related to the nature and extent of (multiple) organ dysfunction and individual patient characteristics. In patients with multi-organ failure, the mean t1/2 (± SD) is 21.5 (± 3.3) hours, the (apparent) volume of distribution at steady state is 1.5 (± 0.8) L/kg, and plasma clearance is 2.1 (± 0.8) ml/kg/min (see section "Dosage and administration").

Clinical characteristics.

Indications.

Rocuronium bromide is indicated in adults and children (from term neonates to adolescents [0 to <18 years]) as an adjunct to general anesthesia to facilitate tracheal intubation during routine rapid sequence induction and to provide skeletal muscle relaxation during surgical procedures. In adults, rocuronium bromide is also indicated to facilitate tracheal intubation during rapid sequence induction and as an adjunct in intensive care units (ICU) to facilitate intubation and mechanical ventilation.

Contraindications.

Hypersensitivity to rocuronium, bromide ions, or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Listed below are medicinal products that affect the intensity and/or duration of action of non-depolarizing neuromuscular blocking agents.

Effect of other medicinal products on rocuronium bromide

Enhancement of effect:

• Halogenated inhalational anesthetics potentiate the neuromuscular blockade produced by rocuronium bromide. This effect is evident only during maintenance dosing (see section "Administration and dosage"). Recovery of neuromuscular transmission with acetylcholinesterase inhibitors may be inhibited;
• High doses of thiopental, methohexital, ketamine, fentanyl, gamma-hydroxybutyrate, etomidate, and propofol;
• Other non-depolarizing neuromuscular blockers;
• Following intubation with succinylcholine (see section "Special precautions");
• Prolonged concomitant use of corticosteroids and rocuronium bromide in ICU may lead to prolonged neuromuscular blockade or myopathy (see sections "Special precautions" and "Adverse reactions").

Other medicinal products:

• Antibiotics (aminoglycosides, lincosamides, polypeptide antibiotics, acylamino-penicillins, tetracycline, high doses of metronidazole);
• Diuretics, thiamine, MAO inhibitors, quinidine and its isomer quinine, protamine, adrenergic receptor blockers, magnesium salts, calcium channel blockers, lithium salts, local anesthetics (intravenous lidocaine, epidural bupivacaine), and acute administration of phenytoin or beta-blockers.

Recurarization has been reported after postoperative administration of aminoglycoside, lincosamide, polypeptide, and acylamino-penicillin antibiotics, quinidine, quinine, and magnesium salts (see section "Special precautions").

Reduction of effect:

• Neostigmine, edrophonium, pyridostigmine, aminopyridine derivatives;
• Prior chronic administration of corticosteroids, phenytoin, or carbamazepine;
• Norepinephrine (noradrenaline), azathioprine (only transient and limited effect), theophylline, calcium chloride, potassium chloride;
• Protease inhibitors (gabexate, ulinastatin).

Variable effect:

• Administration of other non-depolarizing neuromuscular blockers in combination with rocuronium bromide may result in decreased or increased neuromuscular blockade, depending on the sequence of administration and the neuromuscular blocker used;
• Succinylcholine administered after rocuronium bromide may enhance or reduce the neuromuscular blocking effect of rocuronium bromide.

Effect of rocuronium bromide on other medicinal products

Rocuronium bromide in combination with lidocaine may lead to a faster onset of action of lidocaine.

Children

Formal interaction studies have not been conducted. The above-mentioned interactions and special warnings and precautions applicable to adults (see section "Special precautions") should also be considered when administering rocuronium bromide to children.

Special precautions for use

Since rocuronium bromide causes paralysis of the respiratory muscles, artificial ventilation of the lungs must be performed in patients receiving this drug until adequate spontaneous respiration is restored. As with all neuromuscular blocking agents, it is important to anticipate difficulties with intubation, especially when the drug is used as part of a rapid sequence induction technique.

As with other neuromuscular blocking agents, residual neuromuscular blockade has been reported after administration of rocuronium bromide. To prevent complications due to residual neuromuscular blockade, extubation is recommended only after the patient has sufficiently recovered from neuromuscular blockade. Elderly patients (aged 65 years and older) may have an increased risk of developing residual neuromuscular blockade. Other factors that may contribute to residual neuromuscular blockade after extubation in the postoperative period should also be considered (e.g., drug interactions or patient condition). If the use of the drug is not part of standard clinical practice, consideration should be given to using a reversal agent (e.g., sugammadex or acetylcholinesterase inhibitors), especially in cases where residual neuromuscular blockade is most likely.

Cross-sensitivity among neuromuscular blocking agents has frequently been reported. Therefore, whenever possible, hypersensitivity to other neuromuscular blocking agents should be ruled out before administering rocuronium bromide. Rocuronium bromide should be used only if absolutely necessary in patients with known hypersensitivity. Patients who experience hypersensitivity reactions under general anesthesia should subsequently be tested for hypersensitivity to other neuromuscular blocking agents.

Rocuronium may increase heart rate.

In general, prolonged paralysis and/or skeletal muscle weakness have been observed in ICU patients after prolonged use of neuromuscular blocking agents. To prevent possible prolongation of neuromuscular blockade and/or overdose, monitoring of neuromuscular transmission is strongly recommended throughout the entire period of administration of muscle relaxants. In addition, patients should receive adequate analgesia and sedation. Furthermore, doses of muscle relaxants should be individually titrated to achieve the desired effect by experienced physicians familiar with these drugs, or by another specialist under the supervision of such a physician, and with the use of appropriate methods for monitoring neuromuscular function.

Myopathies have been regularly reported after prolonged administration of other non-depolarizing muscle relaxants in combination with corticosteroid therapy in ICU patients. Therefore, for patients receiving both muscle relaxants and corticosteroids, the duration of muscle relaxant administration should be kept as short as possible.

If succinylcholine is used for intubation, administration of rocuronium bromide should be delayed until clinical recovery from succinylcholine-induced neuromuscular blockade has occurred.

Since rocuronium bromide is always used in combination with other medicinal products and due to the risk of malignant hyperthermia during anesthesia—even in the absence of known triggering factors—physicians should be informed about the early symptoms confirming the diagnosis and the treatment methods for malignant hyperthermia prior to the start of anesthesia. Animal studies have shown that rocuronium bromide is not a trigger for malignant hyperthermia. Rare cases of malignant hyperthermia during rocuronium bromide administration have been observed in post-marketing surveillance; however, a causal relationship has not been established.

This medicinal product contains less than 1 mmol (23 mg) of sodium per 1 ml, i.e., it is essentially "sodium-free."

The following conditions may affect the pharmacokinetics and/or pharmacodynamics of rocuronium bromide:

Liver and/or biliary tract disorders and renal impairment

Since rocuronium is excreted in urine and bile, it should be used with caution in patients with clinically significant liver and/or biliary tract disorders and/or renal impairment. In these patient groups, prolonged duration of action of rocuronium bromide has been observed at doses of 0.6 mg/kg.

Increased circulation time

Conditions associated with increased circulation time, such as cardiovascular disease, advanced age, and edema leading to increased volume of distribution, may result in a slower onset of action of the drug. Duration of action may also be prolonged due to reduced plasma clearance.

Neuromuscular disorders

As with other muscle relaxants, rocuronium bromide should be used with special caution in patients with neuromuscular disorders or in patients who have had poliomyelitis, as the response to muscle relaxants may be significantly altered in these cases. The magnitude and direction of these changes can vary widely. In patients with severe myasthenia gravis or myasthenic (Eaton-Lambert) syndrome, even small doses of rocuronium bromide may produce an enhanced effect; therefore, the dose of rocuronium bromide should be titrated to achieve the appropriate response.

Hypothermia

During surgical procedures performed under hypothermic conditions, the neuromuscular blocking effect of rocuronium bromide is enhanced and its duration prolonged.

Obesity

As with other muscle relaxants, rocuronium bromide may have a prolonged effect, and spontaneous recovery after its administration may be prolonged in obese patients when doses are calculated based on actual body weight.

Burns

It is known that patients with burns develop resistance to non-depolarizing muscle relaxants. Dose titration to achieve the appropriate response is recommended.

Conditions that may potentiate the effect of rocuronium bromide

Hypokalemia (e.g., after severe vomiting, diarrhea, or diuretic therapy), hypermagnesemia, hypocalcemia (after massive blood transfusions), hypoproteinemia, dehydration, acidosis, hypercapnia, and cachexia may potentiate the effect of rocuronium bromide. Therefore, serious electrolyte imbalances, pH changes, or dehydration should be corrected whenever possible.

Use during pregnancy or breastfeeding

Pregnancy

There are no clinical data on the effects of rocuronium bromide on pregnancy. Animal studies have not revealed any direct or indirect harmful effects on pregnancy, embryonic/fetal development, labor, or postnatal development. Rocuronium bromide should be used with caution in pregnant women.

Cesarean section

Rocuronium bromide may be used in patients undergoing cesarean section as part of a rapid sequence induction technique, provided that no intubation difficulties are expected and an adequate dose of anesthetic agent is administered, or after intubation with succinylcholine. After administration of rocuronium bromide at a dose of 0.6 mg/kg, up to 90 seconds may be required to achieve adequate conditions for intubation. This dose has been shown to be safe for parturients undergoing cesarean section.

Rocuronium bromide does not affect Apgar scores, muscle tone, or cardiorespiratory adaptation of the fetus. Analysis of umbilical cord blood shows that only a limited amount of rocuronium bromide crosses the placental barrier, resulting in no clinically observed adverse effects in neonates.

Note 1. Doses of 1.0 mg/kg have been studied during rapid sequence induction of anesthesia, but not in patients undergoing cesarean section. Therefore, a dose of 0.6 mg/kg is recommended for this patient group.

Note 2. Recovery from neuromuscular blockade induced by muscle relaxants may be inhibited or inadequate in patients receiving magnesium salts for the treatment of pregnancy-induced toxemia, as magnesium salts potentiate neuromuscular blockade. Therefore, these patients should receive a reduced dose of rocuronium bromide, and the dose should be titrated to achieve the appropriate twitch response to nerve stimulation.

Breastfeeding period

It is not known whether rocuronium bromide is excreted in human breast milk. Animal studies have shown a low concentration of rocuronium bromide in breast milk. A low concentration of rocuronium bromide was detected in the milk of lactating rats. There are no data on the use of rocuronium bromide during lactation in humans. Other drugs in this class show minimal excretion into breast milk and low absorption in breastfed infants. Rocuronium bromide should be administered to breastfeeding women only if, in the opinion of the physician, the benefits outweigh the risks. After a single dose, it is recommended to withhold breastfeeding for five elimination half-lives of rocuronium (approximately 6 hours).

Fertility

There are no data on the effect of this drug on fertility.

Ability to affect reaction speed when driving or operating machinery

Rocuronium bromide significantly affects the ability to drive or operate machinery. Since rocuronium bromide is used as an adjunct to general anesthesia, standard post-anesthesia precautions should be followed for outpatient patients. Operating potentially hazardous machinery or driving motor vehicles is not recommended during the first 24 hours after full recovery from the neuromuscular blocking effects of rocuronium bromide.

Method of Administration and Dosage

Rocuronium bromide is administered intravenously either as a bolus injection or as a continuous infusion.

Rocuronium bromide, like other neuromuscular blocking agents, should be administered only by experienced physicians familiar with the actions and use of such agents, or under the supervision of such physicians.

As with other neuromuscular blocking agents, the dose of rocuronium bromide should be individualized for each patient. Factors to consider when determining dosage include the anesthetic technique and anticipated duration of surgery, the sedation method and expected duration of mechanical ventilation, potential interactions with concomitantly administered drugs, and the patient’s clinical condition.

To assess neuromuscular blockade and recovery of neuromuscular transmission, appropriate neuromuscular monitoring techniques are recommended.

Inhalational anesthetics enhance the neuromuscular blocking effect of rocuronium bromide. This potentiation becomes clinically significant during anesthesia when tissue concentrations of volatile agents reach levels sufficient for such interaction. Therefore, the dose of rocuronium bromide should be adjusted by administering smaller maintenance doses at longer intervals or by reducing the infusion rate of rocuronium bromide during prolonged procedures (longer than 1 hour) performed under inhalational anesthesia (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

In adult patients, the dosage recommendations below serve as general guidelines for tracheal intubation and for providing muscle relaxation during surgical procedures ranging from short to prolonged duration, as well as for use in intensive care units.

Surgical Procedures

Tracheal Intubation

The standard dose of rocuronium bromide for intubation during routine anesthesia is 0.6 mg/kg, after which adequate intubation conditions are achieved within 60 seconds in nearly all patients. A dose of 1.0 mg/kg of rocuronium bromide is recommended to facilitate intubation conditions during rapid sequence induction of anesthesia, after which adequate intubation conditions are established within 60 seconds in nearly all patients. If a dose of 0.6 mg/kg of rocuronium bromide is used for rapid sequence induction, intubation should be performed 90 seconds after administration.

For use of rocuronium bromide during rapid sequence induction of anesthesia in patients undergoing cesarean section, see section "Use in Pregnancy or Lactation".

Higher Doses

When higher doses are considered appropriate for individual patients, clinical studies have shown no evidence that initial doses of up to 2 mg/kg of rocuronium bromide are associated with increased frequency or severity of cardiovascular adverse effects. However, the use of such high doses of rocuronium bromide delays onset and prolongs duration of action (see section "Pharmacodynamics").

Maintenance Doses

The recommended maintenance dose of rocuronium bromide is 0.15 mg/kg; during prolonged inhalational anesthesia, the dose should be reduced to 0.075–0.1 mg/kg of rocuronium bromide. Maintenance doses are best administered when the amplitude of muscle twitch responses has recovered to 25% of control or when 2–3 responses are present in a train-of-four (TOF) nerve stimulation sequence.

Continuous Infusion

When rocuronium bromide is administered by continuous infusion, it is recommended to give an initial loading dose of 0.6 mg/kg and begin the infusion when neuromuscular transmission starts to recover. The infusion rate should be adjusted to maintain muscle twitch amplitude at 10% of control or to maintain 1–2 responses in a train-of-four (TOF) nerve stimulation sequence. In adults under intravenous anesthesia, the infusion rate required to maintain neuromuscular blockade at this level ranges from 0.3–0.6 mg/kg/hour (300–600 mcg/kg/hour), while under inhalational anesthesia, the infusion rate is 0.3–0.4 mg/kg/hour. Continuous monitoring of the degree of neuromuscular blockade is essential, as infusion rate requirements vary among patients and depend on the anesthetic technique used.

Children

For neonates (0–27 days), infants (28 days–2 months), toddlers (3–23 months), children (2–11 years), and adolescents (12–17 years), the recommended dose for intubation during routine anesthesia and the maintenance dose are similar to those in adults.

However, the duration of action of a single intubation dose will be longer in neonates and infants compared to older children (see section "Pharmacodynamics").

For continuous infusion in pediatric patients, the infusion rate, except in children aged 2–11 years, is the same as in adults. Children aged 2–11 years may require a higher infusion rate.

Therefore, for children (2–11 years), the same initial infusion rate as in adults is recommended, followed by adjustment during the procedure to maintain muscle twitch amplitude at 10% of control or to maintain 1–2 responses in a train-of-four (TOF) nerve stimulation sequence.

Experience with rocuronium bromide for rapid sequence induction of anesthesia in children is limited; therefore, rocuronium bromide is not recommended for facilitating tracheal intubation during rapid sequence induction in pediatric patients.

Elderly Patients and Patients with Hepatic and/or Biliary Tract Disorders and/or Renal Impairment

The standard intubation dose for elderly patients and younger patients with hepatic and/or biliary tract disorders and/or renal impairment under routine anesthesia is 0.6 mg/kg of rocuronium bromide. A dose of 0.6 mg/kg should be considered for rapid sequence induction in patients in whom a prolonged duration of action is expected. Regardless of the anesthetic method used, the recommended maintenance dose for these patients is 0.075–0.1 mg/kg of rocuronium bromide, and the recommended infusion rate is 0.3–0.4 mg/kg/hour (see "Continuous Infusion" and section "Special Warnings and Precautions for Use").

Patients with Excessive Body Weight and Obesity

When administering the drug to patients with excessive body weight or obesity (whose body weight exceeds ideal body weight by 30% or more), doses should be reduced based on ideal body weight.

Procedures in Intensive Care

Tracheal Intubation

For tracheal intubation, the same doses described above for surgical procedures should be used.

Maintenance Doses

An initial loading dose of 0.6 mg/kg of rocuronium bromide is recommended, followed by continuous infusion as soon as neuromuscular recovery reaches 10% of control or when 1–2 responses appear in a train-of-four (TOF) nerve stimulation sequence. The dose should always be titrated to effect for each individual patient. The recommended initial infusion rate to maintain neuromuscular blockade at 80–90% (1–2 responses to TOF stimulation) in adult patients is 0.3–0.6 mg/kg/hour during the first hour of infusion, which should be reduced over the next 6–12 hours depending on the individual patient’s response. Thereafter, individual dose requirements remain relatively constant.

Controlled clinical studies have shown considerable inter-patient variability in hourly infusion rates. The average hourly infusion rate is 0.2–0.5 mg/kg/hour, depending on the nature and extent of organ dysfunction, concomitant medication, and individual patient characteristics. To ensure optimal individual patient management, neuromuscular transmission monitoring is strongly recommended. Administration of the drug has been studied for up to 7 days.

Special Patient Groups

Rocuronium bromide is not recommended for facilitating mechanical ventilation in intensive care settings in children and elderly patients due to lack of safety and efficacy data.

Rocuronium bromide at concentrations of 0.5 mg/mL and 2.0 mg/mL is compatible with 0.9% sodium chloride solution, 5% dextrose solution, 5% dextrose in saline, sterile water for injection, and lactated Ringer’s solution. Infusion should be started immediately after mixing and completed within 24 hours.

Unused medicinal products or waste materials should be disposed of in accordance with local requirements.

Children

Rocuronium bromide is administered to pediatric patients: neonates (0–27 days), infants (28 days–2 months), toddlers (3–23 months), older children (2–11 years), and adolescents (12–17 years).

Overdose

In case of overdose and prolonged neuromuscular blockade, the patient should continue to receive ventilation and sedation. There are two options for reversing neuromuscular blockade.

(1) In adults, sugammadex can be used to reverse profound (deep) blockade. The dose of sugammadex to be administered depends on the degree of neuromuscular blockade.

(2) An acetylcholinesterase inhibitor (e.g., neostigmine, edrophonium, pyridostigmine) or sugammadex can be administered in appropriate doses after the onset of spontaneous recovery. If administration of an acetylcholinesterase inhibitor fails to reverse the neuromuscular blockade induced by rocuronium bromide, ventilation should be continued until spontaneous respiration returns. Re-administration of an acetylcholinesterase inhibitor may be hazardous.

In animal studies, severe cardiovascular depression leading ultimately to cardiovascular collapse was not observed until a cumulative dose of 750 x ED90 (135 mg/kg of rocuronium bromide) was administered.

Adverse Reactions

During administration of the drug, the most frequently observed adverse reactions in patients are: pain/reactions at the injection site, changes in vital functions, and prolonged neuromuscular blockade. The most commonly reported serious adverse reactions during post-marketing surveillance are anaphylactic and anaphylactoid reactions and associated symptoms.

Frequency of adverse reactions: uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data). Frequencies are derived from post-marketing surveillance reports and data from the published literature. For the categories "uncommon" and "rare", post-marketing data do not allow precise determination of incidence. Therefore, the reporting frequency has been grouped into two rather than five categories (listed as "uncommon/rare").

Immune system disorders: very rare – hypersensitivity, anaphylactic reaction, anaphylactoid reaction, anaphylactic shock, anaphylactoid shock.

Nervous system disorders: very rare – floppy paralysis.

Cardiac disorders: uncommon/rare – tachycardia; frequency not known – Koornneef syndrome.

Vascular disorders: uncommon/rare – hypotension; very rare – vascular collapse and shock, facial flushing.

Respiratory, thoracic and mediastinal disorders: very rare – bronchospasm.

Skin and subcutaneous tissue disorders: very rare – angioneurotic edema, urticaria, rash, erythematous rash.

Musculoskeletal and connective tissue disorders: muscle weakness, steroid myopathy (after prolonged use in ICU).

General disorders and administration site conditions: uncommon/rare – drug ineffective, drug effect/therapeutic response decreased, drug effect/therapeutic response increased, injection site pain, injection site reaction; very rare – facial swelling.

Injury, poisoning and procedural complications: uncommon/rare – prolonged neuromuscular blockade, delayed recovery from anesthesia; very rare – airway complications during anesthesia.

Anaphylaxis

Although very rare, serious anaphylactic reactions to neuromuscular blocking agents, including rocuronium bromide, have been reported. Anaphylactic/anaphylactoid reactions include: bronchospasm, cardiovascular changes (e.g., hypotension, tachycardia, vascular collapse – shock), and skin manifestations (e.g., angioneurotic edema, urticaria). In some cases, these reactions have led to fatal outcomes. Therefore, the possibility of such severe reactions should always be considered when administering the drug, and appropriate precautionary measures must be taken.

Since neuromuscular blocking agents are known to induce histamine release both locally at the injection site and systemically, the potential for itching and erythematous reactions at the injection site and/or generalized (anaphylactoid) histamine-mediated reactions should always be considered during administration of these drugs (see also information on anaphylactic reactions above).

In clinical studies, only a slight increase in mean plasma histamine levels was observed after rapid bolus administration of 0.3–0.9 mg/kg rocuronium bromide.

Prolonged neuromuscular blockade

The most common adverse effect of non-depolarizing neuromuscular blocking agents as a class is extension of the drug's pharmacological effect beyond the required duration. The degree of this effect may vary from skeletal muscle weakness to profound and prolonged paralysis of skeletal muscles, leading to respiratory insufficiency or apnea.

Myopathy

Myopathy has been reported following the use of various neuromuscular blocking agents in combination with corticosteroids in the ICU (see section "Special precautions for use").

Injection site reactions

Pain on injection has been reported during rapid sequence induction of anesthesia, particularly when the patient is not fully unconscious, especially when propofol is used as the induction agent. In clinical studies, injection site pain was observed in 16% of patients undergoing rapid sequence induction with propofol, and in less than 0.5% of patients undergoing rapid sequence induction with fentanyl and thiopental.

Shelf life.

2 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store in a refrigerator at 2 to 8 °C. Do not freeze.

Keep out of the reach of children.

Storage outside the refrigerator

Rocuronium bromide may also be stored outside the refrigerator at temperatures not exceeding 25 °C for up to 12 weeks, after which it must be discarded. If the medicinal product has been stored outside the refrigerator, it must not be returned to refrigerated storage. The total storage period must not exceed the shelf life.

After dilution

After dilution with infusion solutions (see section "Dosage and administration"), chemical and physical stability has been demonstrated for 72 hours at 30 °C.

From a microbiological standpoint, the solution should be used immediately. If not used immediately, the user is responsible for in-use storage conditions and duration. Typically, storage should not exceed 24 hours at 2 to 8 °C, unless dilution has been carried out under well-controlled and validated aseptic conditions.

Incompatibilities.

This medicinal product must not be mixed with other medicinal products except those specified in the section "Dosage and administration".

Rocuronium bromide is physically incompatible with solutions of the following drugs: amphotericin, amoxicillin, azathioprine, cefazolin, cloxacillin, dexamethasone, diazepam, enoximone, erythromycin, famotidine, furosemide, hydrocortisone sodium succinate, insulin, Intralipid, methohexital, methylprednisolone, prednisolone sodium succinate, thiopental, trimethoprim, and vancomycin.

If rocuronium bromide is administered through the same infusion line used for other medicinal products, it is essential that the infusion line be adequately flushed (e.g., with 0.9% sodium chloride solution) between administration of rocuronium bromide and any drug known to be incompatible with or not established as compatible with rocuronium bromide.

Packaging.

5 ml in vials made of colorless glass of hydrolytic class I, stoppered with rubber stoppers and sealed with aluminum crimp caps.

5 vials in a blister pack (tray) made of polystyrene film.

2 blister packs (trays) together with the package leaflet in a cardboard carton.

Prescription status.

Prescription only.

Manufacturer.

Manufacturer responsible for batch release: JSC "Kalceks".

Manufacturer's address and place of business.

71E Krustpils Street, Riga, LV-1057, Latvia.

Marketing Authorization Holder.

JSC "Kalceks".

Address of the Marketing Authorization Holder.

71E Krustpils Street, Riga, LV-1057, Latvia.