Rocuronium-novo

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROCURONIUM-NOVO (ROCURONIUM-NOVO)

Composition:

Active substance: rocuronium bromide;

1 ml of solution contains rocuronium bromide 10 mg;

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

Pharmaceutical form. Injection solution.

Main physico-chemical properties: clear aqueous solution ranging from colorless to light brown.

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-acting non-depolarizing neuromuscular blocking agent with all the pharmacological properties typical of this class of drugs (curare-like). It blocks nicotinic cholinergic receptors at the motor end plate of the skeletal muscle. The antagonists of this effect are acetylcholinesterase inhibitors, such as neostigmine, edrophonium, and pyridostigmine.

Pharmacodynamic effects

The ED90 (the dose of rocuronium bromide required to produce 90% suppression of the twitch response of the adductor pollicis muscle upon stimulation of the ulnar nerve) during intravenous anaesthesia is approximately 0.3 mg/kg. The ED95 value is lower in infants than in adults and children (0.25, 0.35 and 0.4 mg/kg, respectively).

The clinical duration of action (time to spontaneous recovery of neuromuscular twitch response to 25% of control) following a dose of rocuronium bromide of 0.6 mg/kg body weight is 30–40 minutes. The total duration of action (time to spontaneous recovery to 90% of control) is 50 minutes. The mean time for spontaneous recovery from 25% to 75% of control (recovery index) after a bolus dose of 0.6 mg/kg body weight is 14 minutes.

With lower doses of rocuronium bromide — 0.3–0.45 mg/kg body weight (1–1½ × ED90) — the onset of action is slower and the duration of action is shorter. With higher doses — 2 mg/kg body weight — the clinical duration of action is 110 minutes.

Intubation during routine anaesthesia

Within 60 seconds after intravenous administration of rocuronium bromide at a dose of 0.6 mg/kg (2 × ED90 under balanced anaesthesia), adequate intubating conditions are achieved in nearly all patients, with excellent intubating conditions in 80% of them. Complete relaxation of skeletal muscles sufficient for any surgical procedure is achieved within 2 minutes. After administration of a 0.45 mg/kg dose, acceptable intubating conditions are established within 90 seconds.

Rapid sequence induction

During rapid sequence induction of anaesthesia using propofol or fentanyl/thiopental, adequate intubating conditions are achieved within 60 seconds in 93% and 96% of patients, respectively, following administration of a 1.0 mg/kg dose of rocuronium bromide. Among these, intubating conditions are rated as excellent in 70% of patients. The clinical duration of action at this dose approaches 1 hour, after which neuromuscular transmission can be safely reversed. After administration of a 0.6 mg/kg dose of rocuronium bromide, adequate intubating conditions are achieved within 60 seconds in 81% and 75% of patients undergoing rapid sequence induction with propofol or fentanyl/thiopental, respectively.

Special patient populations

Children. The mean onset time of rocuronium bromide in infants and children at an intubating dose of 0.6 mg/kg is slightly shorter than in adults. Comparative studies in pediatric groups showed that the mean time to onset in neonates and adolescents (1 minute) was slightly longer than in infants, young children, and older children (0.4, 0.6, and 0.8 minutes, respectively). In children, the duration of relaxation and the recovery period of neuromuscular transmission are shorter compared to infants and adults. Comparative studies in pediatric groups showed that the mean time to recovery of T3 was prolonged in neonates and infants (56.7 and 60.7 minutes, respectively) compared to young children, older children, and adolescents (45.4, 37.6, and 42.9 minutes, respectively).

Mean time to onset and clinical duration of action after administration of 0.6 mg/kg rocuronium as initial intubating dose* during sevoflurane/nitrous oxide and isoflurane/nitrous oxide (maintenance) anaesthesia in pediatric patients.

	Time to maximum block ** (min)	Time to onset of T3** (min)
Neonates (0–27 days) n = 10	0.98 (0.62)	56.69 (37.04) n = 9
Infants (28 days – 2 months) n = 11	0.44 (0.19) n = 10	60.71 (16.52)
Young children (3 months – 23 months) n = 28	0.59 (0.27)	45.46 (12.94) n = 27
Older children (2–11 years) n = 34	0.84 (0.29)	37.58 (11.82)
Adolescents (12–17 years) n = 31	0.98 (0.38)	42.90 (15.83) n = 30

* Dose of rocuronium is administered over 5 seconds.

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

Elderly patients and patients with hepatic and biliary disorders and/or renal impairment.

The duration of action of rocuronium bromide at a maintenance dose of 0.15 mg/kg may be slightly longer when enflurane and isoflurane anesthesia is used in elderly patients and in patients with hepatic and/or renal disease (approximately 20 minutes), compared to patients without impaired excretory organ function under intravenous anesthesia (approximately 13 minutes). With repeated administration of maintenance doses within the recommended range, cumulative effect (progressive prolongation of duration of action) has not been observed.

Intensive Care Unit

In the intensive care unit, after continuous infusion, the time to recovery of the train-of-four (TOF) ratio to 0.7 depends on the degree of blockade at the end of infusion. After continuous infusion for 20 hours or more, the mean time (range) between return of T2 in response to TOF 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 undergoing cardiac surgery, the most common cardiovascular changes observed during maximal blockade after administration of 0.6–0.9 mg/kg rocuronium bromide are mild and clinically insignificant increases in heart rate of up to 9% and increases in mean arterial pressure of up to 16% from baseline.

Reversibility of Muscle Relaxation

Administration of sugammadex or acetylcholinesterase inhibitors (neostigmine, pyridostigmine, or edrophonium) reverses the effect of rocuronium. Sugammadex may be administered for standard reversal (at 1–2 post-tetanic twitches prior to the return of T2) or immediate reversal (3 minutes after administration of rocuronium bromide). Acetylcholinesterase inhibitors may be administered upon return of T2 or at the first signs of clinical recovery.

Pharmacokinetics.

Distribution and Elimination

After intravenous administration of a single bolus dose of rocuronium bromide, its plasma concentration declines in three exponential phases. In healthy adults, the mean (95% confidence interval) elimination half-life is 73 (66–80) minutes, the (steady-state) volume of distribution is 203 (193–214) mL/kg body weight, and plasma clearance is 3.7 (3.5–3.9) mL/kg/min.

Rocuronium is excreted in urine and bile. Renal excretion reaches 40% within 12–24 hours. After administration of radiolabeled rocuronium bromide, excretion averaged 47% in urine and 43% in feces over 9 days. Approximately 50% of the drug is excreted unchanged. Metabolites are not detected in plasma.

Children

The pharmacokinetics of rocuronium bromide in children (n = 146) across age groups (0–17 years) were studied using a population analysis of pooled pharmacokinetic data from two clinical trials of anesthesia with sevoflurane (induction) and isoflurane/nitrous oxide (maintenance anesthesia). All pharmacokinetic parameters were linearly proportional to body weight, as confirmed by similar clearance (L/h/kg). Volume of distribution (L/kg) and elimination half-life (h) decreased with age (years).

Pharmacokinetic parameters (PKPs) in typical pediatric patients by age groups are summarized below.

Probable PKPs (mean standard deviation) of rocuronium bromide in typical pediatric patients during administration of sevoflurane and nitrous oxide (induction) and isoflurane/nitrous oxide (maintenance anesthesia)

CL (l/h/kg)	Age range of patients
	Neonates (0–27 days)	Infants (28 days – 2 months)	Young children (3–23 months)	Older children (2–11 years)	Adolescents (12–17 years)
Clearance (l/h/kg)	0.31 (0.07)	0.30 (0.08)	0.33 (0.10)	0.35 (0.09)	0.29 (0.14)
Volume of distribution (l/kg)	0.42 (0.06)	0.31 (0.03)	0.23 (0.03)	0.18 (0.02)	0.18 (0.01)
t½ β (h)	1.1 (0.2)	0.9 (0.3)	0.8 (0.2)	0.7 (0.2)	0.8 (0.3)

Geriatric patients and patients with hepatic and/or biliary and/or renal impairment

Controlled studies have shown that plasma clearance is reduced in geriatric patients and in patients with impaired renal function; however, in most studies, the observed differences did not reach statistical significance. The elimination half-life increases by an average of 30 minutes in patients with liver disease, and clearance decreases by 1 ml/kg/min (see section "Dosage and administration").

Intensive care unit

When administered as a continuous infusion to facilitate mechanical ventilation for 20 hours or longer, the mean elimination half-life and mean (apparent) volume of distribution at steady state increase. Controlled clinical studies have demonstrated substantial individual variability in these parameters, related to the varying etiology and severity of multiorgan failure and individual patient characteristics. In patients with multiorgan failure, the mean (± standard deviation) elimination half-life was 21.5 (± 3.3) hours, the (apparent) volume of distribution at steady state was 1.5 (± 0.8) L/kg, and plasma clearance was 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 newborns to adolescents – from 0 to < 18 years of age) as an adjunct to general anesthesia to facilitate tracheal intubation during routine rapid sequence induction of anesthesia and to provide skeletal muscle relaxation during surgical procedures.

In adults, rocuronium bromide is also indicated to facilitate tracheal intubation during rapid sequence induction of anesthesia and as an adjunct to assist mechanical ventilation in intensive care units.

Contraindications.

Hypersensitivity to rocuronium, bromides, or to any excipient of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Medicinal products affecting the intensity and/or duration of action of non-depolarizing neuromuscular blocking agents

Enhanced effect

• Halogenated volatile anesthetics potentiate the neuromuscular blockade caused by rocuronium bromide. This effect is observed only when maintenance doses are administered (see section "Dosage and administration"). Recovery of neuromuscular transmission with acetylcholinesterase inhibitors may be delayed.

• Following intubation using succinylcholine (see section "Special precautions").

• Prolonged concomitant use of corticosteroids and rocuronium bromide in intensive care units may lead to prolonged neuromuscular blockade or myopathy (see sections "Special precautions" and "Undesirable effects").

• Other medicinal products:

  • antibiotics (aminoglycosides, lincosamides, polypeptides, and acylamino-penicillins);
  • diuretics, quinidine and its isomer quinine, magnesium salts, calcium channel blockers, local anesthetics (intravenous lidocaine, epidural bupivacaine), and emergency administration of phenytoin or beta-blockers.

Cases of recurarization have been reported after postoperative administration of the following antibiotics: aminoglycosides, lincosamides, polypeptides, and acylamino-penicillins, as well as quinidine, quinine, and magnesium salts (see section "Special precautions").

Reduced effect

• Neostigmine, edrophonium, pyridostigmine;
• prolonged use of phenytoin or carbamazepine;
• norepinephrine (noradrenaline), azathioprine (only transient and limited effect), theophylline, calcium chloride, potassium chloride;
• protease inhibitors (gabexate, ulinastatin).

Altered effect

• Administration of other non-depolarizing neuromuscular blockers in combination with rocuronium bromide may result in either reduction or potentiation of neuromuscular blockade, depending on the sequence of administration and the specific neuromuscular blocking agent 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 precautions and warnings applicable to adult use (see section "Special precautions") should also be considered when administering the drug to children.

Special precautions for use.

Rocuronium bromide should only be administered by an anaesthesiologist experienced in the use of neuromuscular blocking agents. Equipment for emergency controlled ventilation, oxygen delivery, and tracheal intubation must be readily available when administering this medicinal product.

Appropriate management and monitoring

Since rocuronium bromide causes paralysis of respiratory muscles, artificial ventilation of the lungs must be maintained until adequate spontaneous respiration is restored in patients receiving this medicinal product. As with all neuromuscular blocking agents, potential difficulties with tracheal intubation should be anticipated, particularly when the drug is used as part of a rapid sequence induction technique. If intubation difficulties arise, leading to a clinical need for immediate reversal of rocuronium-induced neuromuscular blockade, the use of a reversal agent should be considered. It is essential to ensure that the patient is breathing spontaneously, deeply, and regularly before leaving the operating room after anaesthesia.

Residual curarization

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

Anaphylaxis

Anaphylactic reactions may occur after administration of neuromuscular blocking agents. Precautions should always be taken to prevent such reactions. Special precautions are particularly necessary in patients with a history of anaphylactic reactions to any neuromuscular blocking agents, as cross-reactive allergic reactions to neuromuscular blockers have been reported.

Rocuronium may increase heart rate.

Long-term use in intensive care units

In general, after prolonged use of neuromuscular blocking agents in patients in intensive care units, paralysis and/or skeletal muscle weakness have been observed. To prevent possible prolongation of neuromuscular blockade and/or overdose, continuous monitoring of neuromuscular transmission is strongly recommended throughout the period of neuromuscular blocker administration. Patients should also receive adequate analgesia and sedative medications. Furthermore, neuromuscular blockers should be administered in carefully adjusted doses according to individual patient response, under the supervision of an experienced physician, and using appropriate neuromuscular block monitoring techniques.

Myopathy has been regularly reported after prolonged administration of non-depolarizing neuromuscular blockers in combination with corticosteroid therapy in intensive care units. Therefore, for patients receiving both neuromuscular blockers and corticosteroids, the duration of neuromuscular blocker treatment should be as short as possible.

Use with succinylcholine

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

Hyperthermia

Since rocuronium bromide is always used in combination with other medicinal products and there is a risk of malignant hyperthermia during anaesthesia—even in the absence of known triggering factors—physicians must be familiar with early symptoms, diagnosis confirmation, and treatment of malignant hyperthermia before initiating anaesthesia. Animal studies have shown that rocuronium bromide is not a triggering agent for malignant hyperthermia. Rare cases of malignant hyperthermia have been reported during post-marketing surveillance with rocuronium bromide; however, a causal relationship has not been established.

Risk of death due to medication errors

Administration of rocuronium bromide leads to paralysis, which may result in respiratory arrest and death, particularly in patients for whom this medicinal product was not intended. Care must be taken to ensure correct selection of the prescribed medicinal product and to avoid confusion with other injectable solutions available in intensive care units and other clinical settings. If the drug is administered by another healthcare professional, ensure that the administered dose is clearly specified and confirmed.

Factors that may affect the pharmacokinetics and/or pharmacodynamics of rocuronium bromide

Liver and/or biliary tract disorders and renal insufficiency

Since rocuronium bromide 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 insufficiency. Prolonged duration of action of rocuronium bromide at doses of 0.6 mg/kg body weight has been observed in such patients.

Increased circulation time

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

Neuromuscular disorders

As with other neuromuscular blockers, rocuronium bromide should be used with extreme caution in patients with neuromuscular disorders or those who have had poliomyelitis, as the response to muscle relaxants may be significantly altered in these cases. The magnitude and direction of such changes may vary widely. In patients with severe myasthenia gravis or myasthenic syndrome (Lambert-Eaton syndrome), even small doses of rocuronium bromide may cause profound neuromuscular blockade; therefore, the dose should be titrated according to individual patient response.

Hypothermia

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

Obesity

As with other neuromuscular blockers, rocuronium bromide may have a prolonged effect in obese patients, and spontaneous recovery of neuromuscular conduction after administration may be prolonged when the dose is calculated based on actual body weight.

Burns

Patients with burns may develop resistance to non-depolarizing neuromuscular blockers. Dose titration according to patient response is recommended.

Conditions that may potentiate the effect of rocuronium bromide

Hypokalemia (e.g., after prolonged vomiting, diarrhea, or diuretic therapy), hypermagnesemia, hypocalcemia (after massive blood transfusions), hypoproteinemia, dehydration, acidosis, hypercapnia, and cachexia.

Therefore, severe disturbances in fluid and electrolyte balance, blood pH, or dehydration should be corrected, if possible, before initiating rocuronium bromide.

Use during pregnancy or breastfeeding.

Pregnancy. There are no clinical data on the use of this medicinal product during pregnancy. Animal studies have not revealed any direct or indirect harmful effects of the drug on pregnancy, embryonal/fetal development, parturition, or postnatal development. Rocuronium bromide should be used with caution in pregnant women.

Caesarean section. Rocuronium bromide may be used for caesarean section as part of a rapid sequence induction technique, provided that no difficulties with intubation are expected and an adequate dose of anaesthetic has been administered, or after intubation with succinylcholine.

Administration of rocuronium bromide at a dose of 0.6 mg/kg has been shown to be safe in women undergoing caesarean section. Rocuronium bromide did not affect Apgar scores or muscle tone and cardiorespiratory adaptation of the newborn. Analysis of umbilical cord blood showed that only a minimal amount of rocuronium bromide crosses the placental barrier, resulting in no clinically significant adverse reactions in neonates.

Note 1. Doses of 1.0 mg/kg have been studied during rapid sequence induction of anaesthesia in other patient groups, except in patients undergoing caesarean section. Therefore, only the 0.6 mg/kg dose is recommended for use in this patient group.

Note 2. Recovery of neuromuscular conduction after administration of neuromuscular blockers may be delayed or inadequate in patients who have received magnesium salts for the treatment of pregnancy toxemia, as magnesium salts potentiate neuromuscular blockade. For such patients, the dose of rocuronium bromide should be reduced and titrated according to muscular response.

Breastfeeding. It is not known whether rocuronium bromide is excreted in human milk. Animal studies have demonstrated low levels of the drug in milk. Rocuronium bromide may be used during breastfeeding only if, in the physician’s opinion, the expected benefit to the woman outweighs the potential risk to the infant. After a single dose, it is recommended to withhold breastfeeding for five elimination half-lives of rocuronium, i.e., approximately 6 hours.

Ability to influence reaction speed when driving or operating machinery.

Since rocuronium bromide is used as an adjunct in general anaesthesia, patients undergoing outpatient procedures should follow standard post-anaesthesia precautions.

Method of Administration and Dosage

Administration of rocuronium bromide, like other neuromuscular blocking agents, must be performed only by a physician experienced in the use of such medicinal products or under the supervision of such a specialist. The medicinal product should be administered only in a hospital setting. Rocuronium bromide is administered intravenously either as a bolus or by continuous infusion.

The dose of rocuronium bromide, as with other neuromuscular blocking agents, must be individually adjusted for each patient. When determining the dose, consider the type of anesthesia and expected duration of surgery, the method of premedication and anticipated duration of mechanical ventilation, potential interactions with other concurrently administered medicinal products, and the patient’s overall condition.

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

Inhalational anesthetics enhance the blocking effect of rocuronium bromide on neuromuscular transmission. This potentiation may become clinically significant only when, during general anesthesia, the tissue concentration of inhaled agents reaches a level sufficient for such interaction. Therefore, the dose of rocuronium bromide should be adjusted by administering the smallest maintenance doses at longer intervals or by reducing the infusion rate to a minimum during prolonged procedures (over 1 hour) involving inhalational anesthesia.

Risk of medication errors: accidental administration of neuromuscular blockers may cause serious adverse effects, including fatal outcomes. Store rocuronium bromide in its original, undamaged packaging (to prevent compromise of vial integrity) with clear labeling to minimize the risk of selecting the wrong medicinal product.

The dosage recommendations provided for adult patients can be used as a general guideline for tracheal intubation, ensuring muscle relaxation during surgical procedures of varying duration, and when used in intensive care units.

Surgical Procedures

Tracheal Intubation

The standard dose of rocuronium bromide, after which adequate conditions for tracheal intubation are established within approximately 60 seconds in nearly all patients under routine (planned) anesthesia, is 0.6 mg/kg body weight. For rapid sequence induction of anesthesia, the recommended dose of rocuronium bromide is 1 mg/kg body weight. When using rocuronium bromide at a dose of 0.6 mg/kg body weight for rapid sequence induction, tracheal intubation should be performed 90 seconds after administration of the drug.

For information on the use of rocuronium bromide during rapid sequence induction of anesthesia in patients undergoing cesarean section, see section "Use during pregnancy or breastfeeding."

Maintenance Doses

The recommended maintenance dose of rocuronium bromide is 0.15 mg/kg body weight; during prolonged inhalational anesthesia, this should be reduced to 0.075–0.1 mg/kg body weight. Maintenance doses should ideally be administered when the amplitude of muscle twitch responses has recovered to 25% of the control level or when 2–3 responses are observed during monitoring using train-of-four (TOF) stimulation.

Continuous Infusion

If rocuronium bromide is administered by continuous infusion, a loading dose of 0.6 mg/kg body weight is recommended. When neuromuscular transmission begins to recover, infusion should be initiated. The infusion rate should be adjusted to maintain skeletal muscle twitch response at 10% of the control level or to sustain 1–2 responses during TOF monitoring. In adults undergoing intravenous general anesthesia, the infusion rate required to maintain neuromuscular blockade at this level ranges from 0.3–0.6 mg/kg/h, while under inhalational anesthesia, it is 0.3–0.4 mg/kg/h. Continuous neuromuscular monitoring is recommended, as the required infusion rate may vary depending on the anesthetic technique and individual patient characteristics.

Pediatric Patients

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 the same as for adults.

However, the duration of action of a single dose during intubation will be longer in neonates and infants than in older children.

For continuous administration of the drug to pediatric patients (except children aged 2–11 years), the infusion rate is the same as for adults. For children aged 2–11 years, a higher infusion rate may be required. For children aged 2–11 years, initial infusion rates are recommended to be the same as for adults, but should be adjusted during the procedure to maintain muscle twitch amplitude at 10% of the control amplitude or to sustain 1–2 responses during TOF monitoring.

Experience with the use of rocuronium bromide in children during rapid sequence induction is limited; therefore, rocuronium bromide is not recommended for use in children to facilitate tracheal intubation during rapid sequence induction.

Dosing in elderly patients, patients with hepatic and/or biliary disorders and/or renal impairment

The standard dose of rocuronium bromide for intubation in elderly patients (>65 years), patients with hepatic and/or biliary disorders and/or renal impairment during routine anesthesia is 0.6 mg/kg body weight. For these patients, where a longer duration of action is expected, a dose of 0.6 mg/kg should be considered for rapid sequence induction. Regardless of the anesthetic technique 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/h (see also "Continuous Infusion" above).

Dosing in patients with increased body weight and obesity

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

Use in the Intensive Care Unit

Tracheal Intubation

For endotracheal intubation, the same doses should be used as for surgical procedures.

Maintenance Doses

Rocuronium bromide is recommended to be administered with an initial loading dose of 0.6 mg/kg body weight, followed immediately by continuous infusion once neuromuscular response has recovered to 10% of the control level or 1–2 responses are observed during TOF monitoring. Doses of rocuronium bromide should always be titrated according to individual patient response. The recommended initial infusion rate to maintain neuromuscular blockade at 80–90% (1–2 responses during TOF stimulation) in adult patients is 0.3–0.6 mg/kg/h during the first hour of administration, after which the infusion rate should be gradually reduced over 6–12 hours according to individual patient response. After this period, individual dose requirements remain relatively constant.

Controlled clinical studies have shown considerable inter-patient variability in hourly infusion rates, with a mean range of 0.2–0.5 mg/kg/h depending on the cause and degree of organ dysfunction, concomitant medication, and individual patient characteristics. To ensure optimal management of each patient, neuromuscular monitoring is strongly recommended. Drug administration has been studied for durations up to 7 days.

Special Patient Groups

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

Compatibility when mixed with other medicinal products

Rocuronium bromide at concentrations of 0.5 mg/mL and 2.0 mg/mL is compatible with 0.9% sodium chloride solution, 5% glucose solution, 5% glucose in saline solution, sterile water for injection, and Ringer’s lactate solution. Administration should begin immediately after mixing and be completed within 24 hours. Unused portions of the medicinal product or used materials must be destroyed in accordance with local requirements.

Children.

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

Overdose.

In case of overdose and prolonged neuromuscular blockade, the patient must be provided with supportive ventilation and sedative therapy. In this situation, there are two options for reversing neuromuscular blockade:

1. Sugammadex can be used to reverse profound (progressing) and deep blockade. The dose of sugammadex depends on the degree of neuromuscular blockade.
2. After spontaneous recovery of respiration begins, an acetylcholinesterase inhibitor (e.g., neostigmine, edrophonium, pyridostigmine) should be administered in appropriate doses. If administration of an acetylcholinesterase inhibitor fails to reverse the blocking effect of rocuronium bromide, artificial ventilation must be continued until spontaneous respiration returns. Repeated administration of acetylcholinesterase inhibitors may be hazardous.

In animal studies, severe cardiovascular depression leading to circulatory collapse was not observed until a cumulative dose of 750 × ED90 (135 mg rocuronium bromide per 1 kg body weight) was administered.

Adverse Reactions

The most commonly observed adverse reactions associated with the use of the medicinal product were: pain/reaction at the injection site, changes in vital signs, and prolonged duration of neuromuscular blockade. During post-marketing surveillance, the most frequently reported serious adverse reactions were anaphylactic and anaphylactoid reactions, as well as associated symptoms (see table below).

Organ systems	Frequency of occurrence1
	Uncommon/rare2 (< 1/100, > 1/10,000)	Very rare (<1/10,000)	Not known
Immune system disorders		Increased sensitivity, anaphylactic reaction, anaphylactoid reaction, anaphylactic shock, anaphylactoid shock
Nervous system disorders		Flaccid paralysis
Cardiac disorders	Tachycardia		Kounis syndrome
Vascular disorders	Hypotension	Vascular collapse and shock, flushing
Respiratory, thoracic and mediastinal disorders		Bronchospasm
Skin and subcutaneous tissue disorders		Angioneurotic edema, urticaria, rash, erythematous rash
Musculoskeletal and connective tissue disorders		Muscle weakness3, steroid myopathy3
General disorders and administration site reactions	Ineffectiveness of the medicinal product, reduced effect of the medicinal product/therapeutic effect, enhanced effect of the medicinal product/therapeutic effect, pain at injection site, reaction at injection site	Facial swelling
Injury, poisoning and procedural complications	Protracted neuromuscular blockade, delayed recovery from anesthesia	Anesthesia-related respiratory complications

1 Frequency determined from post-marketing surveillance reports and published data.

2 Post-marketing surveillance data do not allow precise calculation of the number of cases. For this reason, the frequency of occurrence was divided into 3, rather than 5 categories.

3 After prolonged resuscitation measures.

Anaphylactic reactions

Severe anaphylactic reactions have been reported, although very rarely, following administration of neuromuscular blocking agents, including rocuronium bromide. Anaphylactic/anaphylactoid reactions: bronchospasm, cardiovascular disturbances (e.g., arterial hypotension, tachycardia, circulatory collapse—shock), skin and mucous membrane changes (e.g., angioedema, urticaria). In some cases, these reactions were fatal. Due to the potential severity of such reactions, their possible occurrence must always be considered, and appropriate preventive measures should be taken.

Release of histamine and histamine-mediated reactions

Since administration of neuromuscular blocking agents may induce local and/or systemic histamine release, possible histamine-mediated reactions (anaphylactoid reactions), including local reactions at the injection site (e.g., itching, erythema), must always be considered when administering these medicinal products.

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

Prolonged neuromuscular blockade

The most common adverse reaction associated with the use of non-depolarizing neuromuscular blocking agents as a class is prolonged duration of pharmacological effect beyond the required time period. The severity of this reaction may range from skeletal muscle weakness to profound and prolonged paralysis of skeletal muscles, leading to respiratory insufficiency or apnea.

Myopathy

Myopathy has been reported following administration of various neuromuscular blocking agents in combination with corticosteroids in intensive care units.

Injection site reactions

Pain on injection has been reported during rapid sequence induction of anesthesia, particularly when the patient is still conscious, and especially when propofol is used as the induction agent. In clinical studies, injection 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.

Children

In a meta-analysis of 11 clinical studies evaluating the use of rocuronium bromide (up to 1 mg/kg) in pediatric patients (n = 704), tachycardia was observed as an adverse reaction with an incidence of 1.4%.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after medicinal product registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at 2–8 °C. Keep out of reach of children.

Special storage conditions. The medicinal product may be stored outside the refrigerator at temperatures up to 25 °C for no more than 12 weeks. After storage outside the refrigerator, the product must not be returned to the refrigerator for further storage.

After dilution of the medicinal product with infusion solutions specified in the section "Method of administration and dosage. Compatibility when mixed with other medicinal products," chemical and physical stability has been demonstrated for 72 hours at temperatures not exceeding 25 °C.

From a microbiological standpoint, the diluted medicinal product should be used immediately.

If the solution is not used immediately, the responsibility for the storage time and conditions lies with the healthcare professional administering the product. The storage time should not exceed 24 hours at 2–8 °C, provided that dilution was performed under strict aseptic conditions.

Incompatibilities.

Rocuronium bromide is physically incompatible with solutions of the following medicinal products: 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.

Rocuronium bromide must not be mixed with other medicinal products except 0.9% sodium chloride solution for intravenous infusion, 5% glucose solution for intravenous infusion, 5% glucose in 0.9% sodium chloride solution for intravenous infusion, water for injections, and Ringer's lactate solution.

If rocuronium bromide is administered through the same infusion line used for other medicinal products, it is essential to thoroughly flush the line (e.g., with 0.9% sodium chloride solution) between administration of rocuronium bromide and any medicinal product known to be incompatible with, or for which compatibility with rocuronium bromide has not been established.

Packaging.

5 mL in a vial; 5 vials in a blister pack; 1 blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Limited liability company "Novopharm-Biosyntez".

Manufacturer's address and location of business activity.

Ukraine, 11700, Zhytomyr Oblast, Novohrad-Volynskyi, Zhytomyrska St., 38.