Rocumid

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROCUMID

Composition:

Active substance: rocuronium bromide;

1 ml of solution contains 10 mg of rocuronium bromide;

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

Pharmaceutical form. Solution for injection.

Main physicochemical characteristics: clear liquid, colorless to light brown.

Pharmacotherapeutic group. Peripheral-acting muscle relaxants.

ATC code M03AC09.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

ROCUMID (rocuronium bromide) is a fast-acting, intermediate-duration non-depolarizing neuromuscular blocking agent possessing all pharmacological effects typical of this class of drugs (curare-like). It blocks nicotinic cholinergic receptors at the motor end plate of the skeletal muscle nerve. The antagonists of this action are acetylcholinesterase inhibitors, such as neostigmine, edrophonium, and pyridostigmine.

Pharmacodynamic effects

ED90 (the dose of rocuronium bromide required to produce 90% suppression of the twitch response of the adductor pollicis muscle to ulnar nerve stimulation) during intravenous anesthesia 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 skeletal muscle 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 twitch response (recovery index) after a bolus dose of 0.6 mg/kg body weight is 14 minutes.

When the drug is administered at lower doses—0.3–0.45 mg/kg body weight (1–1½ × ED90)—the onset of action is delayed and the duration of action is shorter. At higher doses—2 mg/kg body weight—the clinical duration is 110 minutes.

Intubation during routine anesthesia

Within 60 seconds after intravenous administration of rocuronium bromide at a dose of 0.6 mg/kg (2×ED90 under balanced anesthesia), adequate conditions for intubation are achieved in virtually all patients, with excellent intubation 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 conditions for intubation are established within 90 seconds.

Rapid sequence induction

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

Special patient groups

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

Elderly 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 may be slightly longer when enflurane or isoflurane anesthesia is used in elderly patients and in patients with hepatic and/or renal impairment (approximately 20 minutes), compared to patients without excretory organ dysfunction under intravenous anesthesia (approximately 13 minutes). With repeated administration of maintenance doses within the recommended range, no cumulative effect (progressive prolongation of duration) has been observed.

Intensive care unit

In the intensive care unit, following 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 longer, 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.

Cardiac surgery

In patients scheduled for cardiac surgery, the most common cardiovascular changes observed during peak blockade after administration of 0.6–0.9 mg/kg rocuronium bromide are a mild and clinically insignificant increase in heart rate by up to 9% and an increase in mean arterial pressure by up to 16% from baseline.

Reversal of muscle relaxation

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

Pharmacokinetics.

After intravenous administration of a single bolus dose of rocuronium bromide, its plasma concentration follows a triphasic exponential decline. 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.

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

Controlled studies have shown that plasma clearance is reduced in elderly patients and in patients with renal impairment, although 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 hepatic disease, and clearance decreases by 1 mL/kg/min (see section "Administration and dosage").

Children

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

Pharmacokinetic parameters (PKP) in typical pediatric patients by age group are summarized below.

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

Intensive care unit

When administered as a continuous infusion to facilitate mechanical ventilation for 20 hours or longer, the mean elimination half-life and the mean (apparent) volume of distribution at steady state increase. Controlled clinical studies have demonstrated significant individual variability in these parameters, related to the different etiology and severity of multiorgan failure and individual patient characteristics. In patients with multiorgan failure, the mean (± SD) 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\»).

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

Clinical characteristics.

Indications.

ROCURONIUM is indicated in adults and children (from newborns to adolescents – from 0 to <18 years) as an adjunct to general anesthesia to facilitate tracheal intubation during routine sequential induction of anesthesia and to provide skeletal muscle relaxation during surgical procedures. In adults, ROCURONIUM 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:

Enhancement of effect

• Halogenated volatile anesthetics potentiate the neuromuscular blockade caused by ROCURONIUM. This effect becomes evident only with administration of maintenance doses (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 in intensive care units may lead to prolonged neuromuscular blockade or myopathy (see sections "Special precautions" and "Adverse reactions").

Other medicinal products:

• antibiotics: aminoglycosides, lincosamides, polypeptide antibiotics, acylamino-penicillin antibiotics;
• diuretics, quinidine and its isomer quinine, magnesium salts, calcium channel blockers, lithium salts, local anesthetics (intravenous lidocaine, epidural bupivacaine), and emergency administration of phenytoin or β-adrenergic blockers.

Recurarization has been reported after postoperative administration of aminoglycosides, lincosamides, polypeptide and acylamino-penicillin antibiotics, quinidine, quinine, and magnesium salts.

Reduction of effect

• prior prolonged administration of phenytoin or carbamazepine;
• protease inhibitors (gabexate, ulinastatin);
• neostigmine, edrophonium, pyridostigmine.

Change in effect

• administration of other non-depolarizing neuromuscular blockers in combination with ROCURONIUM may result in reduced or enhanced neuromuscular blockade, depending on the sequence of administration and the neuromuscular blocking agent used;
• succinylcholine administered after ROCURONIUM may potentiate or reduce the neuromuscular blockade induced by ROCURONIUM.

Effect of ROCURONIUM on other medicinal products

Combination of ROCURONIUM with lidocaine may lead to a faster onset of lidocaine's action.

Children.

No formal interaction studies have been conducted in children. The interactions and special precautions described above for adult patients (see relevant sections) should also be considered when administering rocuronium bromide to children.

Compatibility when mixed with other medicinal products.

ROCURONIUM has been shown to be compatible at nominal concentrations of 0.5 mg/mL and 2 mg/mL with 0.9% sodium chloride solution, 5% glucose solution for intravenous infusion, 5% glucose in 0.9% sodium chloride solution for intravenous infusion, sterile water for injection, and lactated Ringer's solution. Infusion should begin immediately after mixing and must be completed within 24 hours. Any unused solution should be discarded.

Special precautions for use.

ROCURONIUM should be administered only by an anaesthesiologist experienced in using neuromuscular blocking agents. When using ROCURONIUM, equipment for emergency controlled ventilation, oxygen supply, and tracheal intubation must be readily available.

Appropriate management and monitoring

Since ROCURONIUM causes paralysis of respiratory muscles, patients receiving this medicinal product require artificial ventilation until adequate spontaneous respiration is restored. As with all neuromuscular blockers, potential difficulties with tracheal intubation should be anticipated, especially when the drug is used as part of a rapid sequence induction technique. If intubation difficulties arise, leading to a clinical need for urgent reversal of rocuronium-induced neuromuscular blockade, consideration should be given to using a reversal agent. Patients must be confirmed to be breathing spontaneously, deeply, and regularly before leaving the operating room after anaesthesia.

Residual curarization

As with other neuromuscular blockers, residual curarization has been reported after administration of rocuronium bromide. To prevent complications due to residual curarization, extubation is recommended only after recovery of neuromuscular transmission in the patient.

The risk of residual neuromuscular blockade is increased in elderly patients (aged 65 years and older). 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 neuromuscular blockade 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 blockers. Precautions should always be taken to avoid such reactions. Special precautions are particularly necessary in patients with a history of anaphylactic reactions to any neuromuscular blockers, 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, prolonged paralysis and/or skeletal muscle weakness have been observed in ICU patients after long-term use of neuromuscular blockers. 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 sedation. Furthermore, neuromuscular blockers should be administered in carefully titrated doses according to individual patient response, under the supervision of an experienced physician and using appropriate neuromuscular monitoring techniques.

Myopathy has been frequently reported after prolonged administration of non-depolarizing neuromuscular blockers in combination with corticosteroid therapy in ICU settings. 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 should be delayed until the patient has clinically recovered from succinylcholine-induced neuromuscular blockade.

Since rocuronium bromide is always used in combination with other medicinal products and due to the 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 prior to initiating anaesthesia. Animal studies have shown that rocuronium bromide is not a causative agent of 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 fatal outcome due to medication errors

Administration of ROCURONIUM leads to paralysis, which may result in respiratory arrest and death, particularly in patients for whom the drug was not intended. Proper selection of the intended medicinal product must be ensured, and confusion with other injectable solutions available in ICU and other clinical settings must be avoided. If the drug is administered by another healthcare professional, the dose being administered must be clearly specified and confirmed.

Factors that may affect the pharmacokinetics and/or pharmacodynamics of ROCURONIUM

Liver disease and/or biliary tract disorders and renal insufficiency

Since rocuronium bromide is eliminated via 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 prolonged blood circulation time, such as cardiovascular disease, advanced age, and edema leading to increased volume of distribution, may delay the onset of the drug’s effect. Duration of action may also be prolonged due to reduced plasma clearance.

Neuromuscular disorders

As with other neuromuscular blockers, ROCURONIUM 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. The magnitude and direction of such changes may vary widely. In patients with severe myasthenia gravis or myasthenic syndrome (Eaton-Lambert syndrome), even small doses of ROCURONIUM may cause profound neuromuscular blockade; therefore, the dose of ROCURONIUM should be adjusted according to individual patient response.

Hypothermia

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

Obesity

As with other neuromuscular blockers, ROCURONIUM may have a longer duration of effect, and spontaneous recovery of neuromuscular transmission may be prolonged in obese patients 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 enhance the effect of ROCURONIUM

Hypokalaemia (e.g., following prolonged vomiting, diarrhoea, or diuretic therapy), hypermagnesaemia, hypocalcaemia (after massive blood transfusions), hypoproteinaemia, 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.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

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

Caesarean section. ROCURONIUM may be used for caesarean section as part of a rapid sequence induction technique, provided that no intubation difficulties 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 parturients undergoing caesarean section. Rocuronium bromide did not affect Apgar scores or fetal muscle tone and cardiopulmonary adaptation. Analysis of umbilical cord blood showed that only a minimal amount of rocuronium bromide crosses the placental barrier, without causing clinically relevant adverse reactions in newborns.

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

Note 2. Recovery of neuromuscular transmission after administration of neuromuscular blockers may be delayed or inadequate in patients who have received magnesium salts for treatment of pregnancy toxemia, as magnesium salts enhance neuromuscular blockade. For such patients, the dose of ROCURONIUM should be reduced and carefully titrated according to muscle response.

Breastfeeding

It is not known whether rocuronium bromide passes into breast milk. Animal studies have demonstrated low levels of rocuronium bromide in milk. ROCURONIUM may be used during breastfeeding only if, in the physician’s opinion, the expected benefit to the mother outweighs the potential risk to the infant. After a single dose, breastfeeding should be withheld for five elimination half-lives of rocuronium, approximately 6 hours.

Ability to influence reaction speed when driving or operating machinery.

Since ROCURONIUM is used as an adjunct in general anaesthesia, standard post-anaesthesia precautions should be followed for outpatient patients.

Method of Administration and Dosage

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

The dose of ROCUMID, as with other neuromuscular blockers, must be individually adjusted for each patient. When determining the dose, consider the anesthetic method and expected duration of surgery, the premedication method and expected duration of mechanical ventilation, potential interactions with other concurrently administered medicinal products, and the patient’s overall clinical condition.

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

Inhalational anesthetics enhance the neuromuscular blocking effect of ROCUMID. This potentiation becomes clinically significant only when tissue concentrations of inhaled agents reach levels sufficient for interaction during general anesthesia. Therefore, the dose of ROCUMID should be adjusted by administering smaller 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. ROCUMID should be stored with its intact cap and safety seal, and in a manner that minimizes the risk of selecting the wrong product (see section "Special Warnings and Precautions for Use").

The following dosage recommendations for adult patients may be used as a general guideline for tracheal intubation, provision of muscle relaxation during surgical procedures of varying duration, and use in intensive care units.

Surgical Procedures

Tracheal Intubation

The standard dose of rocuronium bromide, after which adequate conditions for tracheal intubation are achieved within 60 seconds in nearly all patients under routine anesthesia, is 0.6 mg/kg body weight. For rapid sequence induction of anesthesia, the recommended dose of rocuronium bromide is 1 mg/kg. 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 ROCUMID.

For information on the use of rocuronium bromide during rapid sequence induction in patients undergoing cesarean section, see section "Use in Pregnancy and Lactation".

Maintenance Doses

The recommended maintenance dose of rocuronium bromide is 0.15 mg/kg body weight; in 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 control level or when 2–3 responses are observed during monitoring using train-of-four (TOF) stimulation.

Continuous Infusion

When ROCUMID is administered by continuous infusion, an initial loading dose of 0.6 mg/kg is recommended, followed by initiation of infusion when neuromuscular transmission begins to recover. The infusion rate should be adjusted to maintain skeletal muscle twitch response at 10% of control level or to sustain 1–2 responses during TOF monitoring. In adult patients undergoing intravenous general anesthesia, the infusion rate required to maintain neuromuscular blockade at this level ranges from 0.3 to 0.6 mg/kg/hour; during inhalational anesthesia, the rate is 0.3 to 0.4 mg/kg/hour. 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), young children (3–23 months), older 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 intubation dose will be longer in neonates and infants than in older children.

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

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

Dosing in Elderly Patients and Patients with Hepatic and/or Biliary and/or Renal Impairment

The standard dose of rocuronium bromide for intubation in elderly patients (>65 years), and in patients with hepatic and/or biliary disease 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 may 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 rocuronium bromide, and the recommended infusion rate is 0.3–0.4 mg/kg/hour (see also "Continuous Infusion").

Dosing in Patients with Increased Body Weight and Obesity

When administering the medicinal product 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 Intensive Care Units

Tracheal Intubation

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

Maintenance Doses

Rocuronium bromide is recommended to be administered as an initial loading dose of 0.6 mg/kg body weight, followed immediately by continuous infusion once neuromuscular response has recovered to 10% of 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/hour during the first hour, followed by a reduction in infusion rate over the next 6–12 hours according to individual patient response. Thereafter, 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/hour depending on the cause and degree of organ dysfunction, concomitant medication, and individual patient characteristics. Continuous neuromuscular monitoring is strongly recommended to ensure optimal patient management. Administration of rocuronium bromide has been studied for durations of up to 7 days.

Special Patient Groups

The medicinal product is not recommended for use in pediatric patients or elderly patients requiring mechanical ventilation during intensive care due to lack of safety and efficacy data in these patient populations.

Pediatric Patients

ROCUMID can be used in pediatric patients: neonates (0–27 days), infants (28 days–2 months), young children (3–23 months), older children (2–11 years), and adolescents (12–17 years).

Overdose

In cases of overdose or prolonged neuromuscular blockade, the patient must be provided with supportive ventilation and sedation. In such situations, two approaches are available to reverse 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 at appropriate doses. If administration of an acetylcholinesterase inhibitor fails to reverse the blocking effect of ROCUMID, 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 cardiovascular collapse was not observed until cumulative doses of 750 × ED90 (135 mg rocuronium bromide per kg body weight) were administered.

Adverse reactions.

The most commonly observed adverse reactions associated with the use of rocuronium bromide 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).

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

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

3 In the context of potential increased permeability or disruption of the blood-brain barrier (BBB).

4 Following prolonged resuscitation efforts.

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 reactions (e.g., angioedema, urticaria). In some cases, these reactions were fatal. Due to the potential severity of such reactions, their occurrence must always be considered, and appropriate preventive measures taken.

Release of histamine and histamine-mediated reactions

Since administration of neuromuscular blocking agents may cause local histamine release at the injection site as well as systemic release, possible occurrence of itching and erythematous reactions at the injection site and/or systemic histamine-mediated reactions (anaphylactoid reactions) must always be considered when administering these medicinal products.

During clinical trials, only a minor 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 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 was used as the induction agent. In clinical trials, injection pain was reported 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

A meta-analysis of 11 clinical trials in children (n=704) who received rocuronium bromide (up to 1 mg/kg) identified tachycardia as an adverse drug reaction with a frequency of 1.4%.

Reporting of adverse reactions.

Reporting of adverse reactions after marketing authorization of the medicinal product is of great importance. 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 through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life.

2 years.

Storage conditions.

Store at 2–8 °C in a place inaccessible to children.

Special storage conditions. The product may be stored outside the refrigerator at temperatures up to 30 °C for no more than 12 weeks. After storage of ROKUMID outside the refrigerator, it must not be returned to the refrigerator for further storage.

After dilution with infusion solutions specified in the section "Compatibility with other medicinal products", chemical and physical stability has been demonstrated for 72 hours at 30 °C.

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

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

Incompatibility.

Physical incompatibility of the medicinal product ROKUMID has been established with solutions containing: amphotericin B, amoxicillin, azathioprine, cefazolin, cloxacillin, dexamethasone, diazepam, enoximone, erythromycin, famotidine, furosemide, hydrocortisone sodium succinate, insulin, intralipid, methohexital, methylprednisolone, prednisolone sodium succinate, thiopental, trimethoprim, and vancomycin.

ROKUMID 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 injection, and Ringer's lactate solution.

If ROKUMID is administered through the same infusion system as other medicinal products, the system must be thoroughly flushed (e.g., with 0.9% NaCl solution) between administration of ROKUMID solution and any incompatible medicinal products, as well as when compatibility has not been established.

Packaging.

5 ml in a vial, 5 vials in a blister, 2 blisters in a carton.

Prescription status.

Prescription only.

Manufacturer.

TOV "BIOLIK FARMА".

Manufacturer's address and location of its business operations.

Legal entity address:

70 Pomirky St., Kharkiv, Kharkiv Oblast, 61070, Ukraine.

Address of business operations:

Pomirky-70, building b/n, Kharkiv, Kharkiv Oblast, 61070, Ukraine.