ROCURONIUM KABI

INSTRUCTIONS for medical use of the medicinal product Rocuronium Kabi (Rocuronium Kabi)

Composition:

active substance: rocuronium bromide;

1 ml of solution contains 10 mg of rocuronium bromide;

excipients: sodium chloride, hydrochloric acid, sodium hydroxide, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear solution ranging from colorless to
light brown in color.

pH of the solution: 2.8–3.2.

Osmolality: 270–330 mOsmol/kg.

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

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Rocuronium Kabi (rocuronium bromide) is a rapid-onset, intermediate-acting, non-depolarizing neuromuscular blocking agent with all the pharmacological effects typical of this class of drugs (curare-like). It blocks nicotinic cholinergic receptors at the motor end plate of the skeletal muscle neuromuscular junction. The antagonists of this effect are acetylcholinesterase inhibitors, such as neostigmine, edrophonium, and pyridostigmine.

ED90 (the dose of rocuronium bromide required to suppress by 90% the twitch response of the adductor pollicis muscle to ulnar nerve stimulation) under balanced anesthesia is approximately 0.3 mg/kg body weight. The ED95 value is lower in infants than in adults and children (0.25, 0.35, and 0.4 mg/kg, respectively).

Intubation during routine anesthesia

Within 60 seconds after intravenous administration of rocuronium bromide at 0.6 mg/kg (2 × ED90 under balanced anesthesia), adequate conditions for intubation are achieved in nearly 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. The clinical duration of action (time to spontaneous recovery of muscle twitch response to 25% of control level) at a dose of 0.6 mg/kg body weight is 30–40 minutes. The total duration (time to spontaneous recovery of muscle twitch response to 90% of control level) 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. With lower doses of 0.3–0.45 mg/kg body weight (1–1½ × ED90), onset is delayed and duration of action is shorter. After administration of 0.45 mg/kg, acceptable conditions for intubation are achieved within 90 seconds. With higher doses (2 mg/kg), the clinical duration of action is 110 minutes.

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 mg/kg dose of rocuronium bromide. Among these, conditions are rated as excellent in 70%. The clinical duration of action at this dose approaches 1 hour, after which neuromuscular conduction can be safely restored.

After administration of a 0.6 mg/kg dose of rocuronium bromide, adequate conditions for intubation are achieved within 60 seconds in 81% and 75% of patients undergoing rapid sequence induction with propofol or fentanyl/thiopental, respectively.

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 longer, the mean (range) time between return of T2 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.

Special patient populations

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

The duration of action of maintenance doses 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 disease (approximately 20 minutes), compared to patients without excretory organ dysfunction under intravenous anesthesia (approximately 13 minutes). With repeated administration of maintenance doses at the recommended level, no cumulative effect (progressive prolongation of duration) has been observed.

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 min) was slightly longer than in infants, toddlers, and older children (0.4, 0.6, and 0.8 min, respectively). In children, the duration of relaxation and neuromuscular recovery time 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 min, respectively) compared to toddlers, older children, and adolescents (45.4, 37.6, and 42.9 min, respectively).

Cardiovascular surgery

In patients undergoing cardiac surgery, the most common cardiovascular changes observed during peak blockade after administration of 0.6–0.9 mg/kg of Rocuronium Kabi are mild and clinically insignificant increases in heart rate of up to 9% and increases in mean arterial pressure of up to 16% of the control value.

Reversal of neuromuscular block

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 (3 minutes after administration of rocuronium bromide). 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 declines in a triphasic exponential manner. In healthy adult volunteers, 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.

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 liver disease, and clearance decreases by 1 mL/kg/min (see "Dosage and administration").

Children

The pharmacokinetics of rocuronium bromide in children (n = 146) across age groups (0–17 years) was studied using a population analysis of pooled pharmacokinetic data from two clinical studies 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). The volume of distribution (L/kg) and elimination half-life (h) decreased with age (years).

Pharmacokinetic parameters (PKP) in typical pediatric patients by age group are summarized in Table 1 below.

Table 1

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 shown considerable inter-individual variability in these parameters, related to the different etiology and severity of (multi)organ 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.

Rocuronium is excreted in urine and bile. Renal excretion reaches 40% within 12–24 hours. After injection 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 have not been detected in plasma.

Clinical characteristics.

Indications.

Rocuronium Kab is indicated in adults and children (from full-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 Kab is also indicated to facilitate tracheal intubation during rapid sequence induction of anesthesia and as an adjunct to assist with artificial ventilation in intensive care units.

Contraindications.

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

Interaction with other medicinal products and other forms of interactions.

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

Enhancement of effect:

• Halogenated volatile anesthetics enhance the neuromuscular blockade caused by rocuronium bromide. This effect becomes noticeable only after administration of maintenance doses (see section "Method of administration and dosage"). 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 "Adverse reactions").

Other medicinal products:

• antibiotics: aminoglycosides, lincosamides, and 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 use of phenytoin or carbamazepine;
• protease inhibitors (gabexate, ulinastatin);
• neostigmine, edrophonium, pyridostigmine.

Altered effect:

• administration of other non-depolarizing neuromuscular blockers in combination with rocuronium bromide may result in reduced or enhanced neuromuscular blockade, depending on the sequence of administration and the neuromuscular blocking agent used;
• administration of succinylcholine after rocuronium bromide may lead to either enhancement or reduction of neuromuscular blockade caused by rocuronium bromide.

Effect of rocuronium bromide on other medicinal products

Concomitant administration of rocuronium bromide with lidocaine may accelerate the onset of action of lidocaine.

Children and adolescents

Formal drug interaction studies involving pediatric patients have not been conducted. The aforementioned interactions in adults and special precautionary statements and preventive measures (see "Special precautions") should also be considered for pediatric patients.

Compatibility when mixed with other medicinal products

Any unused solutions should be discarded.

The solution should be inspected visually before use. Only clear solutions, practically free from particles, should be used.

Rocuronium Kab has been shown to be compatible with: 0.9% sodium chloride solution, 5% glucose solution, 5% glucose in 0.9% sodium chloride solution, lactated Ringer's solution, and sterile water for injection.

Special precautions for use.

Rocuronium Kabiv should be administered only by an experienced anaesthesiologist familiar with the use of neuromuscular blocking agents; equipment for emergency controlled ventilation, oxygen supply, and tracheal intubation must be immediately available when administering the drug.

The medicinal product is intended for single use only.

Proper administration 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 other neuromuscular blockers, difficulties with intubation should be considered, particularly when rocuronium bromide is used for rapid sequence induction of anaesthesia. If intubation difficulties arise requiring immediate reversal of rocuronium-induced neuromuscular blockade, the use of sugammadex 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 neuromuscular blockade has been reported with rocuronium use. To prevent complications associated with residual neuromuscular blockade, extubation should be performed only when the patient has sufficiently recovered from neuromuscular blockade. Elderly patients (aged 65 years and older) may be at increased risk of residual neuromuscular blockade. Other factors that may contribute to residual neuromuscular blockade after surgery and extubation should also be considered (such as drug interactions or the patient's clinical condition). If the drug is used outside standard clinical practice, consideration should be given to using a reversal agent (e.g., sugammadex or acetylcholinesterase inhibitors), especially if prolonged neuromuscular blockade is likely.

Anaphylaxis

Anaphylactic reactions may occur following administration of muscle relaxants. Precautionary measures should always be taken to avoid such reactions. Special precautions are particularly necessary in patients with a history of anaphylactic reactions to any muscle relaxant, as high rates of cross-allergy between neuromuscular blocking agents have been reported.

Long-term use in intensive care units

Prolonged paralysis and/or skeletal muscle weakness have been reported following long-term use of neuromuscular blocking agents in intensive care units. To prevent prolonged neuromuscular blockade and/or overdose, monitoring of neuromuscular transmission is strongly recommended during administration of neuromuscular blockers. Additionally, patients must receive adequate analgesia and sedation. Doses of neuromuscular blocking agents should be adjusted according to the response to stimulation. This should be performed only by experienced physicians or under the supervision of experienced physicians familiar with the drug’s action and appropriate neuromuscular monitoring techniques.

Myopathy has been reported after prolonged use of other non-depolarizing neuromuscular blocking agents in intensive care units, particularly when used in combination with corticosteroid therapy. Therefore, for patients receiving corticosteroids concomitantly, the duration of neuromuscular blocker use should be kept as short as possible.

Use with succinylcholine

Rocuronium may be administered only after complete disappearance of neuromuscular blockade induced by succinylcholine.

Since rocuronium bromide is always used in combination with other medicinal products and considering the risk of malignant hyperthermia during anaesthesia, physicians must be familiar with early symptoms, diagnosis, and treatment of malignant hyperthermia, even in the absence of known triggering factors prior to anaesthesia. Animal studies have shown that rocuronium bromide is not a triggering agent for malignant hyperthermia. However, rare cases of malignant hyperthermia have been reported in post-marketing surveillance within drug safety monitoring programs following administration of rocuronium bromide, although a causal relationship has not been established.

Risk of death due to medication errors

Administration of Rocuronium Kabiv causes paralysis that may lead to respiratory arrest and death, particularly in patients for whom this drug is 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.

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

Liver and/or biliary tract disorders and renal impairment

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

Increased circulation time

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

Neuromuscular disorders

As with other neuromuscular blocking agents, rocuronium bromide should be used with extreme caution in patients with neuromuscular disorders and in those who have had poliomyelitis, as the response to neuromuscular blockers may be significantly altered. The extent and type of these changes may vary considerably. In patients with myasthenia gravis or myasthenic syndrome (Lambert-Eaton syndrome), even small doses of rocuronium bromide may produce profound effects; therefore, the dose of rocuronium bromide should be individualized according to the patient's response.

Hypothermia

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

Obesity

As with other neuromuscular blocking agents, rocuronium bromide may have a prolonged duration of action in obese patients, and the time to spontaneous recovery of neuromuscular transmission may be prolonged if doses are calculated based on total body weight.

Burns

It is known that burn patients may develop resistance to non-depolarizing neuromuscular blocking agents. Dose adjustment based on response to stimulation is recommended.

Conditions that may potentiate the effect of rocuronium bromide: hypokalaemia (e.g., following severe vomiting, diarrhoea, or diuretic therapy), hypermagnesaemia, hypocalcaemia (following massive transfusions), hypoproteinaemia, dehydration, acidosis, hypercapnia, and cachexia.

Therefore, severe electrolyte imbalances, changes in blood pH, or dehydration should be corrected if possible.

Sodium content

This medicinal product contains 3.3 mg of sodium per millilitre, equivalent to 0.17% of the WHO recommended maximum daily intake of sodium for an adult (2 g).

Each 5 ml vial contains 0.72 mmol (or 16.7 mg) of sodium.

Each 10 ml vial contains 1.44 mmol (or 33.4 mg) of sodium.

Use during pregnancy or breastfeeding.

Pregnancy

There are no clinical data on the effects of rocuronium bromide during pregnancy. Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonal/fetal development, labour, or postnatal development. Rocuronium bromide should be used with caution in pregnant women.

Caesarean section

In patients undergoing caesarean section, rocuronium bromide may be used as part of rapid sequence induction of anaesthesia provided that no intubation difficulties are anticipated and an adequate dose of anaesthetic has been administered, or following intubation performed with succinylcholine. The use of rocuronium bromide at a dose of 0.6 mg/kg has been shown to be safe in women undergoing caesarean section. Rocuronium bromide does not affect Apgar scores, fetal muscle tone, or cardiopulmonary adaptation of the newborn.

Umbilical cord blood analyses indicate that rocuronium bromide crosses the placental barrier only in very low concentrations, and no clinically significant adverse effects have been observed in the neonate.

Note 1: The dose of 1.0 mg/kg has been studied during rapid sequence induction of anaesthesia but not in patients undergoing caesarean section.

Therefore, the recommended dose for this patient group is 0.6 mg/kg only.

Note 2: Reversal of neuromuscular blockade induced by neuromuscular blockers may be delayed or inadequate in patients receiving magnesium salts during pregnancy, as magnesium salts potentiate neuromuscular blockade. Therefore, doses of rocuronium bromide in such patients should be reduced and adjusted according to muscle response (muscle contractions).

Breastfeeding

There is no information on whether rocuronium bromide passes into breast milk. Animal studies have shown the presence of a small amount of rocuronium bromide in milk. Rocuronium bromide may be used in breastfeeding women only if the treating physician determines that the benefits of treatment outweigh the risks. Breastfeeding is not recommended for five elimination half-lives of rocuronium after a single dose, i.e., approximately 6 hours.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Rocuronium Kabee, like other neuromuscular blocking agents, must be administered only by a physician experienced in the use of such agents, or under the supervision of such a specialist. The drug should be used only in a hospital setting. Rocuronium Kabee is administered intravenously either as a bolus injection or by continuous infusion. The dosage of Rocuronium Kabee, 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, sedation technique, anticipated duration of mechanical ventilation, potential interactions with concomitant medications, and the patient’s overall clinical condition. Appropriate neuromuscular monitoring techniques are recommended to assess the degree of neuromuscular blockade and recovery of neuromuscular transmission.

Inhalational anesthetics enhance the neuromuscular blocking effect of Rocuronium Kabee. This potentiation may become clinically significant when tissue concentrations of inhaled anesthetic agents reach levels sufficient for interaction during general anesthesia. Therefore, the dose of Rocuronium Kabee 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 lead to serious adverse effects, including death. Store Rocuronium Kabee with its intact cap and safety ring, and in such a way as to minimize the risk of selecting the wrong medication (see section "Special precautions").

The dosage recommendations below for adult patients may be used as a general guideline for endotracheal intubation, for providing muscle relaxation during surgical procedures of varying duration, and when used in intensive care units.

Surgical procedures

Endotracheal intubation

The standard dose of rocuronium bromide, after which adequate conditions for tracheal intubation are achieved within approximately 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 body weight, after which suitable conditions for tracheal intubation are established within approximately 60 seconds in nearly all patients. When using rocuronium bromide at a dose of 0.6 mg/kg for rapid sequence induction, endotracheal intubation should be performed 90 seconds after administration of Rocuronium Kabee. For information on the use of rocuronium bromide during rapid sequence induction in patients undergoing cesarean section, see section "Use during pregnancy or breastfeeding."

Maintenance doses

The recommended maintenance dose is 0.15 mg/kg body weight; however, during prolonged inhalational anesthesia, it 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 value, or when 2–3 responses appear during monitoring with train-of-four (TOF) stimulation.

Continuous infusion

When Rocuronium Kabee is administered by continuous infusion, it is recommended to first give a loading dose of 0.6 mg/kg body weight. When neuromuscular transmission begins to recover, initiate the infusion. The infusion rate should be adjusted to maintain skeletal muscle twitch response at 10% of the control value 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/hour; during inhalational anesthesia, the rate is 0.3–0.4 mg/kg/hour.

Continuous neuromuscular monitoring is recommended, as the required infusion rate may vary depending on the anesthetic technique and individual patient characteristics.

Dosage in elderly patients and patients with hepatic and/or biliary disease or renal impairment

The standard dose of Rocuronium Kabee for intubation in elderly patients and in patients with hepatic and/or biliary disease or renal impairment under routine anesthesia is 0.6 mg/kg body weight. A dose of 0.6 mg/kg is used for rapid sequence induction in patients in whom a prolonged duration of action is anticipated. 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").

Dosage in patients with increased body weight and obesity

In patients with increased body weight or obesity (body weight exceeding ideal body weight by 30% or more), doses should be adjusted based on ideal body weight.

Children

For neonates (0–27 days), infants (28 days – 3 months), young children (3–23 months), older children (2–11 years), and adolescents (12–17 years), the recommended intubation dose and maintenance dose during routine anesthesia are similar to those for adults. However, the duration of action of a single intubation dose will be longer in neonates and infants compared to older children. During continuous administration in pediatric patients, the infusion rate, except for children aged 2–11 years, is the same as in adults. Children aged 2–11 years may require higher infusion rates.

For children aged 2–11 years, initial infusion rates are recommended to be the same as for adults and should be adjusted during the procedure to maintain muscle twitch amplitude at 10% of the control value or to sustain 1–2 responses during TOF monitoring.

Experience with rocuronium bromide in rapid sequence induction in pediatric patients is limited; therefore, rocuronium bromide is not recommended to facilitate tracheal intubation during rapid sequence induction in pediatric patients.

Use in the intensive care unit

Endotracheal intubation

Use the same doses 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 twitch response has recovered to 10% of the control value or 1–2 responses are observed during TOF monitoring. Rocuronium bromide doses 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 gradual reduction in infusion rate over the next 6–12 hours according to individual patient response. Thereafter, individual dosage 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. The drug has been studied for administration periods of up to 7 days.

Special patient groups

The drug is not recommended for use in mechanical ventilation during intensive care in children and elderly patients due to lack of safety and efficacy data in these patient populations.

Children.

Administered to pediatric patients: full-term 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 case of overdose and prolonged neuromuscular blockade, supportive ventilation and sedative therapy must be provided. In this situation, two approaches are available to reverse neuromuscular blockade:

1. In adults, sugammadex can be used to reverse profound (deep) and intense (progressive) neuromuscular blockade. The dose of sugammadex depends on the degree of neuromuscular blockade.
2. After spontaneous recovery has begun, administer an acetylcholinesterase inhibitor (e.g., neostigmine, edrophonium, pyridostigmine) or sugammadex at appropriate doses. If administration of an acetylcholinesterase inhibitor fails to reverse the blockade, continue mechanical ventilation until spontaneous respiration returns. Repeated administration of acetylcholinesterase inhibitors may be hazardous. In animal studies, severe cardiovascular depression leading to cardiovascular collapse did not occur until a cumulative dose of 750 × ED90 (135 mg rocuronium bromide per kg body weight) was administered.

Adverse reactions.

Common adverse reactions include pain/reaction at the injection site, changes in vital signs, and prolonged duration of neuromuscular blockade. The most frequent serious adverse reactions reported following market release are anaphylactic and anaphylactoid reactions and associated symptoms. See also explanations provided after Table 2.

Table 2

a Frequency is calculated based on reports received after marketing authorization and data from general literature.

b Data obtained after marketing authorization cannot reflect precise frequency figures. For this reason, only two frequency categories are presented here instead of five.

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

d After prolonged use in intensive care units.

Anaphylactic reactions.

Serious anaphylactic reactions to neuromuscular blocking agents, including rocuronium bromide, have been reported, although very rarely. Anaphylactic/anaphylactoid reactions include bronchospasm, cardiovascular manifestations (such as hypotension, tachycardia, vascular collapse, and shock), and skin reactions (e.g., angioedema, urticaria). These reactions have been fatal in some cases. Given the potential for serious reactions, appropriate precautions should always be taken.

Local reactions at the injection site.

Pain upon injection has been reported during rapid sequence induction of anesthesia, particularly when the patient is not fully unconscious and especially when propofol is used for induction. In clinical trials, 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.

Elevated histamine levels.

Since neuromuscular blocking agents are known to cause histamine release, both locally at the injection site and systemically, itching and erythematous reactions at the injection site and/or generalized histamine-mediated (anaphylactoid) reactions may be expected upon administration of these drugs (see also "Anaphylactic reactions" above).

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

Prolonged neuromuscular blockade.

The most common adverse reaction associated with non-depolarizing neuromuscular blocking agents is prolonged duration of the drug's pharmacological effect beyond the required time period. Manifestations may range from skeletal muscle weakness to profound and prolonged muscle paralysis leading to respiratory insufficiency or apnea.

Myopathy.

Myopathy has been reported following the use of various neuromuscular blocking agents in combination with corticosteroids (see "Special precautions") in intensive care units.

Children and adolescents.

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

Reporting of suspected adverse reactions

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

Shelf life.

2 years.

Storage conditions.

No special storage conditions are required for this medicinal product.

Keep out of reach of children.

Storage after dilution. Chemical and physical stability of the diluted medicinal product has been demonstrated for 72 hours at a temperature not exceeding 30 °C.

From a microbiological standpoint, the diluted preparation should be used immediately. If not used immediately, the person responsible for administration must determine the storage period and conditions prior to use. The storage duration should not exceed 24 hours at 2–8 °C, provided the dilution was performed under strict aseptic conditions.

Incompatibilities.

Physical incompatibility of Rocuronium Kabivax has been demonstrated with solutions containing the following active substances: 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 Kabivax must not be mixed with other medicinal products except 0.9% sodium chloride solution, 5% glucose solution, 5% glucose in 0.9% sodium chloride solution, lactated Ringer's solution, and sterile water for injection.

If Rocuronium Kabivax 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 Rocuronium Kabivax solution and incompatible drugs, as well as when compatibility has not been established.

Packaging.

5 mL of solution in a glass vial; 5 or 10 vials per cardboard box.

10 mL of solution in a glass vial; 5 or 10 vials per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Fresenius Kabi Austria GmbH.

Manufacturer's location and address of its business premises.

Hafnerstrasse 36, 8055 Graz, Austria.