Noveron

Rocuronium bromide.

Sterile, clear, colorless to yellow orange, and odorless solution.
Each 1 mL Noveron contains 10 mg of Rocuronium Bromide.

Pharmacotherapeutic group: Neuromuscular Blocking Agents. ATC code: M03AC09.
Pharmacology: Pharmacodynamics: Mechanism of Action: Rocuronium bromide is a fast onset, intermediate acting non-depolarising neuromuscular blocking agent (blocking acetylcholine from binding to receptors on motor endplate inhibiting depolarization), possessing all of the characteristic pharmacological actions of this class of drugs (curariform). It acts by competing for nicotinic cholinoceptors at the motor end-plate.
Pharmacodynamic effects: The ED₉₀ (dose required to produce 90% depression of the twitch response of the thumb to stimulation of the ulnar nerve) during intravenous anaesthesia is approximately 0.3 mg/kg rocuronium bromide. The ED95 in infants is lower than in adults and children (0.25, 0.35 and 0.40 mg/kg respectively).
The clinical duration (the duration until spontaneous recovery to 25% of control twitch height) with 0.6 mg/kg rocuronium bromide is 30-40 minutes. The total duration (time until spontaneous recovery 90% of control twitch height) is 50 minutes. The mean time of spontaneous recovery of twitch response from 25 to 75% (recovery index) after a bolus dose of 0.6 mg/kg rocuronium bromide is 14 minutes. With lower dosages of 0.3-0.45 mg/kg rocuronium bromide (1-1½ x ED90), onset of action is slower and duration of action is shorter. With high dose of 2 mg/kg, clinical duration is 110 minutes.
Intubation during routine anesthesia: Within 60 seconds after intravenous administration of a dose of 0.6 mg/kg rocuronium bromide (2 x ED90 under intravenous anaesthesia), adequate intubation conditions can be achieved in nearly all patients. In 80% of these patients intubation conditions are rated excellent. Within 2 minutes general muscle paralysis adequate for any type of procedure is established. After administration of 0.45 mg/kg rocuronium bromide, acceptable intubation conditions are reached after 90 seconds.
Rapid sequence induction: During rapid sequence induction of anaesthesia under propofol or fentanyl/thiopental anaesthesia, adequate intubation conditions are achieved within 60 seconds in 93% and 96% of the patients respectively, after administration of a dose of 1.0 mg/kg rocuronium bromide. Of these, 70% are rated excellent. The clinical duration with this dose approaches 1 hour, at which time the neuromuscular block can be safely reversed. After administration of a dose of 0.6 mg/kg rocuronium bromide, adequate intubation conditions are achieved within 60 seconds in 81% and 75% of the patients during a rapid sequence induction technique with propofol or fentanyl/thiopental, respectively.
Paediatric population: Mean onset time in infants, toddlers and children at an intubation dose of 0.6 mg/kg is slightly shorter than adults. (See Table 1.)

Click on icon to see table/diagram/image

Geriatric patients and patients with hepatic and/or biliary tract disease and/or renal failure: The duration of action of maintenance doses of 0.15 mg/kg rocuronium bromide might be longer under enflurane and isoflurane anaesthesia in geriatric and in patients with hepatic and/or renal disease (approximately 20 minutes) than in patients without impairment of excretory organ function under intravenous anaesthesia (approximately 13 minutes). No accumulation of effect (progressive increase in duration of action) with repetitive maintenance dosing at the recommended level has been observed.
Intensive care unit: Following continuous infusion in the Intensive Care Unit, the time to recovery of the train of four ratio to 0.7 depends on the level of block at the end of the infusion. After a continuous infusion for 20 hours or more the median (range) time between return of T₂ to train of four stimulation and recovery of the train of four ratio to 0.7 approximates 1.5 (1-5) hours in patients without multiple organ failure and 4 (1-25) hours in patients with multiple organ failure.
Cardiovascular surgery: In patients scheduled for cardiovascular surgery the most common cardiovascular changes during the onset of maximum block following 0.6-0.9 mg/kg rocuronium bromide are a slight and clinically insignificant increase in heart rate up to 9% and an increase in mean arterial blood pressure up to 16% from the control values.
Reversal of muscle relaxation: Administration of acetylcholinesterase inhibitors, such as neostigmine, pyridostigmine or edrophonium, antagonises the action of rocuronium bromide.
Pharmacokinetics: Adult: Onset of action: Good intubation conditions within 1-2 minutes (depending on dose administered) maximum neuromuscular blockade within 4 minutes.
Duration: 30 minutes (with standard dose, increases with higher doses and inhalational anesthetic agents; patient age dependent).
Distribution: Volume of distribution is 0.22-0.26 L/kg.
Protein binding: Approximately 30%.
Metabolism: Minimally hepatic, converted to 17-desacetylrocuronium as main metabolite (5%-10% activity of parent drug).
Half-life elimination: Alpha elimination: 1-2 minutes.
Beta elimination Adults: 1.4-2.4 hours.
Excretion: Feces 31% and Urine 26%.
Paediatric population: The pharmacokinetics parameters of typical paediatrics within each age group are summarized as follows: See Table 2.

Click on icon to see table/diagram/image

Geriatric patients and patients with hepatic and/or biliary tract disease and/or renal failure: In controlled studies the plasma clearance in geriatric patients and in patients with renal dysfunction was reduced, in most studies however without reaching the level of statistical significance. In patients with hepatic disease, the mean elimination half-life is prolonged by 30 minutes and the mean plasma clearance is reduced by 1 mL/kg/min.
Intensive care unit: When administered as a continuous infusion to facilitate mechanical ventilation for 20 hours or more, the mean elimination half-life and the mean (apparent) volume of distribution at steady state are increased. A large between patient variability is found in controlled clinical studies, related to nature and extent of (multiple) organ failure and individual patient characteristics. In patients with multiple organ failure a mean (±SD) elimination half-life of 21.5 (±3.3) hours, a volume of distribution at steady state of 1.5 (±0.8) L/kg and a plasma clearance of 2.1 (±0.8) mL/kg/min were found.

Rocuronium bromide is indicated in adult and pediatric patients as an adjunct to general anaesthesia to facilitate tracheal intubation during routine sequence induction and to provide skeletal muscle relaxation during surgery. In adults is also indicated to facilitate tracheal intubation during rapid sequence induction and as an adjunct in the ICU to facilitate intubation and mechanical ventilation.

Recommended dose: Doses of neuromuscular blockers need to be carefully titrated for individual patients according to response, and may vary with the procedure, the other drug administered, and the state of the patient. Monitoring of the degree of block is recommended in order to reduce the risk.
Neuromuscular blockade (intermediate duration) during surgery and intubation initially by intravenous injection: Adult: Initially 0.6 mg/kg; (by intravenous injection) maintenance 0.15 mg/kg, alternatively (by intravenous infusion) maintenance 0.3-0.6 mg/kg/hr, adjusted according to response.
**Higher dose of 1 mg/kg are recommended for intubation during rapid sequence induction for anesthesia.
Elderly: Initially 0.6 mg/kg; (by intravenous injection) maintenance 0.075-0.1 mg/kg, alternatively (by intravenous infusion) maintenance up to 0.4 mg/kg/hr, adjusted according to response.
Neonate and child: Same as adult dose.
Neuromuscular blockade (intermediate duration) during intensive care Initially by intravenous injection: Adult: Initially 0.6 mg/kg, initial dose is optional; (by intravenous infusion) maintenance 0.3-0.6 mg/kg/hr for first hour, then (by intravenous infusion), adjusted according to response.
Administration in hepatic and renal impairment: The recommended initial dose is 0.6 mg/kg by intravenous injection and a reduced maintenance dose of 0.075-0.1 mg/kg by intravenous injection, or 0.3-0.4 mg/kg/hr by continuous infusion.
Doses at extreme of bodyweight: To avoid excessive dosage in obese patients, dose should be calculated on the basis of ideal bodyweight.
Rocuronium bromide may exhibit a prolonged duration and a prolonged spontaneous recovery in obese patients, when the administered doses are calculated on actual bodyweight.
Mode of administration: Rocuronium bromide solution for injection is administered intravenously (i.v.) either as a bolus injection or as a continuous infusion.
Noveron could be diluted in infusion solutions: 0.9% sodium chloride, 5% dextrose, 5% dextrose in 0.9% sodium chloride, ringer's lactate solution and water for injection use within 72 hours of preparation (see Storage condition under Storage).

In the event of overdose and prolonged neuromuscular block, the patient should continue to receive ventilatory support and sedation. Upon start of spontaneous recovery an acetylcholinesterase inhibitor (e.g. neostigmine, edrophonium, pyridostigmine) should be administered in adequate doses. When administration of an acetylcholinesterase inhibiting agent fails to reverse the neuromuscular effects of rocuronium bromide, artificial ventilation must be continued until spontaneous breathing is restored. Repeated dosages of an acetylcholinesterase inhibitor can be dangerous.

Rocuronium bromide is contraindicated in patients with hypersensitivity to rocuronium bromide or to the bromide ion or to any of the excipients; Sodium acetate, Sodium chloride, Acetic acid glacial and water.

Since Rocuronium bromide solution for injection causes paralysis of the respiratory muscles, ventilatory support is mandatory for patients treated with this active substance until adequate spontaneous respiration is restored. As with all neuromuscular blocking agents, it is important to anticipate intubation difficulties, particularly when used as part of a rapid sequence induction technique.
As with other neuromuscular blocking agents, residual neuromuscular blockade has been reported for rocuronium bromide solution for injection. In order to prevent complications resulting from residual neuromuscular blockade, it is recommended to extubate only after the patient has recovered sufficiently from neuromuscular block. Geriatric patients (65 years or older) may be at increased risk for residual neuromuscular block. Other factors which could cause residual neuromuscular blockade after extubation in the post-operative phase (such as drug interactions or patient condition) should also be considered. If not used as part of standard clinical practice, the use of a reversal agent (such as sugammadex or acetylcholinesterase inhibitors) should be considered, especially in those cases where residual neuromuscular blockade is more likely to occur.
High rates of cross-sensitivity between neuromuscular blocking agents have been reported. Therefore, where possible, before administering Rocuronium bromide solution for injection, hypersensitivity to other neuromuscular blocking gents should be excluded. Rocuronium bromide solution for injection should only be used when absolutely essential in susceptible patients. Patients who experience a hypersensitivity reaction under general anaesthesia should be tested subsequently for hypersensitivity to other neuromuscular blockers.
Rocuronium may increase the heart rate.
In general, following long term use of neuromuscular blocking agents in the ICU, prolonged paralysis and/or skeletal muscle weakness has been noted. In order to help preclude possible prolongation of neuromuscular block and/or overdosage it is strongly recommended that neuromuscular transmission is monitored throughout the use of neuromuscular blocking agents. In addition, patients should receive adequate analgesia and sedation. Furthermore, neuromuscular blocking agents should be titrated to effect in the individual patients by or under supervision of experienced clinicians who are familiar with their actions and with appropriate neuromuscular monitoring techniques.
Myopathy after long term administration of other non-depolarising neuromuscular blocking agents in the ICU in combination with corticosteroid therapy has been reported regularly. Therefore, for patients receiving both neuromuscular blocking agent and corticosteroids, the period of use of the neuromuscular blocking agent should be limited as much as possible.
If suxamethonium is used for intubation, the administration of Rocuronium bromide solution for injection should be delayed until the patient has clinically recovered from the neuromuscular block induced by suxamethonium.
Because rocuronium bromide is always used with other drugs and because of the risk of malignant hyperthermia during anesthesia, even in the absence of known triggering factors, physicians should be aware of the early symptoms, confirmatory diagnosis and treatment of malignant hyperthermia prior to the start of anesthesia. Animal studies have shown that rocuronium bromide is not a triggering factor for malignant hyperthermia.
The following conditions may influence the pharmacokinetics and/or pharmacodynamics of rocuronium bromide: Hepatic and/or biliary tract disease and renal failure: Rocuronium bromide is excreted in urine and bile. Therefore, it should be used with caution in patients with clinically significant hepatic and/or biliary diseases and/or renal failure. In these patient groups prolongation of action has been observed with doses of 0.6 mg/kg rocuronium bromide.
Prolonged circulation time: Conditions associated with prolonged circulation time such as cardiovascular diseases, old age and an oedematous state resulting in an increased volume of distribution, may contribute to a slower onset of action. The duration of action may also be prolonged due to a reduced plasma clearance.
Neuromuscular disease: Like other neuromuscular blocking agents, rocuronium bromide should be used with extreme caution in patients with a neuromuscular disease or after poliomyelitis since the response to neuromuscular blocking agents may be considerably altered in these cases. The magnitude and direction of this alteration may vary widely. In patients with myasthenia gravis or with the myasthenic (Eaton-Lambert) syndrome, small doses of rocuronium bromide may have profound effects and rocuronium bromide solution for injection or infusion should be titrated to the response.
Hypothermia: In surgery under hypothermic conditions, the neuromuscular blocking effect of rocuronium bromide injection is increased and the duration prolonged.
Burns: Patients with burns are known to develop resistance to non-depolarising neuromuscular blocking agents. It is recommended that the dose is titrated to response.
Conditions which may increase the effects of Rocuronium bromide: Hypokalemia (e.g. after severe vomiting, diarrhoea or diuretic therapy), hypermagnesaemia, hypocalcaemia (after massive transfusions), hypoproteinaemia, dehydration, acidosis, hypercapnia and cachexia.
Severe electrolyte disturbances, altered blood pH or dehydration should therefore be corrected when possible.

Pregnancy: There are very limited data on the use of rocuronium bromide during human pregnancy. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Caution should be exercised when prescribing Rocuronium bromide to pregnant women.
Caesarean section: In patients undergoing Caesarean section, rocuronium bromide can be used as part of a rapid sequence induction technique, provided no intubation difficulties are anticipated and a sufficient dose of anaesthetic agent is administered or following suxamethonium facilitated intubation. However, rocuronium bromide administered in doses of 0.6 mg/kg may not produce adequate conditions for intubation until 90 seconds after administration. This dose has been shown to be safe in patients undergoing Caesarean section.
Rocuronium bromide does not affect Apgar score, foetal muscle tone or cardiorespiratory adaptation. From umbilical cord blood sampling it is apparent that only limited placental transfer of rocuronium bromide occurs which does not lead to the observation of clinical adverse effects in the newborn.
Note 1: Doses of 1.0 mg/kg have been investigated during rapid sequence induction of anaesthesia, but not in Caesarean section patients. Therefore, only a dose of 0.6 mg/kg is recommended in this patient group.
Note 2: Reversal of neuromuscular block induced by neuromuscular blocking agents may be inhibited or unsatisfactory in patients receiving magnesium salts for toxemia of pregnancy because magnesium salts enhance neuromuscular blockade. Therefore, in these patients the dosage of Noveron should be reduced and be titrated to twitch response.
Lactation: It is unknown whether rocuronium bromide is excreted in human breast milk. Animal studies have shown insignificant levels in breast milk. Insignificant levels of rocuronium bromide were found in the milk of lactating rats.
There are no human data on the use of rocuronium bromide solution for injection during lactation. Rocuronium bromide solution for injection should be given to lactating women only when the attending physician decides that the benefits outweigh the risks.

The most commonly occurring adverse drug reactions and the most frequently reported serious adverse drug reactions during post-marketing surveillance are Anaphylaxis, Prolonged neuromuscular block, Myopathy, Local injection site reactions and Pain near the site of injection, Tachycardia, The drug is not effective enough, The drug works for longer than expected, Lowering of blood pressure.

Avoid concomitant use of Rocuronium with any of the following: Quinine.
Medicines which increase the effect/toxicity of Noveron: Aminoglycosides, Certain medicines for heart disease or high blood pressure (loop diuretics, calcium channel blockers, beta-blockers and quinidine), Capreomycin, Colistimethate, Inhalation Anesthetic, Ketorolac (nasal and systemic), Lincosamide antibiotics, Lithium, Medicines for manic depressive illness (bipolar disorder), Magnesium salts, Polymyxin B, Procainamide, Quinidine, Quinine, Spironolactone, Tetracycline derivatives, Vancomycin.
Medicines which decrease the effect of Noveron: Acetylcholinesterase inhibitors, Loop diuretics.
Medicines which increased effect by Noveron: Cardiac Glycosides, Corticosteroids (Systemic), Onabotulinum-Toxin A, RimabotulinumtoxinB.

Storage condition: Store at 2°C-8°C, do not freeze, protected from light. Preservative free.
Noveron may also be stored outside the refrigerator at a temperature of up to 30°C for a maximum of 12 weeks, after which it should be discarded. The product should not be placed back into the refrigerator, once it has been kept outside. Diluted Noveron remains effective for 72 hours at 30˚C and 2-8˚C. Unused solutions should be discarded.

Neuromuscular Blocking Agents

M03AC09 - rocuronium bromide ; Belongs to the class of other quaternary ammonium-containing agents used as peripherally-acting muscle relaxants.

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