In the event of overdosage and prolonged neuromuscular block, the patient should continue to receive ventilatory support and sedation. There are two options for the reversal of neuromuscular block: (1) In adults, sugammadex can be used for reversal of intense (profound) and deep block. The dose of sugammadex to be administered depends on the level of neuromuscular block. (2) An acetylcholinesterase inhibitor (e.g. neostigmine, edrophonium, pyridostigmine) or sugammadex can be used once spontaneous recovery starts and should be administered in adequate doses. When administration of an acetylcholinesterase inhibiting agent fails to reverse the neuromuscular effects of Fada Rocuronio, ventilation must be continued until spontaneous breathing is restored. Repeated dosage of an acetylcholinesterase inhibitor can be dangerous.
In animal studies, severe depression of cardiovascular function, ultimately leading to cardiac collapse did not occur until a cumulative dose of 750 x ED90 (135 mg/kg rocuronium bromide) was administered.
In the event of overdosage and prolonged neuromuscular block, the patient should continue to receive ventilatory support and sedation. There are two options for the reversal of neuromuscular block: (1) In adults, sugammadex can be used for reversal of intense (profound) and deep block. The dose of sugammadex to be administered depends on the level of neuromuscular block. (2) An acetylcholinesterase inhibitor (e.g. neostigmine, edrophonium, pyridostigmine) or sugammadex can be used once spontaneous recovery starts and should be administered in adequate doses. When administration of an acetylcholinesterase inhibiting agent fails to reverse the neuromuscular effects of Fada Rocuronio, ventilation must be continued until spontaneous breathing is restored. Repeated dosage of an acetylcholinesterase inhibitor can be dangerous.
In animal studies, severe depression of cardiovascular function, ultimately leading to cardiac collapse did not occur until a cumulative dose of 750 x ED90 (135 mg/kg Fada Rocuronio) was administered.
Hypersensitivity to rocuronium or to the bromide ion or to any of the excipients.
Physical incompatibility has been documented for Fada Rocuronio when added to solutions containing the following drugs: amphotericin, amoxicillin, azathioprine, cefazolin, cloxacillin, dexamethasone, diazepam, enoximone, erythromycin, famotidine, furosemide, hydrocortisone sodium succinate, insulin, intralipid, methohexital, methylprednisolone, prednisolone sodium succinate, thiopental, trimethoprim and vancomycin.
If Fada Rocuronio is administered via the same infusion line that is also used for other drugs, it is important that this infusion line is adequately flushed (e.g. with 0.9% NaCl) between administration of Fada Rocuronio and drugs for which incompatibility with Fada Rocuronio has been demonstrated or for which compatibility with Fada Rocuronio has not been established.
Physical incompatibility has been documented for Fada Rocuronio when added to 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.
If Fada Rocuronio is administered via the same infusion line that is also used for other medicinal products, it is important that this infusion line is adequately flushed (e.g. with sodium chloride 9 mg/ml (0.9% w/v) solution) between administration of Rocuronium bromide and medicinal products for which incompatibility with Fada Rocuronio has been demonstrated or for which compatibility with Fada Rocuronio has not been established.
Summary of the safety profile
The most commonly occurring adverse drug reactions include injection site pain/reaction, changes in vital signs and prolonged neuromuscular block. The most frequently reported serious adverse drug reactions during post-marketing surveillance is 'anaphylactic and anaphylactoid reactions' and associated symptoms. See also the explanations below the table.
Tabulated list of adverse reactions
| MedDRA SOC | Preferred term1 | |
| Uncommon/rare2 (<1/100, >1/10 000) | Very rare (<1/10 000) | |
| Immune system disorders | Hypersensitivity | |
| Anaphylactic reaction | ||
| Anaphylactoid reaction | ||
| Anaphylactic shock | ||
| Anaphylactoid shock | ||
| Nervous system disorders | Flaccid paralysis | |
| Cardiac disorders | Tachycardia | |
| Vascular disorders | Hypotension | Circulatory collapse and shock |
| Flushing | ||
| Respiratory, thoracic and mediastinal disorders | Bronchospasm | |
| Skin and subcutaneous tissue disorders | Angioneurotic oedema | |
| Urticaria | ||
| Rash | ||
| Erythematous rash | ||
| Musculoskeletal and connective tissue disorders | Muscular weakness3 | |
| Steroid myopathy3 | ||
| General disorders and administration site conditions | Drug ineffective | Face oedema |
| Drug effect/ therapeutic response decreased | ||
| Drug effect/ therapeutic response increased | ||
| Injection site pain | ||
| Injection site reaction | ||
| Injury, poisoning and procedural complications | Prolonged neuromuscular block | Airway complication of anaesthesia |
| Delayed recovery from anaesthesia | ||
| MedDRA version 8.1 | ||
Anaphylaxis
Although very rare, severe anaphylactic reactions to neuromuscular blocking agents, including Fada Rocuronio, have been reported. Anaphylactic/anaphylactoid reactions are: bronchospasm, cardiovascular changes (e.g. hypotension, tachycardia, circulatory collapse - shock), and cutaneous changes (e.g. angioedema, urticaria). These reactions have, in some cases, been fatal. Due to the possible severity of these reactions, one should always assume they may occur and take the necessary precautions.
Since neuromuscular blocking agents are known to be capable of inducing histamine release both locally at the site of injection and systemically, the possible occurrence of itching and erythematous reaction at the site of injection and/or generalised histaminoid (anaphylactoid) reactions (see also under anaphylactic reactions above) should always be taken into consideration when administering these drugs.
In clinical studies only a slight increase in mean plasma histamine levels has been observed following rapid bolus administration of 0.3-0.9 mg/kg rocuronium bromide.
Prolonged neuromuscular block
The most frequent adverse reaction to nondepolarising blocking agents as a class consists of an extension of the drug's pharmacological action beyond the time period needed. This may vary from skeletal muscle weakness to profound and prolonged skeletal muscle paralysis resulting in respiratory insufficiency or apnea.
Myopathy
Myopathy has been reported after the use of various neuromuscular blocking agents in the ICU in combination with corticosteroids.
Local injection site reactions
During rapid sequence induction of anaesthesia, pain on injection has been reported, especially when the patient has not yet completely lost consciousness and particularly when propofol is used as the induction agent. In clinical studies, pain on injection has been noted in 16% of the patients who underwent rapid sequence induction of anaesthesia with propofol and in less than 0.5% of the patients who underwent rapid sequence induction of anaesthesia with fentanyl and thiopental.
Paediatric population
A meta-analysis of 11 clinical studies in paediatric patients (n=704) with rocuronium bromide (up to 1 mg/kg) showed that tachycardia was identified as adverse drug reaction with a frequency of 1.4%.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
1 Frequencies are estimates derived from post-marketing surveillance reports and data from the general literature.
2 Post-marketing surveillance data cannot give precise incidence figures. For that reason, the reporting frequency was divided over two rather than five categories.
3 after long-term use in the ICU
The most commonly occurring adverse drug reactions include injection site pain/reaction, changes in vital signs and prolonged neuromuscular block. The most frequently reported serious adverse drug reactions during post-marketing surveillance is 'anaphylactic and anaphylactoid reactions' and associated symptoms. See also the explanations below the table.
| MedDRA SOC | Preferred term1 | ||
| Uncommon/rare2 (<1/100, >10 000) | Very rare (<1/10 000) | Frequency unknown | |
| Immune system disorders | Hypersensitivity Anaphylactic reaction Anaphylactoid reaction Anaphylactic shock Anaphylactoid shock | ||
| Nervous system disorders | Flaccid paralysis | ||
| Cardiac disorders | Tachycardia | ||
| Vascular disorders | Hypotension | Circulatory collapse and shock Flushing | |
| Respiratory, thoracic and mediastinal disorders | Bronchospasm | Apnoea Respiratory insufficiency | |
| Skin and subcutaneous tissue disorders | Angioneurotic edema Urticaria Rash Erythematous rash Itching Exanthema | ||
| Musculoskeletal and connective tissue disorders | Muscular weakness3 Steroid myopathy | ||
| General disorders and administration site conditions | Drug ineffective Drug effect/ therapeutic response decreased Drug effect/ therapeutic response increased Injection site pain Injection site reaction | Face oedema | |
| Injury, poisoning and procedural complications | Prolonged neuromuscular block Delayed recovery from anesthesia | ||
| MedDRA version 8.1 |
1 Frequencies are estimates derived from post-marketing surveillance reports and data from the general literature.
2 Post-marketing surveillance data cannot give precise incidence figures. For that reason, the reporting frequency was divided over two rather than five categories.
3 after long-term use in the ICU
Anaphylaxis
Although very rare, severe anaphylactic reactions to neuromuscular blocking agents, including Fada Rocuronio, have been reported. Anaphylactic/anaphylactoid reactions are: bronchospasm, cardiovascular changes (e.g. hypotension, tachycardia, circulatory collapse - shock), and cutaneous changes (e.g. angioedema, urticaria). These reactions have, in some cases, been fatal. Due to the possible severity of these reactions, one should always assume they may occur and take the necessary precautions.
Since neuromuscular blocking agents are known to be capable of inducing histamine release both locally at the site of injection and systemically, the possible occurrence of itching and erythematous reaction at the site of injection and/or generalized histaminoid (anaphylactoid) reactions (see also under anaphylactic reactions above) should always be taken into consideration when administering these drugs.
In clinical studies only a slight increase in mean plasma histamine levels has been observed following rapid bolus administration of 0.3-0.9 mg/kg Fada Rocuronio.
Prolonged neuromuscular block
The most frequent adverse reaction to nondepolarising blocking agents as a class consists of an extension of the drug's pharmacological action beyond the time period needed. This may vary from skeletal muscle weakness to profound and prolonged skeletal muscle paralysis resulting in respiratory insufficiency or apnoea.
Myopathy
Myopathy has been reported after the use of various neuromuscular blocking agents in the ICU in combination with corticosteroids.
Local injection site reactions
During rapid sequence induction of anaesthesia, pain on injection has been reported, especially when the patient has not yet completely lost consciousness and particularly when propofol is used as the induction agent. In clinical studies, pain on injection has been noted in 16% of the patients who underwent rapid sequence induction of anaesthesia with propofol and in less than 0.5% of the patients who underwent rapid sequence induction of anaesthesia with fentanyl and thiopental.
Paediatric patients
A meta-analysis of 11 clinical studies in paediatric patients (n=704) with Fada Rocuronio (up to 1 mg/kg) showed that tachycardia was identified as adverse drug reaction with a frequency of 1.4%.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
There is no proper animal model to mimic the usually extremely complex clinical situation of the ICU patient. Therefore the safety of Fada Rocuronio when used to facilitate mechanical ventilation in the Intensive Care Unit is mainly based on results obtained in clinical studies.
No chronic toxicity studies of Fada Rocuronio have been conducted.
In vivo and in vitro mutagenicity studies have revealed no mutagenic potential of Fada Rocuronio.
No carcinogenicity studies of Fada Rocuronio have been conducted.
Studies using sub-pharmacological intravenous doses of Fada Rocuronio in rats during organogenesis have produced no evidence of embryolethal effects, teratological alterations or foetal growth inhibition. Fada Rocuronio crosses the placental barrier in rats to a limited extent, and is recovered in milk in small amounts.
Fada Rocuronio is indicated in adult and paediatric patients (from term neonates to adolescents [0 to <18 years]) as an adjunct to general anaesthesia to facilitate tracheal intubation during routine sequence induction and to provide skeletal muscle relaxation during surgery. In adults Fada Rocuronio is also indicated to facilitate tracheal intubation during rapid sequence induction and as an adjunct in the intensive care unit (ICU) to facilitate intubation and mechanical ventilation.
Fada Rocuronio is indicated as an adjunct to general anaesthesia to facilitate tracheal intubation during routine and rapid sequence induction, and to provide skeletal muscle relaxation during surgery.
It is also indicated as an adjunct in the intensive care unit (ICU) (e.g. to facilitate intubation), for short term use.
1.Pharmacotherapeutic group: Muscle relaxants, peripherally acting agents, ATC code: M03AC09.
Mechanism of Action
Fada Rocuronio (rocuronium bromide) is a fast onset, intermediate acting non-depolarising neuromuscular blocking agent, 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. This action is antagonised by acetylcholinesterase inhibitors such as neostigmine, edrophonium and pyridostigmine.
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 to 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 doses of 2 mg/kg, clinical duration is 110 minutes.
Intubation during routine anaesthesia
Within 60 seconds following 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 of which in 80% intubation conditions are rated excellent. General muscle paralysis adequate for any type of procedure is established within 2 minutes. After administration of 0.45 mg/kg rocuronium bromide, acceptable intubation conditions are present 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, following 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. Following 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 in adults. Comparison within paediatric age groups showed that the mean onset time in neonates and adolescents (1.0 min.) is slightly longer than in infants, toddlers and children (0.4, 0.6 and 0.8 min., respectively). The duration of relaxation and the time to recovery tend to be shorter in children compared to infants and adults. Comparing within paediatric age groups demonstrated that mean time to reappearance of T3 was prolonged in neonates and infants (56.7 and 60.7 min., respectively) when compared to toddlers, children and adolescents (45.4, 37.6 and 42.9 min., respectively).
Mean (SD) time to onset and clinical duration following 0.6 mg/kg rocuronium initial intubating dose* during sevoflurane/nitrous oxide and isoflurane/nitrous oxide (maintenance) anaesthesia (Paediatric patients) PP group
| Time to maximum block ** (min) | Time to reappearance 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)
|
| Toddler (3 months-23 months) n=28 | 0.59 (0.27)
| 45.46 (12.94) n=27 |
| 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 administered within 5 seconds.
** Calculated from the end of administration of the rocuronium intubating dose
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 somewhat longer under enflurane and isoflurane anaesthesia in geriatric patients and in patients with hepatic and/or renal disease (approximately 20 minutes) than in patients without impairment of excretory organ functions 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, (neostigmine, pyridostigmine or edrophonium) at reappearance of T2 or at the first signs of clinical recovery, antagonises the action of Fada Rocuronio.
Pharmacotherapeutic group: Muscle relaxants, peripherally acting agents, other quaternary ammonium compounds ATC code: M03AC09
Mechanism of Action
Fada Rocuronio is a fast onset, intermediate acting non-depolarising neuromuscular blocking agent, possessing all of the characteristic pharmacological actions of this class of medicinal products (curariform agents). It acts by competing for nicotinic cholinoceptors at the motor end-plate. This action is antagonised by acetylcholinesterase inhibitors such as neostigmine, edrophonium and pyridostigmine.
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 Fada Rocuronio. 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 Fada Rocuronio is 30-40 minutes. The total duration (time until spontaneous recovery to 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 Fada Rocuronio is 14 minutes. With lower dosages of 0.3-0.45 mg/kg Fada Rocuronio (1 -1½ x ED90), onset of action is slower and duration of action is shorter (13 - 26 min). With high doses of 2 mg/kg, clinical duration is 110 minutes.
Intubation during routine anaesthesia
Within 60 seconds following intravenous administration of a dose of 0.6 mg/kg Fada Rocuronio (2 x ED90 under intravenous anaesthesia), adequate intubation conditions can be achieved in nearly all patients of which in 80% intubation conditions are rated excellent. General muscle paralysis adequate for any type of procedure is established within 2 minutes. After administration of 0.45 mg/kg Fada Rocuronio, acceptable intubation conditions are present 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, following a dose of 1.0 mg/kg Fada Rocuronio. 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. Following a dose of 0.6 mg/kg Fada Rocuronio, 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.
Doses higher than 0.1 mg/kg Fada Rocuronio do not improve intubation conditions in a perceptible way, however the duration of action is prolonged. Doses higher than 4 x ED90 were not studied.
Special populations
Mean onset time in infants and children at an intubation dose of 0.6 mg/kg is slightly shorter than in adults. The duration of relaxation and the time to recovery tend to be shorter in children compared to infants and adults.
The duration of action of maintenance doses of 0.15 mg/kg Fada Rocuronio might be somewhat longer under enflurane and isoflurane anaesthesia in geriatric patients and in patients with hepatic and/or renal disease (approximately 20 minutes) than in patients without impairment of excretory organ functions 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
The use of rocuronium in the Intensive Care Unit was studied in two open-label trials. A total of 95 adult patients were treated with an initial dose of 0.6 mg Fada Rocuronio per kg body weight, followed by a continuous infusion of 0.2 - 0.5 mg/kg/h during the first hour of administration as soon as twitch height recovers to 10 % or upon reappearance of 1 to 2 twitches to train-of-four (TOF) stimulation. The dosages were individually titrated. In the following hours, doses were decreased under regular monitoring of the TOF stimulation. Administration for a time period of up to 7 days has been investigated.
Adequate neuromuscular blockade was achieved, but a high variability in hourly infusion rates between patients and a prolonged recovery from neuromuscular blockade was observed.
The time to recover of the train of four ratio to 0.7 is not significantly correlated to the total duration of rocuronium 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 varied between 0,8 and 12,5 hours in patients without multiple organ failure and 1.2 - 25.5 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 Fada Rocuronio 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, (neostigmine, pyridostigmine or edrophonium) at reappearance of T2 or at the first signs of clinical recovery, antagonises the action of Fada Rocuronio.
After intravenous administration of a single bolus dose of rocuronium bromide the plasma concentration time course runs in three exponential phases. In normal adults, the mean (95% CI) elimination half-life is 73 (66-80) minutes, the (apparent) volume of distribution at steady state conditions is 203 (193-214) ml/kg and plasma clearance is 3.7 (3.5-3.9) ml/kg/min.
Rocuronium is excreted in urine and bile. Excretion in urine approaches 40% within 12-24 hours. After injection of a radiolabeled dose of rocuronium bromide, excretion of the radiolabel is on average 47% in urine and 43% in faeces after 9 days. Approximately 50% is recovered as the parent compound. No metabolites are detected in plasma.
Paediatric population
Pharmacokinetics of rocuronium bromide in paediatric patients (n=146) with ages ranging from 0 to 17 years were evaluated using a population analysis of the pooled pharmacokinetic datasets from two clinical trials under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia. All pharmacokinetic parameters were found to be linearly proportional to body weight illustrated by a similar clearance (l.hr-1.kg-1). The volume of distribution (l.kg-1) and elimination half-life (h) decrease with age (years). The pharmacokinetic parameters of typical paediatrics within each age group are summarized below:
Estimated PK parameters (Mean [SD]) of rocuronium bromide in typical paediatric patients during sevoflurane and nitrous oxide (induction) and isoflurane/nitrous oxide (maintenance anaesthesia)
| PK Parameters | Patient age range | ||||
| Term newborn infants (0-27 days) | Infants (28 days to 2 months) | Toddlers (3-23 months) | Children (2-11 years) | Adolescents (12-17 years) | |
| CL (L/kg/hr) |
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) |
| t ½ β (hr) |
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 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 (apparent) 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.
After intravenous administration of a single bolus dose of Fada Rocuronio the plasma concentration time course runs in three exponential phases. In normal adults, the mean (95%CI) elimination half-life is 73 (66-80) minutes, the (apparent) volume of distribution at steady state conditions is 203 (193-214) ml/kg and plasma clearance is 3.7 (3.5-3.9) ml/kg/min.
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 infants (28 days to 23 months), the apparent volume of distribution at steady state conditions is increased compared to adults and children (2-11 years). In older children (3-8 years), a trend is seen towards higher clearance and shorter elimination half-life (approximately 20 minutes) compared to adults, younger children and infants.
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.).
Fada Rocuronio is excreted in urine and bile. Excretion in urine approaches 40% within 12-24 hours.
After injection of a radiolabeled dose of Fada Rocuronio, excretion of the radiolabel is on average 47% in urine and 43% in faeces after 9 days. Approximately 50% is recovered as the parent compound. No metabolites are detected in plasma.
Since Fada Rocuronio causes paralysis of the respiratory muscles, ventilatory support is mandatory for patients treated with this drug 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 Fada Rocuronio. 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 Fada Rocuronio, hypersensitivity to other neuromuscular blocking agents should be excluded. Fada Rocuronio 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 agents 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 Fada Rocuronio 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. Rare cases of malignant hyperthermia with Fada Rocuronio have been observed thru post-marketing surveillance; however, the causal association has not been proven.
The following conditions may influence the pharmacokinetics and/or pharmacodynamics of Fada Rocuronio:
Hepatic and/or biliary tract disease and renal failure
Because rocuronium is excreted in urine and bile, 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 disease, old age and 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, Fada Rocuronio 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 Fada Rocuronio may have profound effects and Fada Rocuronio should be titrated to the response.
Hypothermia
In surgery under hypothermic conditions, the neuromuscular blocking effect of Fada Rocuronio is increased and the duration prolonged.
Obesity
Like other neuromuscular blocking agents, Fada Rocuronio may exhibit a prolonged duration and a prolonged spontaneous recovery in obese patients when the administered doses are calculated on actual body weight.
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 Fada Rocuronio
Hypokalaemia (e.g. after severe vomiting, diarrhoea and diuretic therapy), hypermagnesaemia, hypocalcaemia (after massive transfusions), hypoproteinaemia, dehydration, acidosis, hypercapnia, cachexia.
Severe electrolyte disturbances, altered blood pH or dehydration should therefore be corrected when possible.
Fada Rocuronio should be administered only by an experienced staff familiar with the use of neuromuscular blocking agents. Adequate facilities and staff for endotracheal intubation and artificial ventilation have to be available for immediate use.
Since Fada Rocuronio causes paralysis of the respiratory muscles, ventilatory support is mandatory for patients treated with this medicinal product 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 Fada Rocuronio. 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. 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 reversal agent (such as sugammadex or acetylcholinesterase inhibitors) should be considered, especially in those cases where residual neuromuscular blockade is more likely to occur.
Anaphylactic reactions can occur following the administration of neuromuscular blocking agents. Precautions for treating such reactions should always be taken. Particularly in the case of previous anaphylactic reactions to neuromuscular blocking agents, special precautions should be taken since allergic cross-reactivity to neuromuscular blocking agents has been reported.
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 agents 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 Fada Rocuronio should be delayed until the patient has clinically recovered from the neuromuscular block induced by suxamethonium.
The following conditions may influence the pharmacokinetics and/or pharmacodynamics of Fada Rocuronio:
Hepatic and/or biliary tract disease and renal failure
Because rocuronium is excreted in urine and bile, 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 Fada Rocuronio.
Prolonged circulation time
Conditions associated with prolonged circulation time such as cardiovascular disease, old age and 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, Fada Rocuronio 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 Fada Rocuronio may have profound effects and Fada Rocuronio should be titrated to the response.
Hypothermia
In surgery under hypothermic conditions, the neuromuscular blocking effect of Fada Rocuronio is increased and the duration prolonged.
Obesity
Like other neuromuscular blocking agents, Fada Rocuronio may exhibit a prolonged duration and a prolonged spontaneous recovery in obese patients when the administered doses are calculated on actual body weight.
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 Fada Rocuronio
Hypokalaemia (e.g. after severe vomiting, diarrhoea and diuretic therapy), hypermagnesaemia, hypocalcaemia (after massive transfusions), hypoproteinaemia, dehydration, acidosis, hypercapnia, cachexia.
Severe electrolyte disturbances, altered blood pH or dehydration should therefore be corrected when possible.
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially “sodium-freeâ€.
Since Fada Rocuronio is used as an adjunct to general anaesthesia, the usual precautionary measures after a general anaesthesia should be taken for ambulatory patients.
Fada Rocuronio has a major influence on the ability to drive and use machines. Since Fada Rocuronio is used as an adjunct to general anaesthesia, the usual precautionary measures after a general anaesthesia should be taken for ambulatory patients. In the first 24 hours after complete resolution of neuromuscular block, the patient should not operate any machinery, or should participate in road traffic only with an escort.
Posology
Like other neuromuscular blocking agents, Fada Rocuronio should only be administered by, or under supervision of, experienced clinicians who are familiar with the action and use of these drugs.
As with other neuromuscular blocking agents, the dosage of Fada Rocuronio should be individualised in each patient. The method of anaesthesia and the expected duration of surgery, the method of sedation and the expected duration of mechanical ventilation, the possible interaction with other drugs that are administered concomitantly, and the condition of the patient should be taken into account when determining the dose.
The use of an appropriate neuromuscular monitoring technique is recommended for the evaluation of neuromuscular block and recovery.
Inhalational anaesthetics do potentiate the neuromuscular blocking effects of Fada Rocuronio. This potentiation however, becomes clinically relevant in the course of anaesthesia, when the volatile agents have reached the tissue concentrations required for this interaction. Consequently, adjustments with Fada Rocuronio should be made by administering smaller maintenance doses at less frequent intervals or by using lower infusion rates of Fada Rocuronio during long lasting procedures (longer than 1 hour) under inhalational anaesthesia.
In adult patients the following dosage recommendations may serve as a general guideline for tracheal intubation and muscle relaxation for short to long lasting surgical procedures and for use in the intensive care unit.
Surgical Procedures
Tracheal intubation
The standard intubating dose during routine anaesthesia is 0.6 mg/kg rocuronium bromide, after which adequate intubation conditions are established within 60 seconds in nearly all patients. A dose of 1.0 mg/kg rocuronium bromide is recommended for facilitating tracheal intubation conditions during rapid sequence induction of anaesthesia, after which adequate intubation conditions are established within 60 seconds in nearly all patients. If a dose of 0.6 mg/kg rocuronium bromide is used for rapid sequence induction of anaesthesia, it is recommended to intubate the patient 90 seconds after administration of rocuronium bromide.
Higher doses
Should there be reason for selection of larger doses in individual patients, there is no indication from clinical studies that the use of initial doses up to 2 mg/kg rocuronium bromide is associated with an increased frequency or severity of cardiovascular effects. The use of these high dosages of rocuronium bromide decreases the onset time and increases the duration of action.
Maintenance dosing
The recommended maintenance dose is 0.15 mg/kg rocuronium bromide; in the case of long-term inhalational anaesthesia this should be reduced to 0.075-0.1 mg/kg rocuronium bromide. The maintenance doses should best be given when twitch height has recovered to 25% of control twitch height, or when 2 to 3 responses to train of four stimulation are present.
Continuous infusion
If rocuronium bromide is administered by continuous infusion, it is recommended to give a loading dose of 0.6 mg/kg rocuronium bromide and, when neuromuscular block starts to recover, to start administration by infusion. The infusion rate should be adjusted to maintain twitch response at 10% of control twitch height or to maintain 1 to 2 responses to train of four stimulation. In adults under intravenous anaesthesia, the infusion rate required to maintain neuromuscular block at this level ranges from 0.3-0.6 mg/kg/h (300-600 micrograms/kg/h) and under inhalational anaesthesia the infusion rate ranges from 0.3-0.4 mg/kg/h. Continuous monitoring of neuromuscular block is essential since infusion rate requirements vary from patient to patient and with the anaesthetic method used.
Paediatric population
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 intubation dose during routine anaesthesia and maintenance dose are similar to those in adults.
However, the duration of action of the single intubating dose will be longer in neonates and infants than in children.
For continuous infusion in paediatrics, the infusion rates, with the exception of children (2-11 years), are the same as for adults. For children aged 2-11 years higher infusion rates might be necessary.
Thus, for children (2-11 years) the same initial infusion rates as for adults are recommended and then this should be adjusted to maintain twitch response at 10% of control twitch height or to maintain 1 or 2 responses to train of four stimulation during the procedure.
The experience with rocuronium bromide in rapid sequence induction in paediatric patients is limited. Rocuronium bromide is therefore not recommended for facilitating tracheal intubation conditions during rapid sequence induction in paediatric patients.
Geriatric patients and patients with hepatic and/or biliary tract disease and/or renal failure
The standard intubation dose for geriatric patients and patients with hepatic and/or biliary tract disease and/or renal failure during routine anaesthesia is 0.6 mg/kg rocuronium bromide. A dose of 0.6 mg/kg should be considered for rapid sequence induction of anaesthesia in patients in which a prolonged duration of action is expected.)
Overweight and obese patients
When used in overweight or obese patients (defined as patients with a body weight of 30% or more above ideal body weight) doses should be reduced taking into account ideal body weight.
Intensive Care Procedures
Tracheal intubation
For tracheal intubation, the same doses should be used as described above under surgical procedures.
Maintenance dosing
The use of an initial loading dose of 0.6 mg/kg rocuronium bromide is recommended, followed by a continuous infusion as soon as twitch height recovers to 10% or upon reappearance of 1 to 2 twitches to train of four stimulation. Dosage should always be titrated to effect in the individual patient. The recommended initial infusion rate for the maintenance of a neuromuscular block of 80-90% (1 to 2 twitches to TOF stimulation) in adult patients is 0.3-0.6 mg/kg/h during the first hour of administration, which will need to be decreased during the following 6-12 hours, according to the individual response. Thereafter, individual dose requirements remain relatively constant.
A large between patient variability in hourly infusion rates has been found in controlled clinical studies, with mean hourly infusion rates ranging from 0.2-0.5 mg/kg/h depending on nature and extent of organ failure(s), concomitant medication and individual patient characteristics. To provide optimal individual patient control, monitoring of neuromuscular transmission is strongly recommended. Administration up to 7 days has been investigated.
Special populations
Fada Rocuronio is not recommended for the facilitation of mechanical ventilation in the intensive care in paediatric and geriatric patients due to a lack of data on safety and efficacy.
Method of administration
Fada Rocuronio is administered intravenously either as a bolus injection or as a continuous infusion.
Fada Rocuronio should only be administered by, or under supervision of, experienced clinicians who are familiar with the action and use of these medicinal products.
The dosage of Fada Rocuronio should be individualized in each patient. The method of anaesthesia and the expected duration of surgery, the method of sedation and the expected duration of mechanical ventilation, the possible interaction with other medicinal products that are administered concomitantly, and the condition of the patient should be taken into account when determining the dose.
The use of an appropriate neuromuscular monitoring technique is recommended for the evaluation of neuromuscular block and recovery.
Inhalational anaesthetics do potentiate the neuromuscular blocking effects of Fada Rocuronio.
This potentiation however, becomes clinically relevant in the course of anaesthesia, when the volatile agents have reached the tissue concentrations required for this interaction. Consequently, adjustments with Fada Rocuronio should be made by administering smaller maintenance doses at less frequent intervals or by using lower infusion rates of Fada Rocuronio during long lasting procedures (longer than 1 hour) under inhalational anaesthesia.
In adult patients the following dosage recommendations may serve as a general guideline for tracheal intubation and muscle relaxation for short to long lasting surgical procedures and for use in the intensive care unit.
Surgical Procedures
Tracheal intubation
The standard intubating dose during routine anaesthesia is 0.6 mg/kg Fada Rocuronio, after which adequate intubation conditions are established within 60 seconds in nearly all patients.
A dose of 1.0 mg/kg Fada Rocuronio is recommended for facilitating tracheal intubation conditions during rapid sequence induction of anaesthesia, after which adequate intubation conditions are established within 60 seconds in nearly all patients. If a dose of 0.6 mg/kg Fada Rocuronio is used for rapid sequence induction of anaesthesia, it is recommended to intubate the patient 90 seconds after administration of Fada Rocuronio.
Higher doses
Should there be reason for selection of larger doses in individual patients, there is no indication from clinical studies that the use of initial doses up to 2 mg/kg Fada Rocuronio is associated with an increased frequency or severity of cardiovascular effects. The use of these high dosages of Fada Rocuronio decreases the onset time and increases the duration of action.
Maintenance dosing
The recommended maintenance dose is 0.15 mg/kg Fada Rocuronio; in the case of long-term inhalational anaesthesia this should be reduced to 0.075-0.1 mg/kg Fada Rocuronio.
The maintenance doses should best be given when twitch height has recovered to 25% of control twitch height, or when 2 to 3 responses to control twitch height (train-of-four stimulation) are present.
Continuous infusion
If Fada Rocuronio is administered by continuous infusion, it is recommended to give a loading dose of 0.6 mg/kg Fada Rocuronio and, when neuromuscular block starts to recover, to start administration by infusion. The infusion rate should be adjusted to maintain twitch response at 10% of control twitch height or to maintain 1 to 2 responses to control twitch height (train-of-four stimulation).
In adults under intravenous anaesthesia, the infusion rate required to maintain neuromuscular block at this level ranges from 0.3-0.6 mg/kg/h (300-600 micrograms/kg/h) and under inhalational anaesthesia the infusion rate ranges from 0.3-0.4 mg/kg/h. Continuous monitoring of neuromuscular block is essential since infusion rate requirements vary from patient to patient and with the anaesthetic method used.
Dosage in pregnant patients:
In patients undergoing Caesarean section, it is recommended to only use a dose of 0.6 mg Fada Rocuronio per kg body weight, since a 1.0 mg/kg dose has not been investigated in this patient group.
Reversal of neuromuscular block induced by neuromuscular blocking agents may be inhibited or unsatisfactory in patients receiving magnesium salts for toxaemia of pregnancy because magnesium salts enhance neuromuscular blockade. Therefore, in these patients the dosage of rocuronium should be reduced and be titrated to twitch response.
Paediatric patients
For infants (28 days-23 months), children (2-11 years) and adolescents (12-18 years) the recommended intubation dose during routine anaesthesia and maintenance dose are similar to those in adults.
For continuous infusion in paediatrics, the infusion rates, with the exception of children, are the same as for adults. For children higher infusion rates might be necessary. For children the same initial infusion rates as for adults are recommended and this should be adjusted to maintain twitch response at 10% of control twitch height or to maintain 1 or 2 responses to control twitch height (train-of-four stimulation) during the procedure.
There are insufficient data to support dose recommendations for the use of Fada Rocuronio in new-born infants (0-1 month).
The experience with Fada Rocuronio in rapid sequence induction in paediatric patients is limited. Fada Rocuronio is therefore not recommended for facilitating tracheal intubation conditions during rapid sequence induction in paediatric patients.
Geriatric patients and patients with hepatic and/or biliary tract disease and/or renal failure
The standard intubation dose for geriatric patients and patients with hepatic and/or biliary tract disease and/or renal failure during routine anaesthesia is 0.6 mg/kg Fada Rocuronio. A dose of 0.6 mg/kg should be considered for rapid sequence induction of anaesthesia in patients in which a prolonged duration of action is expected however adequate conditions for intubation may not be established for 90 seconds after administration of Fada Rocuronio. Regardless of the anaesthetic technique used, the recommended maintenance dose for these patients is 0.075-0.1 mg/kg Fada Rocuronio, and the recommended infusion rate is 0.3-0.4 mg/kg/h (see also Continuous infusion).
Overweight and obese patients
When used in overweight or obese patients (defined as patients with a body weight of 30% or more above ideal body weight) doses should be reduced taking into account ideal body weight.
Intensive Care Procedures
Tracheal intubation
For tracheal intubation, the same doses should be used as described above under surgical procedures.
Fada Rocuronio is not recommended for the facilitation of mechanical ventilation in the intensive care due to a lack of data on safety and efficacy.
Administration
This medicinal product is for single use only. Any unused solution should be discarded.
Fada Rocuronio is administered intravenously either as a bolus injection or as a continuous infusion.
Compatibility studies with the following infusion fluids have been performed: In nominal concentrations of 0.5 mg/ml and 2.0 mg/ml Fada Rocuronio has been shown to be compatible with: 0.9% NaCl, 5% dextrose, 5% dextrose in saline, sterile water for injections, Lactated Ringers and Haemaccel. Administration should be begun immediately after mixing, and should be completed within 24 hours. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Compatibility studies with the following infusion fluids have been performed: in nominal concentration of 5 mg/ml Fada Rocuronio has been shown to be compatible with: sodium chloride 9 mg/ml (0.9%) solution, glucose 50 mg/ml (5%) solution, glucose 33 mg/ml (3.3 %) in sodium chloride 3 mg/ml (0.3%) solution, water for injections and Lactated Ringers. Administration should begin immediately after mixing, and should be completed within 24 hours.
Single use only. Any unused product or waste material should be disposed of in accordance with local requirements.
Do not use Fada Rocuronio if you notice that the solution is not clear and not free from particles.
