Symptoms
Accidental intravascular injections of local anaesthetics may cause immediate (within seconds to a few minutes) systemic toxic reactions. In the event of overdose, peak plasma concentrations may not be reached for one to two hours, depending on the site of the injection, and signs of toxicity may thus be delayed.
Treatment
If signs of acute systemic toxicity appear, injection of the local anaesthetic should be stopped immediately and CNS symptoms (convulsions, CNS depression) must promptly be treated with appropriate airway/respiratory support and the administration of anticonvulsant drugs.
If circulatory arrest should occur, immediate cardiopulmonary resuscitation should be instituted. Optimal oxygenation and ventilation and circulatory support as well as treatment of acidosis are of vital importance.
If cardiovascular depression occurs (hypotension, bradycardia), appropriate treatment with intravenous fluids, vasopressor, and or inotropic agents should be considered. Children should be given doses commensurate with age and weight.
Should cardiac arrest occur, a successful outcome may require prolonged resuscitative efforts.
3 years.
Shelf life after first opening:
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C.
In alkaline solutions precipitation may occur as ropivacaine shows poor solubility at pH > 6.
Sodium chloride
Hydrochloric acid
Sodium hydroxide
Water for injections
General
The adverse reaction profile for Naropin is similar to those for other long acting local anaesthetics of the amide type. Adverse drug reactions should be distinguished from the physiological effects of the nerve block itself e.g. a decrease in blood pressure and bradycardia during spinal/epidural block.
Table 4 Table of adverse drug reactions
: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to < 1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data).|
System Organ Class |
Frequency |
Undesirable Effect |
|
Immune system disorders |
Rare |
Allergic reactions (anaphylactic reactions, angioneurotic oedema and urticaria) |
|
Psychiatric disorders |
Uncommon |
Anxiety |
|
Nervous System disorders |
Common |
Paraesthesia, Dizziness, Headache |
|
Uncommon |
Symptoms of CNS toxicity (Convulsions, Grand mal convulsions, Seizures, Light headedness, Circumoral paraesthesia, Numbness of the tongue, Hyperacusis, Tinnitus, Visual disturbances, Dysarthria, Muscular twitching, Tremor)*, Hypoaesthesia | |
|
Not known |
Dyskinesia | |
|
Cardiac disorders |
Common |
Bradycardia, Tachycardia |
|
Rare |
Cardiac arrest, Cardiac arrhythmias | |
|
Vascular disorders |
Very common |
Hypotensiona |
|
Common |
Hypertension | |
|
Uncommon |
Syncope | |
|
Respiratory, Thoracic and Mediastinal disorders |
Uncommon |
Dyspnoea |
|
Gastrointestinal disorders |
Very common |
Nausea |
|
Common |
Vomitingb | |
|
Musculoskeletal and connective tissue disorders |
Common |
Back pain |
|
Renal and Urinary disorders |
Common |
Urinary retention |
|
General disorders and Administrative site conditions |
Common |
Temperature elevation, Chills |
|
Uncommon |
Hypothermia |
a Hypotension is less frequent in children (>1/100).
b Vomiting is more frequent in children (>1/10).
Class-related adverse drug reactions
Neurological complications
Neuropathy and spinal cord dysfunction (e.g. anterior spinal artery syndrome, arachnoiditis, cauda equina), which may result in rare cases of permanent sequelae, have been associated with regional anaesthesia, regardless of the local anaesthetic used.
Total spinal block
Total spinal block may occur if an epidural dose is inadvertently administered intrathecally.
Acute systemic toxicity
Systemic toxic reactions primarily involve the central nervous system (CNS) and the cardiovascular system (CVS). CNS reactions are similar for all amide local anaesthetics, while cardiac reactions are more dependent on the drug, both quantitatively and qualitatively.
Central nervous system toxicity
Central nervous system toxicity is a graded response with symptoms and signs of escalating severity. Initially symptoms such as visual or hearing disturbances, perioral numbness, dizziness, light-headedness, tingling and paraesthesia are seen. Dysarthria, muscular rigidity and muscular twitching are more serious and may precede the onset of generalised convulsions. These signs must not be mistaken for neurotic behaviour. Unconsciousness and grand mal convulsions may follow, which may last from a few seconds to several minutes. Hypoxia and hypercarbia occur rapidly during convulsions due to the increased muscular activity, together with the interference with respiration. In severe cases even apnoea may occur. The respiratory and metabolic acidosis increases and extends the toxic effects of local anaesthetics.
Recovery follows the redistribution of the local anaesthetic drug from the central nervous system and subsequent metabolism and excretion. Recovery may be rapid unless large amounts of the drug have been injected.
Cardiovascular system toxicity
Cardiovascular toxicity indicates a more severe situation. Hypotension, bradycardia, arrhythmia and even cardiac arrest may occur as a result of high systemic concentrations of local anaesthetics. In volunteers the intravenous infusion of ropivacaine resulted in signs of depression of conductivity and contractility.
Cardiovascular toxic effects are generally preceded by signs of toxicity in the central nervous system, unless the patient is receiving a general anaesthetic or is heavily sedated with drugs such as benzodiazepines or barbiturates.
In children, early signs of local anaesthetic toxicity may be difficult to detect since they may not be able to verbally express them.
Paediatric population
Frequency, type and severity of adverse reactions in children are expected to be the same as in adults except for hypotension which happens less often in children (<1 in 10) and vomiting which happens more often in children (>1 in 10).
)Treatment of acute systemic toxicity
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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.
Based on conventional studies of safety pharmacology, single and repeated dose toxicity, reproduction toxicity, mutagenic potential and local toxicity, no hazards for humans were identified other than those which can be expected on the basis of the pharmacodynamic action of high doses of ropivacaine (e.g. CNS signs, including convulsions, and cardiotoxicity).
Pharmacotherapeutic group: Anaesthetics, local, Amides
ATC code: N01B B09
Mechanism of action
Ropivacaine is a long-acting, amide-type local anaesthetic with both anaesthetic and analgesic effects. At high doses Naropin produces surgical anaesthesia, while at lower doses it produces sensory block with limited and non-progressive motor block.
The mechanism is a reversible reduction of the membrane permeability of the nerve fibre to sodium ions. Consequently the depolarisation velocity is decreased and the excitable threshold increased, resulting in a local blockade of nerve impulses.
The most characteristic property of ropivacaine is the long duration of action. Onset and duration of the local anaesthetic efficacy are dependent upon the administration site and dose, but are not influenced by the presence of a vasoconstrictor (e.g. adrenaline (epinephrine)). For details concerning the onset and duration of action of Naropin, see Table 1 under posology and method of administration.
Healthy volunteers exposed to intravenous infusions tolerated ropivacaine well at low doses and with expected CNS symptoms at the maximum tolerated dose. The clinical experience with this drug indicates a good margin of safety when adequately used in recommended doses.
Absorption
Ropivacaine has a chiral center and is available as the pure S-(-)-enantiomer. It is highly lipid-soluble. All metabolites have a local anaesthetic effect but of considerably lower potency and shorter duration than that of ropivacaine.
There is no evidence of in vivo racemisation of ropivacaine.
The plasma concentration of ropivacaine depends upon the dose , the route of administration and the vascularity of the injection site. Ropivacaine follows linear pharmacokinetics and the Cmax is proportional to the dose.
Ropivacaine shows complete and biphasic absorption from the epidural space with half-lives of the two phases of the order of 14 min and 4 h in adults. The slow absorption is the rate-limiting factor in the elimination of ropivacaine, which explains why the apparent elimination half-life is longer after epidural than after intravenous administration. Ropivacaine shows a biphasic absorption from the caudal epidural space also in children.
Distribution
Ropivacaine has a mean total plasma clearance in the order of 440 ml/min, a renal clearance of 1 ml/min, a volume of distribution at steady state of 47 litres and a terminal half-life of 1.8 h after iv administration. Ropivacaine has an intermediate hepatic extraction ratio of about 0.4. It is mainly bound to α1-acid glycoprotein in plasma with an unbound fraction of about 6%.
An increase in total plasma concentrations during continuous epidural and interscalene infusion has been observed, related to a postoperative increase of α1-acid glycoprotein. Variations in unbound, i.e. pharmacologically active, concentration have been much less than in total plasma concentration.
Elimination
Since ropivacaine has an intermediate to low hepatic extraction ratio, its rate of elimination should depend on the unbound plasma concentration. A postoperative increase in AAG will decrease the unbound fraction due to increased protein binding, which will decrease the total clearance and result in an increase in total plasma concentrations, as seen in the paediatric and adult studies. The unbound clearance of ropivacaine remains unchanged as illustrated by the stable unbound concentrations during postoperative infusion. It is the unbound plasma concentration that is related to systemic pharmacodynamic effects and toxicity.
Ropivacaine readily crosses the placenta and equilibrium in regard to unbound concentration will be rapidly reached. The degree of plasma protein binding in the foetus is less than in the mother, which results in lower total plasma concentrations in the foetus than in the mother.
Ropivacaine is extensively metabolised, predominantly by aromatic hydroxylation. In total, 86% of the dose is excreted in the urine after intravenous administration, of which only about 1% relates to unchanged drug. The major metabolite is 3-hydroxy-ropivacaine, about 37% of which is excreted in the urine, mainly conjugated. Urinary excretion of 4-hydroxy-ropivacaine, the N-dealkylated metabolite (PPX) and the 4-hydroxy-dealkylated accounts for 1-3%. Conjugated and unconjugated 3-hydroxy-ropivacaine shows only detectable concentrations in plasma.
A similar pattern of metabolites has been found in children above one year.
Impaired renal function has little or no influence on ropivacaine pharmacokinetics. The renal clearance of PPX is significantly correlated with creatinine clearance. A lack of correlation between total exposure, expressed as AUC, with creatinine clearance indicates that the total clearance of PPX includes a non-renal elimination in addition to renal excretion. Some patients with impaired renal function may show an increased exposure to PPX resulting from a low non-renal clearance. Due to the reduced CNS toxicity of PPX as compared to ropivacaine the clinical consequences are considered negligible in short-term treatment. Patients with end-stage renal disease undergoing dialysis have not been studied.
Paediatrics
The pharmacokinetics of ropivacaine was characterized in a pooled population PK analysis on data in 192 children between 0 and 12 years. Unbound ropivacaine and PPX clearance and ropivacaine unbound volume of distribution depend on both body weight and age up to the maturity of liver function, after which they depend largely on body weight. The maturation of unbound ropivacaine clearance appears to be complete by the age of 3 years, that of PPX by the age of 1 year and unbound ropivacaine volume of distribution by the age of 2 years. The PPX unbound volume of distribution only depends on body weight. As PPX has a longer half-life and a lower clearance, it may accumulate during epidural infusion.
Unbound ropivacaine clearance (Clu) for ages above 6 months has reached values within the range of those in adults. Total ropivacaine clearance (CL) values displayed in Table 5 are those not affected by the postoperative increase in AAG.
Table 5 Estimates of pharmacokinetic parameters derived from the pooled paediatric population PK analysis
|
Age Group |
BWa kg |
Club (L/h/kg) |
Vuc (L/kg) |
CLd (L/h/kg) |
t1/2e (h) |
t1/2ppxf (h) |
|
Newborn |
3.27 |
2.40 |
21.86 |
0.096 |
6.3 |
43.3 |
|
1m |
4.29 |
3.60 |
25.94 |
0.143 |
5.0 |
25.7 |
|
6m |
7.85 |
8.03 |
41.71 |
0.320 |
3.6 |
14.5 |
|
1y |
10.15 |
11.32 |
52.60 |
0.451 |
3.2 |
13.6 |
|
4y |
16.69 |
15.91 |
65.24 |
0.633 |
2.8 |
15.1 |
|
10y |
32.19 |
13.94 |
65.57 |
0.555 |
3.3 |
17.8 |
a Median bodyweight for respective age from WHO database.
b Unbound ropivacaine clearance.
c Ropivacaine unbound volume of distribution.
d Total ropivacaine clearance.
e Ropivacaine terminal half life.
f PPX terminal half life.
The simulated mean unbound maximal plasma concentration (Cumax) after a single caudal block tended to be higher in neonates and the time to Cumax (tmax) decreased with an increase in age (Table 6).
Table 6 Simulated mean and observed range of unbound Cumax after a single caudal block
|
Age group |
Dose (mg/kg) |
Cumaxa (mg/L) |
tmaxb (h) |
Cumaxc (mg/L) |
|
0-1m |
2.00 |
0.0582 |
2.00 |
0.05-0.08 (n=5) |
|
1-6m |
2.00 |
0.0375 |
1.50 |
0.02-0.09 (n=18) |
|
6-12m |
2.00 |
0.0283 |
1.00 |
0.01-0.05 (n=9) |
|
1-10y |
2.00 |
0.0221 |
0.50 |
0.01-0.05 (n=60) |
a Unbound maximal plasma concentration.
b Time to unbound maximal plasma concentration.
c Observed and dose-normalised unbound maximal plasma concentration.
At 6 months, the breakpoint for change in the recommended dose rate for continuous epidural infusion, unbound ropivacaine clearance has reached 34% and unbound PPX 71% of its mature value. The systemic exposure is higher in neonates and also somewhat higher in infants between 1 to 6 months compared to older children, which is related to the immaturity of their liver function. However, this is partly compensated for by the recommended 50% lower dose rate for continuous infusion in infants below 6 months.
Simulations on the sum of unbound plasma concentrations of ropivacaine and PPX, based on the PK parameters and their variance in the population analysis, indicate that for a single caudal block the recommended dose must be increased by a factor of 2.7 in the youngest group and a factor of 7.4 in the 1 to 10 year group in order for the upper prediction 90% confidence interval limit to touch the threshold for systemic toxicity. Corresponding factors for the continuous epidural infusion are 1.8 and 3.8 respectively.
Simulations on the sum of unbound plasma concentrations of ropivacaine and PPX, based on the PK parameters and their variance in the population analysis, indicate that for 1- to 12- year-old infants and children receiving 3 mg/kg single peripheral (ilioinguinal) nerve block the median unbound peak concentration reached after 0.8 h is 0.0347 mg/L, one-tenth of the toxicity threshold (0.34 mg/L). The upper 90% confidence interval for the maximum unbound plasma concentration is 0.074 mg/L, one-fifth of the toxicity threshold. Similarly, for continuous peripheral block (0.6 mg ropivacaine/kg for 72 h) preceded by a 3 mg/kg single peripheral nerve block, the median unbound peak concentration is 0.053 mg/L. The upper 90% confidence interval for the maximum unbound plasma concentration is 0.088 mg/L, one-quarter of the toxicity threshold.
February 2018
Aspen Pharma Trading Limited,
3016 Lake Drive,
Citywest Business Campus,
Dublin 24, Ireland
Do not store above 30°C. Do not freeze.
10 ml polypropylene ampoules (Polyamp) in packs of 5 and 10.
10 ml polypropylene ampoules (Polyamp) in sterile blister packs of 5 and 10.
20 ml polypropylene ampoules (Polyamp) in packs of 5 and 10.
20 ml polypropylene ampoules (Polyamp) in sterile blister packs of 5 and 10.
Not all pack sizes may be marketed.
The polypropylene ampoules (Polyamp) are specially designed to fit Luer lock and Luer fit syringes.
PL 39699/0080
Naropin products are preservative-free and are intended for single use only. Discard any unused solution.
The intact container must not be re-autoclaved. A blistered container should be chosen when a sterile outside is required.
The medicinal product should be visually inspected prior to use. The solution should only be used if it is clear, practically free from particles and if the container is undamaged.
Date of first authorisation: 3rd October 1995
Date of latest renewal: 13th November 2009
