Local anaesthetics. ATC Code:
Naropin contains ropivacaine, a pure enantiomer, which is a local anaesthetic of the amide type. Ropivacaine reversibly blocks the conduction of impulses in the nerves by inhibiting the transport of sodium ions through the nerve membrane. Similar effects can also be seen on excitatory membranes in the brain and myocardium.
Ropivacaine has anaesthetic and analgesic effects. At high doses surgical anaesthesia is obtained, while lower doses produce sensory block (analgesia) with limited and non-progressive motor block. The duration and intensity of a ropivacaine block is not improved by the addition of adrenaline.
A lower negative inotropic effect was caused in vitro
by ropivacaine than by levo bupivacaine and bupivacaine.
Cardiac effects measured in vivo
in several animal studies showed that ropivacaine has a lower cardiac toxicity than bupivacaine. The differences are both qualitative and quantitative.
Ropivacaine causes less widening of the QRS complex than bupivacaine and the alterations occurs at higher doses of ropivacaine and levobupivacaine than of bupivacaine.
Direct cardiovascular effects of local anaesthetics includes delayed conduction, negative inotropism and finally arrhythmia and cardiac arrest. Dogs given intravenous doses until cardiovascular collapse were easier resuscitated after given ropivacaine than after given levobupivacaine and bupivacaine, despite higher free plasma concentration. This indicates a wider safety margin for ropivacaine following accidental intravascular injection or overdose.
Pregnant ewes showed no greater sensitivity to systemic toxic effects of ropivacaine than non-pregnant ewes.
Healthy volunteers exposed to intravenous infusions showed significantly less potential for CNS toxicity and cardiac toxicity after ropivacaine than after bupivacaine. The CNS symptoms are similar but occurs at lower doses and plasma concentrations and last longer for bupivacaine. Ropivacaine causes a smaller widening of the QRS width than bupivacaine.
Indirect cardiovascular effects (hypotension, bradycardia) can occur after epidural block, depending on the extent of concomitant sympathetic block. These are, however, less pronounced in children.
If large amounts of the drug reach the circulation, central nervous and cardiovascular symptoms rapidly occur (see Overdosage).
Ropivacaine has a chiral center and is available as the pure S-(-)-enantiomer. It is highly lipid-soluble, the pKa value of ropivacaine is 8.1 and the distribution coefficient is 141 (25°C n-octanol/phosphate-buffer with pH 7.4). All metabolites have a local anaesthetic effect but of considerably lower potency and shorter duration than that of ropivacaine.
The plasma concentration of ropivacaine is dependent on the dose, type of block and vascularisation at the injection site. Ropivacaine displays linear pharmacokinetics, i.e. the maximum plasma concentration is proportional to the dose.
Ropivacaine displays complete and bi-phasic absorption from the epidural space, with half-lives for the two phases in the order of 14 minutes and 4 hours respectively. The slow absorption is the rate-limiting factor in the elimination of ropivacaine, which explains why the terminal half-life is longer after epidural than after intravenous administration.
Ropivacaine is mainly bound to α1
- acid glycoprotein in plasma with a free fraction of approximately 6%. The volume of distribution in steady state is 47 litres. An increase in the total plasma concentration of ropivacaine and PPX during continuous epidural infusion has been observed, dependent on a postoperative increase of
-acid glycoprotein. The increase in free, pharmacologically active ropivacaine in plasma has been considerably lower than the increase in total ropivacaine. The average concentration of unbound PPX has been observed to be approximately 7-9 times higher than the average concentration of unbound ropivacaine after continuous epidural infusion up to 72 hours.
Ropivacaine readily crosses the placenta with equilibrium between the mother and foetus in regard to unbound ropivacaine. 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 metabolised in the liver principally by aromatic hydroxylation to 3-hydroxy-ropivacaine (mediated by CYP1A2) and N-dealkylation to PPX (mediated by CYP3A4). PPX is an active metabolite. The threshold for CNS-toxic unbound plasma concentrations of PPX in rats is about twelve times higher than that of unbound ropivacaine. PPX is a metabolite of minor importance after a single dose, but a major metabolite after continuous epidural infusion.
The metabolites are excreted in the urine. Only approximately 1% of a single dose of ropivacaine is excreted as unchanged ropivacaine. Ropivacaine has a mean total plasma clearance in the order of 440 mL/minute, a clearance of unbound ropivacaine of 8 l/minute, and a renal clearance of 1 mL/minute. The terminal half-life is 1.8 hours after intravenous administration, and the hepatic extraction ratio is intermediate, approx. 0.4.
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.
Naropin 2 mg/ml:
Paediatric Patients: The pharmacokinetics of ropivacaine has been characterized in a pooled population analysis of six studies comprising 192 children between 0 and 12 years of age.
During the first years of life, unbound ropivacaine and PPX clearance depend on body weight and age. The effect of age is interpreted as a function of maturation of liver function and body weight normalized clearance reaches a maximum at about 1-3 years of age. Clearance of unbound ropivacaine increases from 2.4 L/h/kg in newborns and 3.6 L/h/kg at 1 month respectively to about 8-16 L/h/kg for infants older than 6 months.
Similarly, the volume of distribution of unbound ropivacaine, normalized to body weight, increases with age and reaches a maximum at the age of 2 years. The volume of distribution of unbound ropivacaine increases from 22 L/kg in newborns and 26 L/kg in a 1 month old infant respectively to 42-46L/kg in infants older than 6 months.
The terminal half-life of ropivacaine is longer, 5-6 hours in newborns and one-month infants compared to 3 hours in older children.
The terminal half-life of PPX is even longer, about 43 hours in newborns and 26 hours in one-month old infants compared to 15 hours in older children.
Depending on the immaturity of the liver function, the systemic exposure is higher in newborns and somewhat higher in 1-6 months old infants, compared to older children. The dosage recommendations for continuous epidural infusion will in part compensate for this difference (see Tables 1 and 2 with simulated and observed unbound concentrations). (See Tables 1 and 2).
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
A number of newborns (n=81) exposed to ropivacaine via the mother during delivery had at birth maximum umbilical blood concentrations in the same order as the infants who received ropivacaine for caudal epidural block (0.03-0.11 mg/L).
In order to assess the safety margin of the recommended doses, simulations of the sum of unbound plasma concentration of ropivacaine and PPX have been performed.
The simulations estimate that an increase of the recommended dose for caudal epidural block by a factor of 2.7 in the youngest dose group (0-1 month) and by a factor of 7.4 in the dose group 1-10 years give rise to an unbound plasma concentration that can reach the threshold value for systemic toxicity (0.34 mg/L) in 5% of the population (the threshold value reaches the 95th percentile of the prediction interval). For continuous epidural infusion it is estimated that an increase of the recommended dose by 1.8 times in the youngest age group (0-1 month) and by 3.8 times in the age group of 1-10 years can result in that the threshold value for systemic toxicity (0.34 mg/L) is reached in 5% of the population.
Toxicology: Preclinical Safety Data:
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).