Naropin

Naropin

ropivacaine

Manufacturer:

Aspen

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Ropivacaine hydrochloride.
Description
Each ampoule contains 2 mg/ml ropivacaine hydrochloride solution for injection/infusion and 7.5 mg/ml ropivacaine hydrochloride for injection.
The plastic ampoules fit syringes with Luer closures ("luer-lock" and "luer-fit").
Excipients/Inactive Ingredients: Sodium chloride, sodium hydroxide/hydrochloric acid (to pH 4.0-6.0) and water for injection.
Action
Pharmacotherapeutic Group: Local anaesthetics. ATC Code: N01B B09.
Pharmacology: Pharmacodynamics: 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).
Pharmacokinetics: 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.
Absorption: 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.
Distribution: 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 α1-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.
Metabolism: 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.
Elimination: 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).

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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).
Indications/Uses
Surgical Anaesthesia: Epidural block for surgery, including Caesarean section and field block.
Acute Pain Management: Continuous epidural infusion or intermittent bolus administration e.g. postoperative or labour pain and field block.
Naropin 2 mg/ml: Acute Pain Relief (Peri- and Postoperative) in Children: Caudal epidural block in infants (>30 days old) and children up to and including 12 years and continuous epidural infusion in infants (>30 days old) and children up to and including 12 years.
Dosage/Direction for Use
Naropin should only be used by, or under the supervision of, clinicians experienced in regional anaesthesia.
Adults and Children Above 12 Years of Age: The following table is a guide to dosage for the more commonly used blocks. The clinician's experience and knowledge of the patient's physical status are of importance when deciding the dose. In general, surgical anaesthesia (e.g. epidural administration) requires the use of the higher concentrations and doses. For analgesia the 2 mg/ml concentration of Naropin is generally recommended. (See Table 3).

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Administration:
In order to avoid intravascular injection, aspiration should be repeated prior to and during administration of the main dose, which should be injected slowly or in incremental doses, at a rate of 25-30 mg/min, while closely observing the patient's vital functions and maintaining verbal contact. When an epidural dose is to be injected, a preceding test dose of 3-5 ml lidocaine (lignocaine) with adrenaline (Xylocaine 1-2% with Adrenaline 1:200,000) is recommended. An inadvertent intravascular injection may be recognised by a temporary increase in heart rate and an accidental intrathecal injection by signs of a spinal block.
If toxic symptoms occur, the injection should be stopped immediately.
In epidural block for surgery, single doses of up to 250 mg ropivacaine have been used and well tolerated.
When prolonged blocks are used, either through continuous epidural infusion or through repeated bolus administration, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered. Cumulative doses up to 675 mg ropivacaine for surgery and postoperative analgesia administered over 24 hours were well tolerated in adults, as were postoperative continuous epidural infusions at rates up to 28 mg/hour for 72 hours. In a limited number of patients, higher doses of up to 800 mg/day have been administered with relatively few adverse reactions.
For treatment of postoperative pain, the following technique can be recommended: Unless preoperatively instituted, an epidural block with Naropin 7.5 mg/ml is induced via an epidural catheter. Analgesia is maintained with Naropin 2 mg/ml infusion. Infusion rates of 6-14 ml (12-28 mg) per hour provide adequate analgesia with only slight and non-progressive motor block in most cases of moderate to severe postoperative pain. The maximum duration of epidural block is 3 days. However, close monitoring of analgesic effect should be performed in order to remove the catheter as soon as the pain condition allows it.
With this technique a significant reduction in the need for opioids has been observed.
For Caesarean section, neither intrathecal administration nor the use of the ropivacaine concentration 10 mg/ml for epidural administration, have been documented. (See Table 4).

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Naropin 2mg/ml: The recommended strength of Naropin solution for injection/infusion for Single Caudal Epidural Block in children >30 days old and up to 12 years and for Continuous Epidural Infusion in children with a body weight up to 25 kg is 2mg/ml.
The doses in the table should be regarded as recommendations when used in children.
Individual variations occur. For overweight children a gradual reduction of the dosage, based on the ideal body weight, is often necessary. The volume for single caudal epidural block and the volume for epidural bolus doses should not exceed 25 mL in any patient.
To prevent inadvertent intravascular injections, great caution should be observed. Careful aspiration is recommended before and during injection of the total dose. The patient´s vital functions should be carefully monitored during the injection. Should toxic signs appear, the injection should be immediately stopped.
When administering the calculated dose, fractionation of the total dose is always recommended.
A single caudal epidural injection of ropivacaine 2 mg/mL produces adequate postoperative analgesia below T12 in the majority of patients when a dose of 2 mg/kg is used in a volume of 1 mL/kg. The volume of the caudal epidural injection may be adjusted to control the spread of the sensory block. Doses up to 3 mg/kg of a concentration of ropivacaine 3 mg/mL have been used safely in children older than 4 years.
For children with a body weight over 25 kg there is limited experience of caudal blocks.
The use of ropivacaine in premature children has not been documented.
Overdosage
Toxicity: After inadvertent intravascular injections in plexus blocks and other peripheral blocks, cases of convulsions have been observed.
After spinal administration, systemic toxicity is not expected to occur, due to the low dose administered. Administration of a too high dose intratechally may lead to total spinal block.
Symptoms: Systemic toxic reactions primarily involve the central nervous system and the cardiovascular system. Such reactions are caused by high blood concentration of local anaesthetics, which may appear due to accidental intravascular injection, overdose or exceptionally rapid absorption from highly vascularised areas (see Precautions). CNS symptoms are similar for all amide local anaesthetics, while cardiac symptoms are more dependent on the drug, both quantitatively and qualitatively.
Accidental intravascular injections of local anaesthetics can cause immediate (within seconds to a few minutes) systemic toxic reactions. In the event of overdose, systemic toxicity appears later (15-60 minutes after injection) due to the slower increase in local anaesthetic blood concentration.
CNS toxicity occurs gradually, with symptoms and reactions of increasing severity. The first symptoms are usually light-headedness, circumoral paresthesia, numbness of the tongue, hyperacusis, tinnitus and visual disturbances. Dysarthria, muscular twitching and or tremors are more serious and precede the onset of generalized convulsions. These signs should not be mistaken for neurotic behavior.
A loss of consciousness and grand mal convulsions can follow these, and last for a few seconds to several minutes. Oxygen deficiency and hypercapnoea rapidly occur during the convulsions due to increased muscle activity and inadequate ventilation together with the possible interference with respiration. In severe cases even apnoe amay occur. Acidosis, hyperkalemia, hypocalcemia and oxygen deficiency increase and extend the toxic effects of local anaesthetics.
Recovery depends on the metabolism of the local anaesthetic and its distribution away from the central nervous system. This takes place rapidly unless very large amounts of the medicinal product have been injected.
Cardiovascular effects generally constitute a more serious situation and is generally preceded by signs of toxicity in the central nervous system Prodromal CNS effects may not appear if the patient is receiving a general anaesthetic or is heavily sedated. A fall in blood pressure, bradycardia, arrhythmia and also cardiac arrest can occur as a result of high systemic concentrations of local anaesthetics but in rare cases, cardiac arrest has occurred without prodromal CNS effects.
In children, the block is often given during general anaesthesia. Careful monitoring of early signs of toxicity is necessary in this patient group.
Treatment: If signs of acute systemic toxicity occur, the administration of local anaesthetics must be stopped immediately. Treatment must be directed at rapidly stopping the CNS symptoms (convulsions and CNS depression) in order to maintain oxygenation and circulation. Oxygen must always be given, and, if required, assisted ventilation. If the convulsions do not cease spontaneously within 15-20 seconds, thiopentone sodium 1-3 mg/kg i.v. must be given to make proper ventilation possible or diazepam 0.1 mg/kg i.v. (acts rather more slowly). Prolonged convulsions jeopardize the patient's breathing and oxygenation. Injection of a muscle relaxant (e.g. suxamethonium 1 mg/kg) improves the conditions for the patient's breathing and oxygenation but requires experience from tracheal intubation and assisted ventilation.
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 there is a fall in blood pressure/bradycardia, a vasopressor such as ephedrine 5-10 mg is given intravenously (can be repeated after 2-3 minutes). In the event of asystole heart massage must be given. Optimal oxygenation and ventilation and circulatory support as well as treatment of acidosis are of vital importance.
Should cardiac arrest occur, a successful outcome may require prolonged resuscitative efforts.
In the treatment of toxicity symptoms, children should be given doses commensurate with their age and weight.
Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Hypersensitivity to local anaesthetics of the amide type.
Special Precautions
Regional anaesthetic procedures should always be performed with equipment necessary for emergency resuscitation immediately available.
Patients receiving major blocks should be in an optimal condition and have an i.v. line inserted before the blocking procedure. The clinician responsible should take the necessary precautions to avoid intravascular injection (see Dosage & Administration) and be appropriately trained and familiar with the diagnosis and treatment of side effects, systemic toxicity and other complications. (See Adverse Reactions and Overdosage). One complication is inadvertent subarachnoid injection which may produce a high spinal block with apnoea and hypotension. Convulsions have occurred most often after brachial plexus block and epidural block. This is likely to be the result of either accidental intravascular injection or rapid absorption from the injection site.
Major peripheral nerve blocks may imply the administration of a large volume of local anaesthetic in highly vascularised areas, often close to large vessels where there is an increased risk of intravascular injection and/or rapid systemic absorption, which can lead to high plasma concentrations.
Certain local anaesthetic procedures such as injections in the head and neck regions may be associated with a higher frequency of serious adverse reactions, regardless of the local anaesthetic used. Caution is required to prevent injections in inflamed areas.
Caution is advised for patients with AV block II or III. Also elderly and patients with advanced liver disease, severe renal dysfunction or in poor general condition require special attention.
Patients treated with anti-arrhythmic drugs class III (e.g. amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive.
There have been rare reports of cardiac arrest during the use of Naropin for epidural anaesthesia or peripheral nerve blockade, especially after unintentional accidental intravascular administration in elderly patients and in patients with concomitant heart disease. In some instances, resuscitation has been difficult. Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the possibility of a successful outcome.
Ropivacaine is metabolised in the liver and should therefore be used with caution in patients with severe liver disease; repeated doses may need to be reduced due to delayed elimination.
Normally there is no need to modify the dose in patients with impaired renal function when used for single-dose or short-term treatment.
Acidosis and reduced plasma protein concentration, frequently seen in patients with chronic renal failure, may increase the risk of systemic toxicity. This risk should also be considered in undernourished patients and patients treated for hypovolaemic shock.
Epidural and spinal anaesthesia may lead to hypotension and bradycardia. The risk of such effects can be reduced by intravenous supply of fluid or by injection of a vasopressor. Hypotension should be treated promptly with, for example, ephedrine 5-10 mg intravenously, repeated as necessary.
When Naropin is administered as intra-articular injection, caution is advised when recent major intra-articular trauma is suspected or extensive raw surfaces within the joint have been created by the surgical procedure, as that may accelerate absorption and result in higher plasma concentrations.
Prolonged administration of ropivacaine should be avoided in patients treated with strong inhibitors of CYP1A2, (such as fluvoxamine and enoxacin,) (see Interactions).
A possible cross–hypersensitivity with other amide–type local anaesthetics should be taken into account.
This medicinal product contains maximum 3.7 mg sodium per mL. To be taken into consideration by patients on a controlled sodium diet.
Naropin solution for injection and infusion is possibly porphyrinogenic and should only be prescribed to patients with acute porphyria when no safer alternative is available. Appropriate precautions should be taken in the case of vulnerable patients.
Higher concentrations than 5 mg/mL have not been documented in children.
There have been post-marketing reports of chondrolysis in patients receiving post-operative intra-articular continuous infusion of local anaesthetics. The majority of reported cases of chondrolysis have involved the shoulder joint. Due to multiple contributing factors and inconsistency in the scientific literature regarding mechanism of action, causality has not been established. Intra-articular continuous infusion is not an approved indication for Naropin.
Effects on Ability to Drive and Use Machines: Besides the direct anaesthetic effect, ropivacaine may possibly have a slight, transient effect on locomotive power and co-ordination.
Use In Pregnancy & Lactation
Use in Pregnancy: Apart from epidural administration for obstetrical use, there are no adequate data on the use of ropivacaine in human pregnancy. Experimental animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).Spinal administration in caesarean section has not been documented.
Use in Lactation: It is not known whether ropivacaine passes into breast milk.
Adverse Reactions
A large number of symptoms have been reported in clinical trials. These may occur irrespective of the local anaesthetic used, they are often physiological effects of the nerve block itself and the clinical situation. Adverse reactions caused by the medicinal product may be difficult to distinguish from physiological effects caused by nerve- and sympathetic block (e.g. hypotension and bradycardia), and events caused directly (e.g. nerve trauma) or indirectly (e.g. epidural abscess) from needle puncture.
Undesirable Effects (from all kinds of blockades): The adverse reactions are displayed within each organ class with the following frequencies: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1 000, <1/100), rare (<1/1 000).

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Class Related Adverse Drug Reactions: The adverse reactions below include complications related to the anaesthetic technique regardless of the local anaesthetic used.
Neurological Complications: Neuropathy and spinal cord dysfunctions (e.g. anterior spinal artery syndrome, arachnoiditis, cauda equina) have been associated with spinal and epidural anaesthesia.
Total Spinal Block: Total spinal block may occur if an epidural dose is inadvertently administered intrathecally, or if a too large spinal dose is administered. The effects of systemic overdoses and inadvertent intravascular injections may be serious (see Overdosage).
Drug Interactions
Ropivacaine must be used with caution together with medicinal products that are structurally similar to local anaesthetics, i.e. class IB antiarrhythmics, as the toxic effects are additive.
Specific interactions studies with local anaesthetics and anti-arrhytmics class III (e.g. amiodarone) have not been performed but caution is advised (see Precautions).
In healthy volunteers ropivacaine clearance was reduced by up to 77% during co-administration of fluvoxamine, a potent competitive inhibitor of CYP1A2. CYP1A2 is involved in the formation of 3-hydroxy-ropivacaine, a major metabolite. Thus strong inhibitors of CYP1A2, such as fluvoxamine and enoxacin, given concomitantly with Naropin can cause a metabolic interaction leading to an increased ropivacaine plasma concentration.
Prolonged administration of ropivacaine should therefore be avoided in patients treated with strong inhibitors of CYP1A2, see also Precautions.
Caution For Usage
Instructions for Use and Handling, and for Disposal: Naropin solution for injection contains no preservative and is intended for single-use only.
Remaining solution must be discarded. Blister packs must be chosen when sterile outer surface of the ampoules are required.
Incompatibilities: Alkalisation can cause precipitation, as ropivacaine is hardly soluble at a pH above 6.0.
Storage
Do not store above 30°C. Do not freeze.
ATC Classification
N01BB09 - ropivacaine ; Belongs to the class of amides. Used as local anesthetics.
Presentation/Packing
Polyamp Duofit Inj (Sterile theatre pack) (sterile, isotonic, isobaric aqueous solutions) 2 mg/mL x 20 mL x 5's. 7.5 mg/mL x 20 mL x 5's.
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