ROPIVACAINE VILLERTON 2 MG / ML SOLUTION FOR INFUSION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Ropivacaine Villerton 2 mg/ml solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution contains ropivacaine hydrochloride monohydrate equivalent to 2 mg ropivacaine hydrochloride.

Each bag of 100 ml solution contains 200 mg ropivacaine hydrochloride.

Each bag of 200 ml solution contains 400 mg ropivacaine hydrochloride.

Each bag of 500 ml solution contains 1000 mg ropivacaine hydrochloride.

Excipients with known effect

Each 100 ml bag contains 14.7 mmol (338 mg) of sodium.

Each 200 ml bag contains 29.4 mmol (676 mg) of sodium.

Each 500 ml bag contains 73.5 mmol (1690 mg) of sodium.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for infusion.

The medicinal product is a clear and colourless solution, free from visible particles.

pH = 4.0 – 6.0

Osmolality = 270 – 320 mOsmol/Kg

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Ropivacaine Villerton 2 mg/ml is indicated for acute pain management

In adults and adolescents above 12 years of age for:

– Continuous epidural infusion or intermittent bolus administration during postoperative or labour pain.

– Field blocks.

– Continuous peripheral nerve block via a continuous infusion or intermittent bolus injections, e.g. postoperative pain management.

In infants from 1 year and children up to and including 12 years of age (per- and postoperative):

– Single and continuous peripheral nerve block.

In neonates, infants and children up to and including 12 years of age for (per- and postoperative):

– Caudal epidural block.

– Continuous epidural infusion

4.2 Posology and method of administration

Ropivacaine Villerton should only be used by, or under the supervision of, clinicians experienced in regional anaesthesia.

For surgical anaesthesia (e.g. epidural administration, caesarean section) and for epidural anaesthesia in which a complete motor block is essential for surgery, higher concentrations and doses are required. For those indications, other strengths of ropivacaine hydrochloride solution for injection are available (7.5 mg/ml and 10 mg/ml). For analgesia (e.g epidural administration for acute pain management) and field block the lower concentration and doses are recommended.

Posology

Table 1: Adults and adolescents above 12 years of age:

The following table is a guide to dosage for the more commonly used blocks. The smallest dose required to produce an effective block should be used. The clinician’s ex­perience and knowledge of the patient’s physical status are of importance when deciding the dose.

The doses in the table are those considered to be necessary to produce a successful block and should be regarded as guidelines for use in adults. Individual variations in onset and duration occur. The figures in the column ‘Dose’ reflect the expected average dose range needed. Standard textbooks should be consulted for both factors affecting specific block techniques and individual patient requirements.

n/a = not applicable.

Method of administration

Perineural and epidural administration by infusion.

Careful aspiration before and during injection is recommended to prevent intravascular injection. When a large dose is to be injected, a test dose of 3–5 ml lidocaine (lignocaine) with adrenaline (epinephrine) 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.

Aspiration should be performed prior to and during administration of the main dose, which should be injected slowly or in incremental doses, at a rate of 25–50 mg/min, while closely observing the patient’s vital functions and maintaining verbal contact. If toxic symptoms occur, the injection should be stopped immediately.

When prolonged blocks are used, either through continuous 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 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 ropivacaine 7.5 mg/ml is induced via an epidural catheter. Analgesia is maintained with Ropivacaine Villerton 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.

In clinical studies an epidural infusion of ropivacaine 2 mg/ml alone or mixed with fentanyl 1–4 ^g/ml has been given for postoperative pain management for up to 72 hours. The combination of ropivacaine and fentanyl provided improved pain relief but caused opioid side effects. The combination of ropivacaine and fentanyl has been investigated only for ropivacaine 2 mg/ml.

When prolonged peripheral nerve blocks are applied, either through continuous infusion or through repeated injections, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered. In clinical studies, femoral nerve block was established with 300 mg ropivacaine 7.5 mg/ml and interscalene block with 225 mg ropivacaine 7.5 mg/ml, respectively, before surgery. Analgesia was then maintained with ropivacaine 2 mg/ml. Infusion rates or intermittent injections of 10–20 mg per hour for 48 hours provided adequate analgesia and were well tolerated.

Paediatric population

Table 2: Paediatric patients from 0 up to and including 12 years of age

Individual variations occur. In children with a high body weight, a gradual reduction of the dosage is often necessary and should be based on the ideal body weight. The volume for single caudal epidural block and the volume for epidural bolus doses should not exceed 25 mL in any patient. Standard textbooks should be consulted for factors affecting specific block techniques and for individual patient requirements.

a Doses in the low end of the dose interval are recommended for thoracic epidural blocks while doses in the high end are recommended for lumbar or caudal epidural blocks.

b Recommended for lumbar epidural blocks. It is good practice to reduce the bolus dose for thoracic epidural analgesia.

The use of ropivacaine in premature children has not been documented.

Table 3: Peripheral nerve blocks: Infants and children aged 1–12 years

The dose in the table should be regarded as guidelines for use in paediatrics.

Individual variations occur in children with a high body weight a gradual reduction of the dosage is often necessary and should be based on the ideal body weight. Standard textbooks should be consulted for factors affecting specific block techniques and fir individual patient requirements.

The doses for peripheral block in infants and children provide guidance for use in children without severe disease.

More conservative doses and close monitoring are recommended for children with severe diseases.

Method of administration

Epidural administration by infusion.

Careful aspiration before and during injection is recommended to prevent intravascular injection. The patient’s vital functions should be observed closely during the injection. If toxic symptoms occur, the injection should be stopped immediately.

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 achieve a different distribution of sensory block, as recommended in standard textbooks. In children above 4 years of age, doses up to 3 mg/kg of a concentration of ropivacaine 3 mg/ml have been studied. However, this concentration is associated with a higher incidence of motor block.

Fractionation of the calculated local anaesthetic dose is recommended, whatever route of administration.

4.3 Contraindications

Hypersensitivity to active substance or to any of the excipients listed in section 6.1 or to other local anaesthetics of the amide type.

General contra-indications related to epidural anaesthesia, regardless of the local anaesthetic used, should be taken into account.

Intravenous regional anaesthesia.

Obstetric paracervical anaesthesia.

Hypovolaemia.

4.4 Special warnings and precautions for use

Regional anaesthetic procedures should always be performed in a properly equipped and staffed area. Equipment and drugs necessary for monitoring and emergency resuscitation should be immediately available.

The clinician responsible should take the necessary precautions to avoid intravascular injection (see section 4.2) and be appropriately trained and familiar with diagnosis and treatment of side effects, systemic toxicity and other complications (see sections 4.8 and 4.9) such as 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.

Caution is required to prevent injections in inflamed areas.

Cardiovascular

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 (see section 4.5).

There have been rare reports of cardiac arrest during the use of ropivacaine 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.

Head and neck blocks

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.

Major peripheral nerve blocks

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.

Hypersensitivity

A possible cross-hypersensitivity with other amide-type local anaesthetics should be taken into account (see section 4.3).

Hypovolaemia

Patients with hypovolaemia due to any cause can develop sudden and severe hypotension during epidural anaesthesia, regardless of the local anaesthetic used (see section 4.3).

Patients in poor general health

Patients in poor general condition due to ageing or other compromising factors such as partial or complete heart conduction block, advanced liver disease or severe renal dysfunction require special attention, although regional anaesthesia is frequently indicated in these patients.

Patients with hepatic and renal impairment

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.

Acute porphyria

Ropivacaine Villerton solution for 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, according to standard textbooks and/or in consultation with disease area experts.

Chondrolysis

There have been post-marketing reports of chondrolysis in patients receiving postoperative intra-articular continuous infusion of local anaesthetics, including ropivacaine. The majority of reported cases of chondrolysis have involved the shoulder joint. Intra-articular continuous infusion is not an approved indication for Ropivacaine Villerton. Intra-articular continuous infusion with Ropivacaine Villerton should be avoided, as the efficacy and safety has not been established.

Prolonged administration

Prolonged administration of ropivacaine should be avoided in patients concomitantly treated with strong CYP1A2 inhibitors, such as fluvoxamine and enoxacin, (see section 4.5).

Paediatric population

Neonates may need special attention due to immaturity of metabolic pathways. The larger variations in plasma concentrations of ropivacaine observed in clinical trials in neonates suggest that there may be an increased risk of systemic toxicity in this age group, especially during continuous epidural infusion. The recommended doses in neonates are based on limited clinical data. When ropivacaine is used in this patient group, regular monitoring of systemic toxicity (e.g. by signs of CNS toxicity, ECG, SpO2) and local neurotoxicity (e.g. prolonged recovery) is required, which should be continued after ending infusion, due to a slow elimination in neonates.

The safety and efficacy of Ropivacaine Villerton 2 mg/ml for peripheral nerve blocks in infants below 1 year has not been established.

The safety and efficacy of Ropivacaine Villerton 2 mg/ml for field block in children up to and including 12 years has not been established.

Important information about excipients

Sodium

This medicinal product contains 338 mg sodium per 100 ml bag, equivalent to 16.9% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This medicinal product contains 676 mg sodium per 200 ml bag, equivalent to 33.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This medicinal product contains 1690 mg sodium per 500 ml bag, equivalent to 84.5% of the WHO recommended maximum daily intake of 2g sodium for an adult.

The maximum daily dose of this product is equivalent to 67.6% of the WHO recommended maximum daily intake for sodium.

Ropivacaine Villerton 2 mg/ml is considered high in sodium. This should be particularly taken into account for those on a low salt diet.

4.5 Interaction with other medicinal products and other forms of interaction

Ropivacaine Villerton should be used with caution in patients receiving other local anaesthetics or agents structurally related to amide-type local anaesthetics, e.g. certain antiarrhythmics, such as lidocaine and mexiletine, since the systemic toxic effects are additive. Simultaneous use of Ropivacaine Villerton with general anaesthetics or opioids may potentiate each others (adverse) effects. Specific interaction studies with ropivacaine and anti-arrhythmic drugs class III (e.g. amiodarone) have not been performed, but caution is advised (see also section 4.4).

Cytochrome P450 (CYP) 1A2 is involved in the formation of 3-hydroxy-ropivacaine, the major metabolite.

In vivo, the plasma clearance of ropivacaine was reduced by up to 77% during co administration of fluvoxamine, a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of CYP1A2, such as fluvoxamine and enoxacin given concomitantly during prolonged administration of ropivacaine, can interact with Ropivacaine Villerton.

Prolonged administration of ropivacaine should be avoided in patients concomitantly treated with strong CYP1A2 inhibitors (see section 4.4).

In vivo, the plasma clearance of ropivacaine was reduced by 15% during coadministration of ketoconazole, a selective and potent inhibitor of CYP3A4. However, the inhibition of this isozyme is not likely to have clinical relevance.

In vitro, ropivacaine is a competitive inhibitor of CYP2D6 but does not seem to inhibit this isozyme at clinically attained plasma concentrations.

4.6 Fertility, pregnancy and lactation

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 section 5.3).

Breastfeeding

There are no data available concerning the excretion of ropivacaine into human milk.

Fertility

There are no data available concerning the fertility.

4.7 Effects on ability to drive and use machines

No data is available. Depending on the dose, local anaesthetics may have a minor influence on mental function and co-ordination even in the absence of overt CNS toxicity and may temporarily impair locomotion and alertness.

4.8 Undesirable effects

General

The adverse reaction profile for ropivacaine 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 of adverse drug reactions

The frequencies used in the table in Section 4.8 are: 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).

Hypotension is less frequent in children (>1/100).

Vomiting is more frequent in children (>1/10).

These symptoms usually occur because of inadvertent intravascular injection,

overdose or rapid absorption (see section 4.9).

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). Such reactions are caused by high blood concentration of a local anaesthetic, which may appear due to (accidental) intravascular injection, overdose or exceptionally rapid absorption from highly vascularized areas (see section 4.4). 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.

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).

In children, early signs of local anaesthetic toxicity may be difficult to detect since they may not be able to verbally express them. (See also section 4.4).

Treatment of acute systemic toxicity

See section 4.9.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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. (see section 4.8).

Treatment

If signs of acute systemic toxicity appear, infusion 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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anaesthetics, local, Amides, ATC code: N01BB09

Mechanism of action

Ropivacaine is a long-acting, amide-type local anaesthetic with both anaesthetic and analgesic effects. At high doses ropivacaine 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.

Pharmacodynamic effects

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. epinephrine). For details concerning the onset and duration of action of Ropivacaine Villerton, (see Table 1 in section 4.2).

Clinical efficacy and safety

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.

5.2 Pharmacokinetic properties

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 intravenous administration. Ropivacaine has an intermediate hepatic extraction ratio of about 0.4. It is mainly bound to al-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 a1– 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 i% 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.

Paediatric population

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 the table below are those not affected by the postoperative increase in AAG.

Table 5: Estimates of pharmacokinetic parameters derived from the pooled paediatric population PK analysis

a b c d e f

Median bodyweight for respective age from WHO database.

Unbound ropivacaine clearance.

Ropivacaine unbound volume of distribution.

Total ropivacaine clearance.

Ropivacaine terminal half life.

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 (see below table). Simulated mean unbound plasma concentrations at the end of a 72 h continuous epidural infusion at recommended dose rates also showed higher levels in neonates as compared to those in infants and children. See also section 4.4.

Table 6: Simulated mean and observed range of unbound Cumax after a single caudal block

a

b

Unbound maximal plasma concentration.

Time to unbound maximal plasma concentration.

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.

5.3 Preclinical safety data

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

6.2 Incompatibilities

In the absense of compatibilities, this medicinal product should not be mixed with other medicinal products.

In alkaline solutions precipitation may occur as ropivacaine shows poor solubility at pH > 6.0.

6.3 Shelf life

2 years

Shelf life after first opening:

From a microbiological point of view, the product should be used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

For mixtures, see section 6.6.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Transparent polyolefin bags equipped with two polyolefin tubing ports, one polyolefin twist off port and one polycarbonate injection port. Each bag is put in a transparent overpouch.

Pack sizes of 5, 10 and 20 bags

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

To be used immediately after the overwrap is opened.

Ropivacaine Villerton 2 mg/ml solution for infusion is chemically and physically compatible with the following drugs:

* The concentration ranges stated in the table are wider than those used in clinical practice. Epidural infusions of ropivacaine/su­fentanil citrate, ropivacaine/mor­phine sulphate and ropivacaine/clo­nidine hydrochloride have not been evaluated in clinical studies.

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.

The mixtures are chemically and physically stable for 72 hours at 20 to 30°C.

From a microbiological point of view, the mixtures should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.