ROPIVACAINE ALTAN 7.5 MG / ML SOLUTION FOR INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Ropivacaine Altan 7.5 mg/ml solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Ropivacaine Altan 7.5 mg/ml solution for injection

1 ml solution for injection contains ropivacaine hydrochloride monohydrate equivalent to7.5 mg ropivacaine hydrochloride.

Each 10 ml ampoule contains ropivacaine hydrochloride monohydrate equivalent to 75 mg ropivacaine hydrochloride.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection.

Clear, colourless solution.

Ropivacaine Altan 7.5 mg/ml solution for injection: pH: 4.5–6.0

Osmolarity: 261–319 mOsmol/kg

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Ropivacaine Altan 7.5 mg/ml is indicated in adults and adolescents older than 12 years in

Surgical anaesthesia:

– Epidural blocks for surgery, including Caesarean section.

– Major nerve blocks.

– Field blocks.

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

– Single and continuous peripheral nerve block.

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

– Caudal epidural block.

– Continuous epidural infusion.

4.2 Posology and method of administration

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

Posology

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.

Table 1 Adults and adolescents above 12 years of age

In general, surgical anaesthesia (e.g. epidural administration) requires the use of the higher concentrations and doses. The 10 mg/ml formulation is recommended for epidural anaesthesia in which a complete motor block is essential for the surgery. For analgesia (e.g. epidural administration for acute pain management) the lower concentrations and doses are recommended.

Renal impairment

Dose modification is not normally required in patients with impaired renal function when single doses or short-term treatments are used (see section 4.4 and 5.2).

Hepatic impairment

Ropivacaine hydrochloride is metabolized in the liver and should be used with caution in patients with severe liver disease. Reduced repeat doses may be required due to delayed elimination (see section 4.4 and 5.2).

Method of administration

Perineural and epidural use.

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 with adrenaline (epinephrine) is recommended (lidocaine 2% with adrenaline (epinephrine 1:200.000). 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 2550 mg/min, while closely observing the patient's vital functions and maintaining verbal contact. 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.

In brachial plexus block a single dose of 300 mg has been used in a limited number of patients and was well tolerated.

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 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 a concentration of 7.5 mg/ml is induced via an epidural catheter. Analgesia is maintained with Ropivacaine Altan 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.

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.

Concentrations above 7.5 mg/ml Ropivacaine have not been documented for Caesarean section.

Prior to administration, the solution should be visually inspected, do not use unless the solution is clear and colorless and the container is not damaged.

For single use only.

Pediatric population

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

The use of Ropivacaine 7.5 and 10 mg/ml may be associated with systemic and central toxic events in children. Lower strengths (2 mg/ml) are more appropriate for administration to this population.

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

Infants and children aged 1–12 years:

The proposed ropivacaine doses for peripheral block in infants and children provide guidelines for use in children without severe disease. More conservative doses and close monitoring are recommended for children with severe disease.

Single injections for peripheral nerve block (e.g. ilioinguinal nerve block, brachial plexus block) should not exceed 2.5–3.0 mg/kg.

Method of administration

Perineural and epidural use

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.

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

Prior to administration, the solution should be visually inspected. Do not use unless the solution is clear and colourless and the container is not damaged.

For single use only.

4.3 Contraindications

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

General contraindications 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. Patients receiving major blocks should be in an optimal condition and have an intravenous line inserted before the blocking procedure. The clinician responsible should take the necessary precautions to avoid intravascular injection (see section 4.2 Posology and method of administration) and be appropriately trained and familiar with diagnosis and treatment of side effects, systemic toxicity and other complications (see sections 4.8 Undesirable effects and 4.9 Overdose) 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.

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.

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.

Cardiovascular effect

Epidural (and accidental administered intrathecal) anaesthesia may lead to hypotension and bradycardia. Hypotension should be treated promptly with a vasopressor intravenously, and with adequate vascular filling.

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 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.

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.

Ropivacaine Altan 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.

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

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

A possible cross-hypersensitivity with other amide-type local anaesthetics should be taken into account.

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 Altan. Intra-articular continuous infusion with Ropivacaine Altan should be avoided, as the efficacy and safety has not been established.

Excipients with recognised action/effect

Ropivacaine Altan 2 mg/ml solution for injection:

This medicinal product contains 3.34 mg of sodium per ml, equivalent to 0.17% of the WHO recommended maximum daily intake of 2 g of sodium for an adult.

Ropivacaine Altan 7.5 mg/ml solution for injection:

This medicinal product contains 3.15 mg of sodium per ml, equivalent to 0.16% of the WHO recommended maximum daily intake of 2 g of sodium for an adult.

Ropivacaine Altan 10 mg/ml injectable solution:

This medicinal product contains 3.03 mg of sodium per ml, equivalent to 0.15% of the WHO recommended maximum daily intake of 2 g of sodium for an adult.

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 7.5 mg/ml and 10 mg/ml in children up to and including 12 years has not been established.

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

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

4.5 Interaction with other medicinal products and other forms of interaction

Ropivacaine Altan 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 Altan 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 Special warnings and precautions for use).

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 Altan, can interact with Ropivacaine Altan. Prolonged administration of ropivacaine should be avoided in patients concomitantly treated with strong CYP1A2 inhibitors (see also 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/fœtal development, parturition or postnatal development (see section 5.3 Preclinical safety data).

Breast-feeding

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

Fertility

There are no data available concerning fertility.

4.7 Effects on ability to drive and use machines

No data are 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. When administered this medicine the doctor should assess on each particular case if the reaction capacity is engaged and if the patient can drive or use machinery.

4.8 Undesirable effects

General

The adverse reaction profile for Ropivacaine Altan 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.

The percentage of patients that is expected to experience adverse reactions varies depending on the route of administration of Ropivacaine Altan. Systemic and local adverse reactions of Ropivacaine Altan are usually likely to be the result of an excessive doses, a rapid absorption or accidental intravascular injection. Undesirable effects more frequently notified, nausea and hypotension, are very common during anaesthesia and surgery generally and it is not possible to distinguish undesirable effects produced by the clinical status from those caused by the drug or blockage.

The frequencies of the undesirable effects listed below are defined using the following convention:

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), Not known (cannot be estimated from the available data).

Table 4 Table of adverse drug reactions

aHypotension is less frequent in children (>1/100). b 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 vascularised areas, see also 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 hypothensio which happens less often in children (< 1 in 10) and vomiting which happens more often in children (> 1 in 10).

In paediatric population, 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 at 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

Equipment and necessary drugs for monitoring and emergency resuscitation should be available at any time. 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 cardiovascular depression occurs (hypotension, bradycardia), 5–10 mg ephedrine intravenously should be administered, and if necessary the process should be repeated after 2–3 minutes. Children should be given doses commensurate with age and weight.

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.

Should cardiac arrest occur, a successful outcome may require prolonged resuscitative efforts.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anaesthetics, local, Amides, ATC code: N01B B09.

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.

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 Ropivacaine Altan, 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.

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.

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 a1-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.

Biotransformation and 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.

There is no evidence of in vivo racemisation of ropivacaine.

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 4 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 (Table 5). 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 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.

5.3 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).

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 absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

Ampoules: 3 years.

Shelf life after first opening:

From a microbiological point of view, unless the method of opening precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

6.4 Special precautions for storage

Do not freeze.

Use immediately after opening For storage after opening, see section 6.3.

6.5 Nature and contents of container

Ropivacaine Altan 7.5 mg/ml solution for injection: 5 glass ampoules of 10 ml.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Ropivacaine Altan are preservative-free and are intended for single use only.

Discard any unused solution.

The intact container must not be re-autoclaved.

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

7 MARKETING AUTHORISATION HOLDER

Altan Pharma Ltd

The Lennox Building, 50 South Richmond street

Dublin 2, D02FK02

Ireland

Deleted:

8 MARKETING AUTHORISATION NUMBER(S)

PL 46788/0021

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/01/2019