Ropivacaine Hydrochloride 2 mg/ml solution for injection/infusion

Solution for injection/infusion Clear, colourless solution with a pH of 4 – 6 and an osmolality of 270 – 320 mOsmol/kg

4.1 Therapeutic indications **Acute pain management in adults and adolescents (> 12 years of age):**

• 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 **Acute pain management in paediatrics:**
• Single and continuous peripheral nerve block in toddlers (from 1 year) and children (≤12 years)
• Caudal epidural block in newborn infants (0-27 days), infants and toddlers (28 days to 23 months) and children (≤12 years) (peri- and postoperative)
• Continuous epidural infusion in newborn infants (0-27 days), infants and toddlers (28 days to 23 months) and children (≤12 years) (peri- and postoperative)4.2 Posology and method of administration Ropivacaine Hydrochloride 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 in the average adult. Standard textbooks should be consulted for factors affecting specific block techniques and for individual patient requirements. 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 on the dose. | | | | | | | | --- | --- | --- | --- | --- | --- | | | **Concentration of Ropivacaine Hydrochloride** | **Volume** | **Dose of Ropivacaine Hydrochloride** | **Onset** | **Duration** | | **mg/ml** | **ml** | **mg** | **minutes** | **hours** | | **ACUTE PAIN MANAGEMENT** | | | | | | | **Lumbar Epidural Administration** | | | | | | | Bolus | 2.0 | 10-20 | 20-40 | 10-15 | 0.5-1.5 | | Intermittent injections (top-up) (e.g. labour pain management) | 2.0 | 10-15 (minimum interval 30 minutes) | 20-30 | | | | Continuous infusion e.g. labour pain | 2.0 | 6-10 ml/h | 12-20 mg/h | n/a | n/a | | Postoperative pain management | 2.0 | 6-14 ml/h | 12-28 mg/h | n/a | n/a) | | **Thoracic Epidural Administration** | | | | | | | Continuous infusion (postoperative pain management) | 2.0 | 6-14 ml/h | 12-28 mg/h | n/a | n/a | | **Field Block** | | | | | | | (e.g. minor nerve blocks and infiltration) | 2.0 | 1-100 | 2-200 | 1-5 | 2-6 | | **Peripheral nerve block (Femoral or interscalene block)** | | | | | | | Continuous infusion or intermittent injections (e.g. postoperative pain management) | 2.0 | 5-10 ml/h | 10-20 mg/h | n/a | n/a | | n/a = not applicable | | | | | | 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 of 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 of up to 28 mg/hour ropivacaine 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. The maximum duration of epidural block is 3 days. **Combination with opioids:** In clinical studies an epidural infusion of 2 mg/ml ropivacaine mixed with fentanyl 1-4 μg/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 undesirable effects. The combination of ropivacaine and fentanyl has been investigated only for ropivacaine 2 mg/ml. ***Paediatric population*** The dose in the table should be regarded as a guideline for use in paediatrics. Individual variations occur. Dosing recommendations can be given for children with a bodyweight up to 25 kg. A total volume of 25 ml should not be exceeded for single caudal epidural block and the volume for epidural bolus application. For children with a higher bodyweight no data is available to give detailed recommendations. 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 for individual patient requirements. | | | | | | --- | --- | --- | --- | | | **Concentration of Ropivacaine Hydrochloride** | **Volume** | **Dose of Ropivacaine Hydrochloride** | | **mg/ml** | **ml/kg** | **mg/kg** | | **ACUTE PAIN MANAGEMENT (peri- and postoperative)** | | | | | **Caudal Epidural Administration** Single injection Blocks below T12, in children with a body weight up to 25 kg | 2.0c | 1 | 2 | | **Continuous Epidural Infusion -** In children with a body weight up to 25 kg | | | | | *0 - 6 months* Bolus dosea Infusion up to 72 hours | 2.0 2.0 | 0.5–1 0.1 ml/kg/h | 1–2 0.2 mg/kg/h | | *6 up to 12 months* Bolus dosea Infusion up to 72 hours | 2.0 2.0 | 0.5–1 0.2 ml/kg/h | 1–2 0.4 mg/kg/h | | *≥1 year* Bolus doseb Infusion up to 72 hours | 2.0 2.0 | 1 0.2 ml/kg/h | 2 0.4 mg/kg/h | | a The lower doses are recommended for thoracic epidural blocks while the higher doses 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. c A single caudal epidural injection of ropivacaine 2mg/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. | | | | **Infants and children aged 1-12 years:** | | | | | | --- | --- | --- | --- | | | **Conc.** | **Volume** | **Dose** | | **mg/ml** | **ml/kg** | **mg/kg** | | **ACUTE PAIN MANAGEMENT** **(per- and postoperative)** | | | | | **Single injections for peripheral nerve block** e.g. ilioinguinal nerve block, brachial plexus block, fascia iliaca compartment block | 2.0 | 0.5-0.75 | 1.0-1.5 | | Multiple blocks | 2.0 | 0.5-1.5 | 1.0-3.0 | | **Continuous infusion for peripheral nerve block in children 1 to 12 years.** Infusion up to 72 hours | 2.0 | 0.1-0.3 ml/kg/h | 0.2-0.6 mg/kg/h | 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 for individual patient requirements. 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. The use of ropivacaine in preterm newborn infants is not established. **Method of administration** For 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 lidocaine 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. Ropivacaine 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.4.3 Contraindications • Hypersensitivity to ropivacaine, to other local anaesthetics of the amide type or to any of the excipients listed in section 6.1 • General contraindications related to regional anaesthesia, including neuraxial anaesthesia, should be taken into account • Intravenous regional anaesthesia (Bier's block) • Obstetric paracervical anaesthesia • Hypovolaemia4.4 Special warnings and precautions for use Regional anaesthetic procedures should always be performed in a properly equipped and staffed area. Equipment and medicinal products 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 responsible clinician 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 risk** Patients treated with anti-arrhythmic agents 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 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. **Hypovolaemia** Patients with hypovolaemia due to any cause can develop sudden and severe hypotension during epidural anaesthesia, regardless of the local anaesthetic used. **Patients in poor general health** Patients in poor general condition due to advanced age 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 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 post-operative intra-articular continuous infusion of local anaesthetics. The majority of reported cases of chondrolysis have involved the shoulder joint. Intra-articular continuous infusion is not an approved indication for Ropivacaine Hydrochloride. Intra-articular continuous infusion with Ropivacaine Hydrochloride 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). **Special warnings/precautions regarding excipients** This medicinal product contains 3.3 mg sodium per ml, equivalent to 0.17% of the WHO recommended maximum daily intake of 2 g 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 2 mg/ml for peripheral nerve blocks has not been established for infants < 1 year. The safety and efficacy of ropivacaine 2 mg/ml for field blocks has not been established for children ≤12 years.4.5 Interaction with other medicinal products and other forms of interaction Ropivacaine 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 with general anaesthetics or opioids may potentiate each others' (adverse) effects. Specific interaction studies with ropivacaine and anti-arrhythmic agents 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 coadministration of fluvoxamine, a selective and potent CYP1A2 inhibitor.. Prolonged administration of ropivacaine should be avoided in patients concomitantly treated with strong CYP1A2 inhibitors, such as fluvoxamine and enoxacin as they can interact with ropivacaine (see section 4.4). *In vivo* the plasma clearance of ropivacaine was reduced by 15% during coadministration with 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 reproductive toxicity (see section 5.3). **Breast-feeding** There is insufficient information on the excretion of ropivacaine into human milk. **Fertility** No clinical data available.4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. 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 reactivity.4.8 Undesirable effects The adverse reaction profile for Ropivacaine Hydrochlorideis similar to those for other long acting local anaesthetics of the amide type. Adverse reactions should be distinguished from the physiological effects of the nerve block itself e.g. a hypotension and bradycardia during spinal/epidural block. The percentage of patients that can be expected to experience adverse reactions varies with the route of administration of ropivacaine. Systemic and localised adverse reactions of ropivacaine usually occur because of excessive dosage, rapid absorption, or inadvertent intravascular injection. The most frequently reported adverse reactions, nausea and hypotension, are very frequent during anaesthesia and surgery in general and it is not possible to distinguish those caused by the clinical situation from those caused by the drug or the type of block. **Table of adverse reactions** | | | | --- | --- | | Very common | (≥ 1/10) | | Common | (≥ 1/100 to <1/10) | | Uncommon | (≥ 1/1,000 to < 1/100) | | Rare | (≥ 1/10,000 to < 1/1,000) | | Very rare | (< 1/10,000) | | Not known | (cannot be estimated from the available data) | Within each system organ class, the adverse reactions have been ranked under the headings of frequency, most frequent reactions first. | | | | --- | --- | | ***System organ class*** | | | *Immune system disorders* | *Rare* allergic reactions (urticaria, angioneurotic oedema and anaphylactic reaction up to anaphylactic shock) | | *Psychiatric disorders* | *Uncommon* anxiety | | *Nervous system disorders* | *Common* paraesthesia, dizziness, headache *Uncommon* symptoms of CNS toxicity (convulsions, grand mal convulsions, seizures, light-headedness, circumoral paraesthesia, numbness of the tongue, hyperacusis, tinnitus, visual disturbances, muscle twitching, dysarthria, tremor, hypoaesthesia)\* *Not known* Dyskinesia | | *Cardiac disorders* | *Common* bradycardia, tachycardia *Rare* cardiac arrest, arrhythmias | | *Vascular disorders* | *Very common* hypotension *Common* hypotension (children), hypertension *Uncommon* syncope | | *Respiratory, thoracic and mediastinal disorders* | *Uncommon* dyspnoea | | *Gastrointestinal disorders* | *Very common* nausea, vomiting (children) *Common* vomiting | | *Musculoskeletal and connective tissue disorders* | *Common* back pain | | *Renal and urinary disorders* | *Common* urinary retention | | *General disorders and* *administration site conditions* | *Common* temperature elevation, chills *Uncommon* hypothermia | \* These symptoms usually occur because of inadvertent intravascular injection, overdose or rapid absorption (see section 4.9). **Class-related adverse reactions** ***Neurological complications*** Neuropathy and spinal cord dysfunctions (e.g. anterior spinal artery syndrome, arachnoiditis*, cauda equina* syndrome), 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. **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). **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 the 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** ***Acute systemic toxicity*** Systemic toxic reactions primarily involve the central nervous system (CNS) and the cardiovascular system. Such reactions are caused by high blood concentrations 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. 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. Early signs of local anaesthetic toxicity may be difficult to detect if the block is performed during general anaesthesia. ***Central nervous system*** Central nervous system toxicity is a graded response with symptoms and signs of escalating severity. Initially, symptoms such as visual or auditory disturbances, perioral numbness, dizziness, light-headedness, tingling and paresthesia are seen. Dysarthria, muscular rigidity and tremor are more serious and may precede the onset of generalised convulsions. These signs must not be mistaken for an underlying neurological disease. Unconsciousness and tonic-clonic (grand mal) convulsions may follow, which may last from a few seconds to several minutes. Hypoxia and hypercapnia 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 prolongs 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 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 toxicity 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 medicinal products such as benzodiazepines or barbiturates. **Treatment** Equipment and medicinal products necessary for monitoring and emergency resuscitation should be immediately available. 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 medicinal products. 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. Should cardiac arrest occur, a successful outcome may require prolonged resuscitative efforts.

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Anaesthetics; local Anaesthetics; Amides ATC code: N01BB09 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, see section 4.2. 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 Ropivacaine has a chiral centre 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 ropivacaine. **Absorption** The plasma concentration of ropivacaine depends upon the dose, the route of administration and the vascularity of the injection site. Ropivacaine, when administered iv, follows linear pharmacokinetics and the Cmax is proportional to the dose up to 80 mg. 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. An increase in total plasma concentrations during continuous epidural and interscalene infusion has been observed, related to a postoperative increase of α1-acid glycoprotein. Variations in unbound, i.e. pharmacologically active, concentration have been much less than in total plasma concentration 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. **Distribution** Ropivacaine has a mean total plasma clearance in the order of 440 ml/min, a renal clearance of 1 ml/min, a volume of distribution at steady state of 47 litres and a terminal half-life of 1.8 h after iv administration. Ropivacaine has an intermediate hepatic extraction ratio of about 0.4. It is mainly bound to α1-acid glycoprotein (AAG) in plasma with an unbound fraction of about 6%. 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. **Biotransformation and elimination** 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 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. There is no evidence of *in vivo* racemisation of ropivacaine. **Elderly** Ropivacaine plasma clearance is reduced and the elimination half-life prolonged in this population. Therefore when injected continuously, the dose should be individualized (eventually decreased) to avoid accumulation of ropivacaine. **Paediatric population** The pharmacokinetics of ropivacaine was characterised 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. ***Estimates of pharmacokinetic parameters derived from the pooled paediatric population PK analysis*** | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | | **Age** | **BWa** | **Club** | **Vuc** | **CL d** | **t 1/2e** | **t 1/2ppx f** | | **Group** | **kg** | **(l/h/kg)** | **(l/kg)** | **(l/h/kg)** | **(h)** | **(h)** | | Newborn | 3.27 | 2.40 | 21.86 | 0.096 | 6.3 | 43.3 | | 1m | 4.29 | 3.60 | 25.94 | 0.143 | 5.0 | 25.7 | | 6m | 7.85 | 8.03 | 41.71 | 0.320 | 3.6 | 14.5 | | 1y | 10.15 | 11.32 | 52.60 | 0.451 | 3.2 | 13.6 | | 4y | 16.69 | 15.91 | 65.24 | 0.633 | 2.8 | 15.1 | | 10y | 32.19 | 13.94 | 65.57 | 0.555 | 3.3 | 17.8 | a Median bodyweight for respective age taken from WHO database. b Unbound ropivacaine clearance c Ropivacaine unbound volume of distribution d Total ropivacaine clearance e Ropivacaine terminal half life f PPX terminal half life The simulated mean unbound maximal plasma concentration (Cumax) after a single caudal block tended to be higher in neonates and the time to Cumax (tmax) decreased with an increase in age. 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). ***Simulated mean and observed range of unbound Cu****max** **after a single caudal block*** | | | | | | | --- | --- | --- | --- | --- | | **Age group** | **Dose** | **Cumaxa** | **tmaxb** | **Cumaxc** | | | **(mg/kg)** | **(mg/l)** | **(h)** | **(mg/l)** | | 0-1m | 2.00 | 0.0582 | 2.00 | 0.05-0.08 (n=5) | | 1-6m | 2.00 | 0.0375 | 1.50 | 0.02-0.09 (n=18) | | 6-12m | 2.00 | 0.0283 | 1.00 | 0.01-0.05 (n=9) | | 1-10y | 2.00 | 0.0221 | 0.50 | 0.01-0.05 (n=60) | a Unbound maximal plasma concentration b Time to unbound maximal plasma concentration c Observed and dose-normalised unbound maximal plasma concentration At 6 months, the breakpoint for change in the recommended dose rate for continuous epidural infusion, unbound ropivacaine clearance has reached 34% and unbound PPX 71% of its mature value. The systemic exposure is higher in neonates and also somewhat higher in infants between 1 and 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 1–10 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.5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development, 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).

6.1 List of excipients Sodium chloride Hydrochloric acid (for pH adjustment) Sodium hydroxide (for pH adjustment) Water for injections6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.6.3 Shelf life **- - unopened:** 3 years **- after first opening of the container:** After first opening the product must be used immediately. **– after dilution or mixture with additives** Chemical and physical stability of mixtures with the solutions listed in section 6.6 has been demonstrated for 30 days at 30 °C. From a microbiological point of view, he product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.6.4 Special precautions for storage Do not store above 30 °C. Do not freeze.6.5 Nature and contents of container Low density polyethylene (LDPE) bottles Contents 200 ml Pack sizes: packs of 1 and 10 Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements. For single use. Discard container and any unused content after use. The medicinal product should be inspected visually before use. Only to be used if solution is clear and colourless and the container and its closure are undamaged. Ropivacaine Hydrochloride is chemically and physically compatible with the following active substances: | | | | --- | --- | | Concentration of ropivacaine: 1–2 mg/ml | | | Additive | Concentration | | Fentanyl citrate | 1-10 microgram/ml | | Morphine sulfate | 20-100 microgram/ml | | Sufentanil citrate | 0.4-4 microgram/ml |