Naropin

(See Table 1.)

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The pH of the solution is adjusted to 4.0-6.0 with sodium hydroxide or hydrochloric acid and the solution is free from preservatives. The solutions are intended for single use only.
Excipients/Inactive Ingredients: Sodium chloride, Hydrochloric Acid, Sodium Hydroxide, water for injections.

Pharmacotherapeutic group: (ATC Code): N01B B09.
Pharmacology: Pharmacodynamics: Ropivacaine is a long-acting, amide-type local anaesthetic with both anaesthetic and analgesic effects. At high doses, it produces surgical anaesthesia, while at lower doses, it produces sensory block (analgesia) with limited and nonprogressive motor block.
Onset and duration of the local anaesthetic effect of Naropin depend on the dose and site of administration, while presence of vasoconstrictor (e.g. adrenaline) has little, if any influence.
Ropivacaine, like other local anaesthetics, causes reversible blockade of impulse propagation along nerve fibres by preventing the inward movement of sodium ions through the cell membrane of the nerve fibres.
Local anaesthetics may have similar effects on other excitable membranes e.g. in the brain and myocardium. If excessive amounts of drug reach the systemic circulation, symptoms and signs of toxicity may appear, emanating from the central nervous and cardiovascular systems.
Cardiac effects measured in vivo in animal studies showed that ropivacaine has a lower cardiac toxicity than bupivacaine.
Pregnant ewes showed no greater sensitivity to systemic toxic effects of ropivacaine than non-pregnant ewes.
Healthy volunteers exposed to intravenous infusions of CNS toxic doses showed significantly less cardiac effects after ropivacaine than after bupivacaine.
Indirect cardiovascular effects (hypotension, bradycardia) may occur after epidural administration, depending on the extent of the concomitant sympathetic block.
Pharmacokinetics: Ropivacaine has a chiral centre and is pure S-(-)-enantiomer. It has a pK_a of 8.1 and a distribution ratio of 141 (25°C n-octanol/phosphate buffer pH 7.4). The metabolites has a pharmacological activity that is less than that of ropivacaine.
The plasma concentration of ropivacaine depends on the dose, route of administration and vascularity of the injection site. Ropivacaine follows linear pharmacokinetics and the maximum plasma concentration 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. 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 has a mean total plasma clearance of the order of 440 ml/min, an unbound plasma clearance of 8 l/min, a renal clearance of 1 ml/min, a volume of distribution at steady-state of 47 l and a terminal half-life of 1.8 h after i.v. administration. Ropivacaine has an intermediate hepatic extraction ratio of about 0.4. It is mainly bound to α₁-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 α₁-acid glycoprotein. Variations in unbound i.e pharmacologically active, concentration have been much less than in total plasma concentration.
Ropivacaine readily crosses the placenta and equilibrium in regard to unbound concentration is 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.
Ropivacaine is extensively metabolised in the liver, predominantly by aromatic hydroxylation to 3-hydroxy-ropivacaine mediated by cytochrome P4501A2, and N-dealkylation to PPX mediated by CYP3A4. After single intravenous administration approximately 37% of the total dose is excreted in the urine as both free and conjugated 3-hydroxy-ropivacaine, the major metabolite. Low concentrations of 3-hydroxy-ropivacaine have been found in the plasma. Urinary excretion of the PPX and other metabolites account for less than 3% of the dose.
During epidural infusion, both PPX and 3-hydroxy-ropivacaine are the major metabolites excreted in the urine. Total PPX concentration in the plasma was about half of that of total ropivacaine, however, mean unbound concentrations of PPX was about 7 to 9 times higher than that of unbound ropivacaine following continuous epidural infusion up to 72 hours. The threshold for central nervous system (CNS)-toxic unbound plasma concentration of PPX in rats is about twelve times higher than that of unbound ropivacaine.
Impaired renal function has little or no influence on ropivacaine pharmacokinetics. The renal clearance of PPX is significantly correlated 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.
There is no evidence of in vivo racemization of ropivacaine.

Surgical Anaesthesia: Epidural block for surgery, including caesarean section; major nerve block; field block.
Acute Pain Management: Continuous epidural infusion or intermittent bolus administration e.g. postoperative or labour pain; field block.

Naropin should only be used by or under the supervision of clinicians experienced in regional anaesthesia.
Adults and children above 12 years of age: The following table is a guide to dosage for the more commonly used blocks. The clinician's experience and knowledge of the patient's physical status are of importance when deciding the dose.
In general, surgical anaesthesia (e.g. epidural administration) requires the use of the higher concentrations and doses. For analgesia, 2 mg/mL concentration of Naropin is generally recommended. (See Table 2.)

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In order to avoid intravascular injection, aspiration should be repeated prior to and during administration of the main dose, which should be injected slowly or in incremental doses, at a rate of 25-50 mg/min, while closely observing the patient's vital functions and maintaining verbal contact. When an epidural dose is injected, a preceding test dose of 3-5 ml lidocaine (Xylocaine 1-2%) with adrenaline is recommended. An inadvertent intravascular injection may be recognized by a temporary increase in heart rate and an accidental intrathecal injection by signs of a spinal block. If toxic symptoms occur, the injection should be stopped immediately.
In epidural block for surgery, single doses of up to 250 mg ropivacaine have been used and are well-tolerated.
When prolonged epidural 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 800 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/hr for 72 hours.
For treatment of postoperative pain, the following technique can be recommended: Unless preoperatively instituted, an epidural block with Naropin 7.5 mg/ml is induced via an epidural catheter. Analgesia is maintained with Naropin 2 mg/ml infusion. Clinical studies have demonstrated that infusion rates of 6-14 ml (12-28 mg) per hour provide adequate analgesia with only slight and nonprogressive motor block in most cases of moderate to severe postoperative pain. With this technique, a significant reduction in the need for opioids has been observed.
In clinical studies, an epidural infusion of Naropin 2 mg/ml alone or mixed with fentanyl 1-4 μ/mL has been given for postoperative pain management for up to 72 hours. Naropin 2 mg/mL (6-14 ml/hour) provided adequate pain relief for the majority of patients. The combination of Naropin and fentanyl provided improved pain relief but caused opioid side effects.
For caesarean section, neither intrathecal administration nor the use of the ropivacaine concentration 10 mg/ml for epidural administration, have been documented.
Until further experience has been gained. Naropin cannot be recommended for use in children below the age of 12 years.

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 Precautions).
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, systemic toxicity appears later (15-60 minutes after injection) due to the slower increase in local anaesthetic blood concentration.
Central nervous system toxicity is a graded response with symptoms and signs of escalating severity. The first symptoms are usually lightheadedness, circumolar paraesthesia, numbness of the tongue, hyperacusis, tinnitus, and visual disturbances. Dysarthria, muscular twitching or tremors are more serious and precede the onset of generalized 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, apnoea may occur. The acidosis increases and extends the toxic effects of local anaesthetics.
Recovery follows the redistribution of the local anaesthetic drug from the CNS and subsequent metabolism and excretion. Recovery may be rapid unless large amounts of the drug have been injected.
Cardiovascular toxicity indicates a more severe situation and is 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. Hypotension, bradycardia, arrhythmia and even cardiac arrest may occur as a result of high systemic concentrations of local anaesthetics.
Treatment of Acute Systemic Toxicity: If signs of acute systemic toxicity appear, injection of the local anaesthetic should be stopped immediately.
In the event of convulsions, treatment will be required. The objectives of treatment are to maintain oxygenation, stop the convulsions and support the circulation. Oxygen must be given and ventilation assisted, when necessary (mask and bag or tracheal intubation). An anticonvulsant should be given i.v. if the convulsions do not stop spontaneously in 15-20 seconds. Thiopentone sodium 1-3 mg/kg i.v. will abort the convulsions rapidly. Alternatively diazepam 0.1 mg/kg i.v. may be used, although its action will be slow. Prolonged convulsions may jeopardize the patient's ventilation and oxygenation. If so, injection of a muscle relaxant (e.g. succinylcholine 1 mg/kg) will rapidly stop the convulsions so that ventilation and oxygentation can be controlled. Endotracheal intubation must be considered in such situations.
If cardiovascular depression is evident (hypotension, bradycardia), ephedrine 5-10 mg i.v. should be given and this dose should be repeated, if necessary, after 2-3 minutes.
Should circulatory arrest 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, prolonged resuscitative efforts may be required to improve the possibility of a successful outcome.

Naropin solutions are contraindicated in patients with hypersensitivity to local anaesthetics of the amide-type.

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 optimal condition and have an i.v. line inserted before the blocking procedure. The clinician responsible should take the necessary precautions to avoid intravascular injection (see Dosage & Administration) and be appropriately trained and familiar with diagnosis and treatment of side effects, systemic toxicity and other complications. (See Overdosage.)
Major peripheral nerve blocks may imply the administration of a large volume of local anaesthetic in highly vascularized 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 aging 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 the optimal anaesthetic technique in these patients. Patients treated with anti-arrhythmic drugs class III (e.g. amiodarone) should be under close surveillance and consider ECG monitoring, since cardiac effects may be additive.
There have been rare reports of cardiac arrest during the use of Naropin for epidural anaesthesia or peripheral nerve blockade, especially after unintentional accidental intravascular administration in elderly patients and in patients with concomitant heart disease. In some instances, resuscitation has been difficult. Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the possibility of a successful outcome.
Ropivacaine is metabolised in the liver. It should therefore be used with caution in patients with severe liver disease and 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.
Epidural anaesthesia may lead to hypotension and bradycardia. The risk of such effects can be reduced e.g. by preloading the circulation or by injecting a vasopressor. Hypotension should be treated promptly with for example ephedrine 5-10 mg intravenously, repeated as necessary.
Prolonged administration of ropivacaine should be avoided in patients treated with strong inhibitors of CYP1A2 such as fluvoxamine and enoxacin (see Interactions).
Naropin solution for injection and infusion is possibly with acute porphyria where no safer alternative is available. Appropriate precautions should be taken in the case of the vulnerable patients.
There have been post-marketing reports of chondrolysis in patients receiving post-operative intra-articular continuous infusion or local anesthetics. The majority of reported cases of chondrolysis have involved the shoulder joint.
Due to multiple contributing factors and inconsistency in the scientific literature regarding mechanism of action, casuality has not been established. Intra-articular continous infusion is not an approved indication for Naropin.
Effects on ability to drive and use machines: Besides the direct anaesthetic effect, local anaesthetics may have a very mild effect on mental function and coordination even in the absence of overt CNS toxicity and may temporarily impair locomotion and alertness.

Use in Pregnancy: Apart from obstetrical use, there are no adequate data on the use of ropivacaine in pregnancy. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.
Use in Lactation: The excretion of ropivacaine or its metabolites in human milk has not been studied. Based on the milk/plasma concentration ratio in rats, the estimated daily dose to a pup will be about 4% of the dose given to the mother. Assuming that the milk/plasma concentration ratio in humans is of the same order, the total ropivacaine dose to which the baby is exposed by breastfeeding is far lower than by exposure in utero in pregnant women at term.

General: The adverse reaction profile for Naropin is similar to that of other amide local anaesthetics. Adverse reactions caused by the drug per se are difficult to distinguish from the physiological effects of the nerve block (eg, decrease in blood pressure, bradycardia), events caused directly (eg, nerve trauma) or indirectly (eg, epidural abscess) by needle puncture. (See Table 3.)

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Class-related adverse drug reactions: This section includes complications related to anaesthetic technique regardless of the local anaesthetic used.
Neurological Complications: Neuropathy and spinal cord dysfunctions (e.g. anterior spinal artery syndrome, arachnoiditis, cauda equina) have been associated with epidural anaesthesia.
Total Spinal Block: Total spinal block may occur if an epidural dose is inadvertently administered intrathecally.

Naropin 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. Specific interaction studies with ropivacaine and anti-arrhythmic drugs class III (e.g. amiodarone) have not been performed, but caution is advised. (See Precautions.)
In healthy volunteers, ropivacaine clearance was reduced by up to 77% during co-administration of fluvoxamine, a potent competitive inhibitor of P4501A2.
CYP1A2 is involved in the formation of 3-hydroxy-ropivacaine, a major metabolite. Thus, strong inhibitors of CYP1A2, such as fluvoxamine and enoxacin, given concomitantly with Naropin, can cause metabolic interaction leading to an increased ropivacaine plasma concentration. Prolonged administration of ropivacaine should therefore be avoided in patients treated with strong inhibitors of CYP1A2 such as fluvoxamine and enoxacin (see Precautions).

Instructions for use and handling: Naropin is free from preservatives and is intended for single use only. Any solution remaining from an opened container should be discarded.
The intact container must not be re-autoclaved. A blister container should be chosen when a sterile exterior is required.
Incompatibilities: Alkalisation may lead to precipitation since ropivacaine is poorly soluble above pH 6.0.

Do not store above 30°C. Do not freeze.

Anaesthetics - Local & General

N01BB09 - ropivacaine ; Belongs to the class of amides. Used as local anesthetics.

P₁S₁S₃