Naropin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NAROPIN (NAROPIN)

Composition:

Active substance: ropivacaine;

1 ml of solution contains ropivacaine hydrochloride monohydrate equivalent to 2 mg, 7.5 mg, or 10 mg of ropivacaine hydrochloride;

Excipients: sodium chloride, 2M sodium hydroxide solution and/or 2M hydrochloric acid solution, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Local anesthetics. Amides.

ATC code N01B B09.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Naropin contains ropivacaine, a pure enantiomer, which is an amide-type local anaesthetic. Ropivacaine reversibly blocks impulse conduction along nerve fibres by inhibiting sodium ion transport across nerve membranes. Similar effects may also occur at excitable membranes of the brain and myocardium.

Ropivacaine has anaesthetic and analgesic effects. Surgical anaesthesia is achieved with higher doses, whereas lower doses produce sensory blockade (analgesia) accompanied by limited and non-progressive motor blockade. The duration and intensity of blockade by ropivacaine are not enhanced by the addition of adrenaline.

Pharmacodynamic effects

In vitro, ropivacaine demonstrated a lower negative inotropic effect than levobupivacaine and bupivacaine.

Assessment of cardiovascular effects in several in vivo animal studies showed that ropivacaine has lower cardiotoxicity than bupivacaine. This difference was both qualitative and quantitative.

Ropivacaine causes less QRS complex widening than bupivacaine, and changes occur at higher doses of ropivacaine and levobupivacaine than of bupivacaine.

Direct cardiovascular effects of local anaesthetics include slowed conduction, negative inotropism, and ultimately arrhythmia and cardiac arrest.

In a study in dogs where drugs were administered intravenously until cardiovascular collapse occurred, revascularization was easier and more successful after ropivacaine than after levobupivacaine and bupivacaine, despite higher plasma concentrations of free ropivacaine. This indicates a wider safety margin for ropivacaine in cases of accidental intravascular injection or overdose.

Sensitivity to systemic toxic effects of ropivacaine in pregnant sheep was no higher than in non-pregnant animals.

Healthy volunteers receiving intravenous infusions demonstrated significantly lower potential for central nervous system (CNS) toxicity and cardiovascular toxicity with ropivacaine than with bupivacaine. CNS symptoms are similar with these agents, but with bupivacaine they occur at lower doses and plasma concentrations and have a longer duration.

Indirect cardiovascular effects (arterial hypotension, bradycardia) may develop after epidural blockade, depending on the degree of associated sympathetic blockade, although this is less pronounced in children.

Rapid onset of symptoms involving the central nervous and cardiovascular systems occurs when large amounts of the drug enter the circulation (see section "Overdose").

Pharmacokinetics.

Ropivacaine has a chiral centre and is available as the pure S-(-)-enantiomer. Ropivacaine is a highly lipid-soluble compound. The pKa of ropivacaine is 8.1, and the partition coefficient is 141 (25 °C n-octanol/phosphate buffer at pH 7.4). All metabolites have local anaesthetic activity, but exhibit significantly lower potency and shorter duration of action than ropivacaine.

Absorption

Plasma concentrations of ropivacaine depend on the dose, type of block, and vascularity at the injection site. Ropivacaine demonstrates linear pharmacokinetics, meaning that maximum plasma concentration is proportional to the administered dose.

Ropivacaine shows complete and biphasic absorption from the epidural space; the half-lives of the two phases are approximately 14 minutes and 4 hours, respectively. Slow absorption is the rate-limiting factor in elimination and explains why the terminal half-life after epidural administration is longer than after intravenous administration.

Distribution

Ropivacaine is primarily bound in plasma to α1-acid glycoprotein; the unbound fraction is approximately 6%. After intravenous administration, the volume of distribution at steady state is 47 litres. During prolonged epidural infusion, increases in total plasma concentrations of ropivacaine and PPX (pipecoloxylidide) were observed, dependent on postoperative increases in α1-acid glycoprotein levels. The increase in the concentration of unbound, pharmacologically active ropivacaine in plasma was considerably smaller than the increase in total ropivacaine plasma concentration. The mean concentration of unbound PPX was approximately 7–9 times higher than the mean concentration of unbound ropivacaine after prolonged epidural infusion lasting up to 72 hours.

Ropivacaine crosses the placenta and equilibrium is reached between the mother and fetus with respect to unbound ropivacaine. Protein binding in fetal plasma is lower than in maternal plasma, resulting in lower total drug concentration in fetal plasma.

Metabolism

Ropivacaine is metabolized in the liver primarily via aromatic hydroxylation to 3-hydroxy-ropivacaine (catalyzed by cytochrome CYP1A2) and via N-dealkylation to PPX (catalyzed by cytochrome CYP3A4). PPX is an active metabolite. The threshold for CNS-toxic plasma concentrations of unbound PPX in rats is approximately 12 times higher than that for unbound ropivacaine. PPX is of minor importance after single doses but becomes the main metabolite after prolonged epidural infusion.

Excretion

Metabolites are excreted in urine. Only about 1% of a single dose of ropivacaine is excreted unchanged. Mean total plasma clearance of ropivacaine is approximately 440 ml/min, unbound clearance is 8 l/min, and renal clearance is 1 ml/min. Terminal half-life is 1.8 hours after intravenous administration, and the intermediate hepatic extraction coefficient is approximately 0.4.

Impaired renal function has little or no effect on the pharmacokinetics of ropivacaine. Renal clearance of PPX is significantly correlated with creatinine clearance. The lack of correlation between AUC values for total and unbound compound exposure and creatinine clearance indicates that total PPX clearance includes non-renal elimination in addition to renal excretion. Some patients with impaired renal function may exhibit increased PPX exposure due to low non-renal clearance. Since CNS toxicity of PPX is lower than that of ropivacaine, the clinical consequences of this during short-term treatment are considered negligible.

Use in paediatric population

Pharmacokinetics of ropivacaine are based on analysis of data from a combined patient population obtained in six studies involving 192 children aged 0 to 12 years.

During the first years of life, clearance of unbound ropivacaine and PPX depends on body weight and age. The effect of age is interpreted in relation to maturation of liver function; clearance normalized to body weight reaches a maximum at approximately 1–3 years. Unbound ropivacaine clearance increases from 2.4 l/h/kg in neonates and 3.6 l/h/kg in one-month-old infants to approximately 8–16 l/h/kg in infants aged 6 months.

In addition, the volume of distribution of unbound ropivacaine, normalized to body weight, increases with age and reaches a maximum at 2 years of age. The volume of distribution increases from 22 l/kg in neonates and 26 l/kg in one-month-old infants to 42–66 l/kg in infants aged 6 months.

The half-life of ropivacaine is longer: 5–6 hours in neonates and one-month-old infants compared to 3 hours in older children.

The half-life of PPX is even longer: approximately 43 hours in neonates and 26 hours in one-month-old infants compared to 15 hours in older children.

Due to immature liver function, systemic exposure is higher in neonates and slightly higher in infants aged 1–6 months compared to older children. Dosing recommendations for prolonged epidural infusion partially compensate for this difference.

Clinical characteristics.

Indications.

Naropin 7.5 mg/mL and 10 mg/mL

• For adults and children aged 12 years and older for anesthesia during surgical procedures:
  • epidural anesthesia for surgical procedures, including cesarean section;
  • major nerve block;
  • peripheral nerve block.

Naropin 2 mg/mL

• For adults and children aged 12 years and older for management of acute pain:
  • continuous epidural infusion or intermittent bolus injections for relief of postoperative pain or labor analgesia;
  • peripheral nerve block;
  • prolonged peripheral nerve block by continuous infusion or intermittent bolus injections, e.g., for relief of postoperative pain.
• For infants from 1 year of age and children under 12 years of age for management of acute pain (during and after surgery):
  • peripheral block with single administration of the drug.
• For neonates, infants from 1 year of age, and children under 12 years of age for caudal epidural block (during and after surgery):
  • continuous epidural infusion.

Contraindications.

Hypersensitivity to ropivacaine or to any of the excipients.

Hypersensitivity to amide-type local anesthetics.

General contraindications associated with epidural or regional anesthesia, regardless of which local anesthetic is used.

Intravenous regional anesthesia.

Paracervical anesthesia in obstetrics.

Epidural anesthesia in patients with hypovolemia.

Interaction with other medicinal products and other types of interactions.

Ropivacaine should be used with caution in combination with medicinal products structurally related to local anesthetics, i.e., Class IB antiarrhythmics such as lidocaine and mexiletine, since their toxic effects are additive. Concomitant use of Naropin with general anesthetics or opioids may potentiate adverse effects of both drugs.

Specific interaction studies between local anesthetics and Class III antiarrhythmics (e.g., amiodarone) have not been conducted, but caution is recommended when used concomitantly (see also section "Special precautions for use").

Cytochrome P450 (CYP) 1A2 is involved in the formation of 3-hydroxy-ropivacaine, the main metabolite. In in vivo conditions, plasma clearance of ropivacaine decreased by up to 77% when administered concomitantly with fluvoxamine, a selective and potent CYP1A2 inhibitor. Therefore, concomitant use of potent CYP1A2 inhibitors such as fluvoxamine and enoxacin with this drug may result in a metabolic interaction leading to increased plasma concentrations of ropivacaine. Thus, prolonged administration of ropivacaine should be avoided in patients receiving concomitant potent CYP1A2 inhibitors (see also section "Special precautions for use").

In in vivo conditions, plasma clearance of ropivacaine decreased by 15% when administered concomitantly with ketoconazole, a selective and potent CYP3A4 inhibitor. However, inhibition of this isoenzyme is unlikely to be of clinical significance.

In in vitro conditions, ropivacaine is a competitive inhibitor of CYP2D6, but it is unlikely to inhibit this isoenzyme when the drug is used at concentrations achieved in plasma under clinical conditions.

Special precautions for use.

Regional anesthesia should always be administered by experienced personnel in properly equipped premises. Equipment and medications necessary for monitoring and emergency resuscitation should be immediately available.

Patients undergoing brachial plexus nerve blocks should be in optimal condition; an intravenous catheter should be placed prior to performing the block. The responsible physician must take necessary precautions to avoid intravascular injection of the drug (see section "Administration and dosage"), and must be adequately trained and familiar with the diagnosis and treatment of adverse effects/overdose, systemic toxicity, and other complications (see sections "Side effects" and "Overdose"). One such complication is accidental injection into the subarachnoid space, which may lead to high-degree spinal block with apnea and arterial hypotension. Seizures most commonly occur after brachial plexus block or epidural block and may result either from accidental intravascular injection or from rapid absorption of the drug from the injection site.

Administration of an excessive dose into the subarachnoid space may lead to total spinal block (see section "Overdose").

Caution is required to prevent injection of the drug into inflamed areas.

When administering Naropin via intra-articular injection, caution is advised in cases of suspected recent extensive intra-articular trauma or in the presence of extensive open surfaces within the joint created during surgical procedures, as this may accelerate absorption and lead to increased plasma concentrations of the drug.

After epidural administration, strong sympathetic blockade or cranial spread of the local anesthetic may sometimes lead to Horner’s syndrome, particularly in pregnant women. Horner’s syndrome is characterized by miosis, ptosis, and anhidrosis. Symptoms resolve spontaneously after discontinuation of the drug. However, careful monitoring of patients receiving epidural anesthesia is recommended to control the potential risk of cardiorespiratory collapse due to profound sympathetic blockade.

Effects on the cardiovascular system

Epidural anesthesia may lead to arterial hypotension and bradycardia. The risk of these effects can be reduced, for example, by administration of vasoconstrictors. Arterial hypotension should be treated promptly with intravenous sympathomimetics, repeated as necessary.

Patients treated with Class III antiarrhythmic drugs (e.g., amiodarone) should be under close surveillance. Additionally, ECG monitoring should be considered in such patients due to the potential for additive cardiac effects.

Rare cases of cardiac arrest have been reported during administration of Naropin for epidural anesthesia or peripheral nerve block, particularly after unintentional accidental intravascular injection in elderly patients or patients with concomitant heart disease. In some cases, resuscitation was complicated. In the event of cardiac arrest, prolonged resuscitation measures may be required to achieve a positive outcome.

Head and neck blocks

Certain procedures involving local anesthetics, such as injections in the head and neck area, may be associated with an increased frequency of serious adverse reactions regardless of the type of local anesthetic used.

Major peripheral nerve blocks

Major peripheral nerve blocks may require large volumes of local anesthetic in highly vascularized areas, which often conceal large blood vessels, increasing the risk of intravascular injection and/or rapid systemic absorption, potentially leading to high plasma concentrations.

Hypersensitivity

Cross-sensitivity with other amide-type local anesthetics should be considered when using this drug (see section "Contraindications").

Hypovolemia

In patients with hypovolemia, sudden and severe arterial hypotension may develop during epidural anesthesia, regardless of the type of local anesthetic used and irrespective of the cause (see section "Contraindications").

Patients with compromised general health

Patients with compromised general health due to advanced age or the presence of compromising factors such as second- or third-degree atrioventricular block, progressive liver disease, or severe renal impairment require special attention, although regional anesthesia is often indicated in such patients.

Patients with hepatic or renal impairment

Ropivacaine is metabolized in the liver; therefore, the drug should be used with caution in patients with severe hepatic disease. Due to delayed elimination, reduced repeat doses may be required. Dose adjustment is generally not necessary in patients with renal impairment when the drug is used for single administration or short-term treatment.

Acidosis and reduced plasma protein concentrations, commonly observed in patients with chronic renal failure, may increase the risk of systemic toxicity.

This risk should also be considered in malnourished patients and in patients treated for hypovolemic shock.

Acute porphyria

The injectable solution of Naropin may provoke an attack of porphyria; therefore, it should be administered to patients with acute porphyria only if no safe alternative is available.

Appropriate preventive measures should be taken for susceptible patients.

Chondrolysis

Post-marketing reports have described cases of chondrolysis in patients who received prolonged infusion of the drug during intra-articular local anesthesia. In most cases, chondrolysis involved the shoulder joint. Due to the presence of several contributing factors and conflicting scientific data on the mechanism of action of ropivacaine, a causal relationship has not been established. Prolonged intra-articular infusion is not an approved route of administration for Naropin.

Excipients with known effect

This medicinal product contains no more than 3.7 mg of sodium per 1 ml. This should be taken into account for patients on a controlled sodium diet.

Long-term use

Prolonged use of ropivacaine should be avoided in patients treated with strong CYP1A2 inhibitors such as fluvoxamine and enoxacin (see section "Interaction with other medicinal products and other forms of interaction").

Children

Due to organ and functional immaturity, neonates may require special attention. Wide fluctuations in plasma ropivacaine concentrations observed during clinical trials in neonates suggest a potentially increased risk of systemic toxicity in this age group, especially during prolonged epidural infusion. Dose recommendations for neonates are based on limited clinical data. In neonates, due to delayed elimination of the drug, regular monitoring is necessary for possible systemic toxicity (e.g., by monitoring signs of CNS toxicity, ECG parameters, and peripheral oxygen saturation) and local neurotoxicity (e.g., prolonged recovery period), which should continue after the end of infusion.

Cases of administration of higher concentrations (above 5 mg/ml) of the drug to children have not been reported.

The safety and efficacy of ropivacaine at doses of 7.5 mg/ml and 10 mg/ml in children under 12 years of age have not been established.

The safety and efficacy of ropivacaine at a dose of 2 mg/ml for regional block in children under 12 years of age have not been established.

The safety and efficacy of ropivacaine at a dose of 2 mg/ml for peripheral nerve block in infants (under 1 year of age) have not been established.

Use during pregnancy or breastfeeding.

Pregnancy

Apart from data on epidural administration of the drug in obstetric practice, sufficient data on the use of the drug in pregnant women are lacking. Data from animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonic/fetal development, labor, or postnatal development.

Spinal administration of the drug during cesarean section has not been reported.

Breastfeeding. It is currently unknown whether ropivacaine passes into breast milk.

Ability to affect reaction speed when driving or operating machinery.

No data are available. Depending on the dose, local anesthetics, in addition to their direct anesthetic effect, may have minor effects on mental function and coordination, even in the absence of overt CNS toxicity, and may temporarily impair motor activity and alertness.

Administration and Dosage

Naropin should be administered only by physicians experienced in regional anesthesia, or under their supervision. To achieve an adequate degree of anesthesia, the lowest possible doses of the drug should be used.

Adults and children aged 12 years and older

The recommended doses of the drug are given below; dosage should be adjusted according to the extent of block and the patient's overall condition.

Anesthesia for surgical procedures generally requires higher doses and higher concentrations than analgesia for management of acute pain, for which a concentration of 2 mg/mL is usually recommended. However, for intra-articular injections, a concentration of 7.5 mg/mL is recommended.

Table 1.

Adults and children aged 12 years and older

The doses listed in Table 1 are required to achieve clinically acceptable nerve block; they should be considered as recommended doses for adults.

There are considerable individual variations in the onset time and duration of effect.

1. The dose for nerve plexus block should be adjusted according to the site of drug administration and the patient's condition. An increased incidence of serious adverse reactions is possible with intercostal block and supraclavicular brachial plexus block regardless of the type of local anesthetic used (see also section "Special precautions").
2. When administering additional doses of ropivacaine by any other technique to the same patient, the total dose should not exceed 225 mg.
3. Since marketing authorization, cases of chondrolysis have been reported in patients receiving prolonged infusion for intra-articular local anesthesia. Prolonged intra-articular infusion is not an approved route of administration for this drug.

It is essential to exercise particular caution to prevent accidental intravascular injections. Aspiration test should be carefully performed before and during injection of the total dose. The total dose should be administered slowly at a rate of 25–50 mg/min or in divided doses, with continuous monitoring of the patient's condition. For epidural administration, it is recommended to administer a test dose of 3–5 mL of lidocaine with adrenaline. Accidental intravascular injection may cause, for example, transient increase in heart rate, while accidental intrathecal injection may lead to signs of spinal block. If symptoms of intoxication occur, administration of the drug should be immediately discontinued.

For surgical procedures, single epidural doses up to 250 mg of ropivacaine have been well tolerated.

With brachial plexus block by administration of 40 mL of Naropin at a concentration of 7.5 mg/mL, maximum plasma concentrations of ropivacaine in some patients may approach levels at which mild symptoms of central nervous system (CNS) toxicity have been described. Therefore, doses exceeding 40 mL of Naropin at a concentration of 7.5 mg/mL (300 mg ropivacaine) are not recommended.

When performing prolonged infusions or repeated bolus injections, the risk of achieving toxic plasma concentrations or local nerve injury should be considered. Total doses of up to 675 mg of ropivacaine administered within 24 hours have been well tolerated in adult patients during anesthesia for surgery and for postoperative pain management. Good tolerability has also been observed in adults receiving prolonged epidural infusions after surgery for up to 72 hours at infusion rates of up to 28 mg/hour. In a limited number of patients, administration of higher doses (up to 800 mg/day) was associated with a relatively low incidence of adverse reactions.

Postoperative pain management. Blockade is performed before surgery by administration of Naropin 10 mg/mL or 7.5 mg/mL, or after surgery by epidural bolus injection of Naropin 7.5 mg/mL. Analgesia is maintained by epidural infusion of Naropin 2 mg/mL. Clinical studies have shown that an infusion rate of 6–14 mL (12–28 mg) per hour generally provides adequate anesthesia for moderate to severe postoperative pain, with only mild and non-progressive motor block observed in most cases. The maximum duration of epidural blockade is 3 days. However, careful monitoring of analgesic effect should be performed so that the catheter can be removed as soon as the pain condition allows. This technique allows a significant reduction in the need for additional opioid analgesics.

Clinical studies have also been conducted in which Naropin at a concentration of 2 mg/mL was administered alone or in combination with fentanyl (1–4 mcg/mL) as an epidural infusion for 72 hours for postoperative analgesia. Naropin 2 mg/mL (6–14 mg/hour) provided adequate pain relief in most patients. The combination of Naropin with fentanyl provided better analgesia but was associated with undesirable opioid-related effects.

For cesarean section, epidural use of ropivacaine at concentrations above 7.5 mg/mL or spinal administration has not been documented.

When performing prolonged peripheral nerve blockade via continuous infusion or repeated injections, the risk of achieving toxic drug concentrations in plasma or causing local neurological injury should be considered. In clinical studies, femoral nerve block prior to surgery was achieved by administration of 300 mg of Naropin at a concentration of 7.5 mg/mL, and intercostal block by administration of 225 mg of Naropin at a concentration of 7.5 mg/mL. Subsequently, analgesia was maintained with Naropin 2 mg/mL. Infusion rates or intermittent injections of 10–20 mg per hour over 48 hours provided sufficient analgesia and were well tolerated.

Children under 12 years of age

Table 2.

Children under 12 years of age

a) For thoracic epidural blocks, doses at the lower end of the dosage range are recommended, whereas for lumbar or caudal epidural blocks, doses at the upper end of the dosage range are recommended.

b) Recommended for lumbar epidural blocks.

When administering the drug to children, the doses listed in Table 2 should be considered as guidelines. Individual variations may occur. Children with excessive body weight often require dose reduction based on ideal body weight. The volume of drug for a single caudal epidural block and the volume of drug administered as bolus doses for epidural block should not exceed 25 ml for any patient.

The use of ropivacaine at concentrations of 7.5 and 10 mg/ml in children may lead to systemic toxic effects and central nervous system toxicity. Therefore, for administration to such patients, the lowest concentration of the drug (2 mg/ml) is more appropriate.

Guidelines for dosing ropivacaine for peripheral nerve blocks in infants and children represent a methodological basis for use in pediatric patients without serious comorbidities. In children with serious underlying conditions, lower doses are recommended, along with careful monitoring.

The use of ropivacaine in preterm neonates has not been documented.

It is essential to exercise greater caution to prevent accidental intravascular injections. Aspiration should be carefully performed before and during injection of the total dose. Vital signs must be closely monitored during drug administration. If signs of toxicity occur, administration of the drug should be immediately discontinued.

When using calculated doses, fractionation of the total dose is recommended regardless of the route of administration.

Caudal epidural injection of ropivacaine at a concentration of 2 mg/ml provides adequate postoperative analgesia below the T12 level in most children when a dose of 2 mg/kg is administered at a volume of 1 ml/kg. The volume of caudal epidural injection may be adjusted to achieve control over the spread of sensory block. Doses of up to 3 mg/kg of ropivacaine at a concentration of 3 mg/ml have been safely used in children aged 4 years and older.

Experience with caudal blocks in children with body weight exceeding 25 kg is limited.

Children

The drug is used in pediatric practice.

Overdose

Toxicity

Seizures have been observed following accidental intravascular injections during brachial plexus blockade and other peripheral nerve blocks.

Systemic toxicity is not expected after spinal administration, as low doses of the drug are used in this case. Intrathecal administration of a very high dose may lead to total spinal block, resulting in severe cardiovascular depression and respiratory failure.

Symptoms

Systemic toxic reactions primarily involve the central nervous system (CNS) and the cardiovascular system. These reactions are caused by high blood concentrations of local anesthetics, which may result from accidental intravascular injection, overdose, or exceptionally rapid absorption from highly vascularized areas (see also section "Special precautions").

CNS symptoms are similar for all amide-type local anesthetics, whereas cardiac symptoms vary more significantly in both quantitative and qualitative terms depending on the specific agent.

Accidental intravascular injections of local anesthetics may cause immediate (within seconds to minutes) systemic toxic reactions. In cases of overdose, systemic toxicity manifests later (15–60 minutes after injection) due to a slower rise in plasma concentration of the local anesthetic.

Treatment

If signs of acute systemic toxicity occur, administration of local anesthetics should be immediately discontinued, and treatment should focus on rapid control of CNS symptoms (seizures and CNS depression) to maintain adequate ventilation, oxygenation, and circulation. Oxygen should always be administered, and artificial ventilation should be performed if necessary. If seizures do not cease spontaneously within 15–20 seconds, intravenous thiopental sodium at a dose of 1–3 mg/kg should be administered to ensure adequate ventilation, or intravenous diazepam at 0.1 mg/kg (which acts more slowly). Prolonged seizures threaten the patient's respiration and oxygenation. Administration of a muscle relaxant (e.g., succinylcholine 1 mg/kg) may create more favorable conditions for ensuring adequate ventilation and oxygenation, but requires experience in tracheal intubation and artificial ventilation.

In the event of circulatory arrest, cardiopulmonary resuscitation should be initiated immediately. Maintaining adequate oxygenation, ventilation, circulation, and correction of acidosis are crucial.

In cases of cardiac depression (hypotension/bradycardia), appropriate treatment should be considered, including intravenous fluid administration, vasopressors (e.g., intravenous ephedrine 5–10 mg, repeatable every 2–3 minutes), and/or inotropes.

In cardiac arrest, successful resuscitation may require prolonged resuscitation efforts.

When treating symptoms of toxicity in children, doses appropriate to the child's age and body weight should be used.

Adverse reactions.

The adverse effect profile of Naropin is similar to that of other long-acting amide-type local anesthetics. A large number of symptoms have been reported during clinical trials, which may develop independently of the type of local anesthetic used and often represent physiological effects resulting from nerve blockade and the clinical situation. Adverse effects caused by the medicinal product are difficult to distinguish from physiological effects due to nerve and sympathetic blockade, as well as phenomena directly related to needle puncture (e.g., spinal hematoma, post-dural puncture headache, meningitis, and epidural abscess). Many of the most commonly reported adverse reactions, such as nausea, vomiting, and arterial hypotension, are very frequently observed during anesthesia and surgical procedures; these adverse reactions arising from the clinical situation cannot be clearly distinguished from those caused by the administration of the medicinal product or resulting from the performance of the block.

Adverse reactions are listed in Table 3.

Adverse reactions are presented by system organ class with the following frequency categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); and not known (cannot be estimated from available data).

Table 3.

Adverse reactions during perineural and epidural administration of the drug.

*These symptoms usually occur as a result of accidental intravascular injection, overdose, or rapid absorption (see also section "Overdose").

aArterial hypotension is less common in children (> 1/100).

bVomiting is very common in children (> 1/10).

Adverse reactions related to the drug class

The adverse reactions listed below include complications associated with the technique of anesthesia, regardless of the type of local anesthetic used.

Neurological complications

Neuropathy and spinal cord dysfunction (e.g., anterior spinal artery syndrome, arachnoiditis, cauda equina syndrome), which may rarely lead to irreversible consequences, have been associated with spinal and epidural anesthesia irrespective of the type of local anesthetic used.

Total spinal block

Total spinal block may develop following accidental intrathecal injection of an epidural dose or administration of a very high spinal dose of the drug. Effects of systemic overdose and accidental intravascular injections may be serious (see section "Overdose").

Acute systemic toxicity

Systemic toxic reactions primarily involve the central nervous system and cardiovascular system. These reactions are caused by high blood concentrations of local anesthetics, which may result from accidental intravascular injection, overdose, or exceptionally rapid absorption from highly vascularized areas (see also section "Special warnings and precautions for use").

Symptoms affecting the CNS are similar for all amide-type local anesthetics, whereas cardiac symptoms depend more on the type of drug, both quantitatively and qualitatively.

Toxic effects on the central nervous system

Toxic effects on the central nervous system (CNS) manifest as a stepwise reaction, with symptoms and signs increasing in severity. Initial symptoms include mild dizziness, perioral paresthesia, tongue numbness, hyperacusis, tinnitus, and visual disturbances. Dysarthria, muscle rigidity, and muscle twitching are more serious symptoms and may herald generalized seizures. These signs should not be mistaken for neurotic behavior. This may be followed by loss of consciousness and a generalized tonic-clonic seizure lasting from several seconds to several minutes. During seizures, hypoxia and hypercapnia develop rapidly due to increased muscular activity, inadequate ventilation, and possible worsening of respiratory function. In severe cases, respiratory arrest may even occur. Development of acidosis, hyperkalemia, hypocalcemia, and oxygen deficiency increases and prolongs the toxic effects of local anesthetics.

Recovery depends on the metabolism and redistribution of the local anesthetic away from the CNS. This occurs rapidly, except when the drug has been administered in very large amounts.

Toxic effects on the cardiovascular system

Toxic effects on the cardiovascular system usually lead to more serious situations. High systemic concentrations of local anesthetics may result in arterial hypotension, bradycardia, arrhythmias, and even cardiac arrest. In volunteers, intravenous infusion of ropivacaine resulted in signs of conduction and contractility depression.

Signs of developing CNS toxicity usually precede cardiovascular toxicity. Prodromal CNS symptoms may not occur in patients receiving the drug for general anesthesia or those under the influence of potent sedatives such as benzodiazepines or barbiturates.

Children

The frequency, type, and severity of adverse effects in children are expected to be similar to those in adults, except for arterial hypotension, which is less common in children (< 1/10), and vomiting, which is more common in children (> 1/10).

Early signs of local anesthetic systemic toxicity are usually difficult to detect in children, as they are unable to describe such symptoms (see also section "Special warnings and precautions for use").

In children, nerve blocks are frequently performed under general anesthesia; therefore, careful monitoring for early signs of toxicity is essential in this patient group.

Treatment of acute systemic toxicity

See section "Overdose".

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years. The product from an opened container (100 ml) may be used within 24 hours.

Storage conditions. Store at temperatures not exceeding 30 °C. Do not freeze. Keep out of reach of children.

Instructions for use and handling

Naropin, injection solution, contains no preservatives and is intended for single use only. Any unused solution should be discarded. An opened infusion bag may be used within 24 hours. Unopened packages should not be re-sterilized by autoclaving. If sterile outer surfaces of ampoules or infusion bags are required, blister packs should be selected.

Naropin, injection solution in containers (Polybag®), is chemically and physically compatible with the following drugs:

The mixtures are chemically and physically stable for 30 days at temperatures not exceeding 30 °C. When the mixture is prepared at the bedside, it should be used immediately due to the risk of microbial contamination. When the mixture is prepared on a LAF bench in a clean area, it can be stored for up to 24 hours at 2−8 °C. When prepared according to methods validated under GMP, the storage period should be adjusted according to the results of physico-chemical stability and microbiological purity testing.

Incompatibilities. Alkalinization of the solution may cause precipitation, as ropivacaine is poorly soluble at pH above 6.0.

Packaging. For 2 mg/mL – 100 mL in a container, 1 container in a blister pack, 5 blister packs in a cardboard box.

For 7.5 mg/mL and 10.0 mg/mL – 10 mL in an ampoule, 1 ampoule in a blister pack, 5 blister packs in a cardboard box.

Prescription status. Prescription only.

Manufacturer. For 2 mg/mL – AstraZeneca Pty Ltd.

For 7.5 mg/mL or 10.0 mg/mL – AstraZeneca AB.

Manufacturer's location and address of the place of business.

For 2 mg/mL – 10-14 Cambridge Road, North Ryde, New South Wales 2113, Australia.

For 7.5 mg/mL or 10.0 mg/mL – Forskargatan 18, Södertälje, 151 36, Sweden.