Ropilong
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROPILOG (ROPILONG)
Composition:
Active substance: ropivacaine;
1 ml of solution contains 10.58 mg of ropivacaine hydrochloride monohydrate, equivalent to 10 mg of ropivacaine hydrochloride;
Excipients: sodium chloride, hydrochloric acid concentrated, sodium hydroxide, water for injections.
Pharmaceutical form. Injection solution.
Main physicochemical properties: clear, colorless liquid.
Pharmacotherapeutic group. Local anesthetics. Amides.
ATC code N01B B09.
Pharmacological properties.
Pharmacodynamics.
Mechanism of action. Ropivacaine is a pure enantiomer and a local anaesthetic of the amide type, which has both anaesthetic and analgesic effects. Surgical anaesthesia is achieved with higher doses, whereas lower doses produce sensory blockade (analgesia) with limited and non-progressive motor blockade.
The mechanism of action involves reversible reduction of the membrane permeability of the nerve fibre to sodium ions. As a result, the rate of depolarisation decreases and the threshold of excitability increases. This ultimately leads to local blockade of nerve impulses.
The onset time and duration of local anaesthesia depend on the site of administration. The duration of action cannot be prolonged by the addition of vasoconstrictors (e.g., adrenaline [epinephrine]). For further details, see Table 1 in the section "Dosage and administration".
Pharmacodynamic effects. In vitro, ropivacaine showed a lower negative inotropic effect than levobupivacaine and bupivacaine.
Assessment of the effects on cardiac function, performed in vivo in several animal studies, demonstrated 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 in which the drugs were administered intravenously until cardiovascular collapse occurred, revascularisation was easier and more successful after ropivacaine than after levobupivacaine and bupivacaine, despite higher free plasma concentrations of ropivacaine. This indicates a wider safety margin for ropivacaine in the case of accidental intravascular injection or overdose.
Sensitivity to the systemic toxic effects of ropivacaine in pregnant sheep was no higher than in non-pregnant animals.
Healthy volunteers tolerated intravenous administration of ropivacaine at maximum tolerated doses very well, with expected central nervous system (CNS) symptoms, and a significantly lower potential for CNS and cardiovascular toxicity was demonstrated compared to bupivacaine. CNS symptoms are similar with administration of 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 concomitant sympathetic blockade, although this is less pronounced in children.
Rapid onset of symptoms in the central nervous and cardiovascular systems occurs when a large amount of the drug enters the bloodstream (see section "Overdose").
Clinical experience with this medicinal product indicates a wide therapeutic range when used at recommended doses.
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 are significantly less potent and have a shorter duration of action than ropivacaine.
Absorption
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. The slow absorption is the rate-limiting factor for elimination of ropivacaine and explains why the terminal half-life after epidural administration is longer than after intravenous administration.
Distribution
The mean value of total plasma clearance of ropivacaine is about 440 ml/min, renal clearance is 1 ml/min, the volume of distribution at steady state is 47 litres, and the terminal half-life is 1.8 hours after intravenous administration. The intermediate hepatic extraction ratio is approximately 0.4.
Ropivacaine is predominantly bound in plasma to α1-acid glycoprotein; the unbound fraction is approximately 6%.
After intravenous administration, the volume of distribution of ropivacaine at steady state is 47 litres. After prolonged epidural infusion, an increase in total plasma concentrations of ropivacaine and PPX (pipecoloxylidide) was observed, dependent on the postoperative increase 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 plasma ropivacaine 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 pregnant woman and the foetus with regard to unbound ropivacaine. The extent of plasma protein binding in the foetus is lower than in the pregnant woman, resulting in lower total drug concentration in foetal plasma.
Metabolism
Ropivacaine is metabolised in the liver primarily by aromatic hydroxylation to 3-hydroxy-ropivacaine (catalysed by cytochrome CYP1A2) and by N-dealkylation to PPX (catalysed 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 a metabolite of minor importance after single doses, but after prolonged epidural infusion it becomes the main metabolite.
Elimination
Ropivacaine has intermediate and low hepatic clearance. Therefore, its elimination rate should depend on the plasma concentration of unbound fractions. The postoperative increase in alpha 1-acid glycoprotein leads to a reduction in the unbound fraction due to increased protein binding. As demonstrated in studies in children and adults, this results in reduced total clearance, causing an increase in total plasma concentration. The clearance of unbound ropivacaine remains unchanged, as evidenced by stable concentrations of the unbound fraction during postoperative infusions. Therefore, pharmacodynamic effects and toxicity are related to the unbound fraction in plasma.
After intravenous administration, 86% of the dose is excreted in urine, of which only about 1% is unchanged. The main metabolite is 3-hydroxy-ropivacaine (approximately 37%), which is excreted mainly in urine as a conjugate. Excretion of 4-hydroxy-ropivacaine, the N-dealkylated metabolite (PPX), and 4-hydroxy-dealkylated metabolite is approximately 1–3% of the dose. Conjugated and unconjugated 3-hydroxy-ropivacaine are present in plasma at concentrations that are easily detectable.
A similar metabolite profile was observed in children aged 1 year and older.
Renal impairment 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 total exposure, expressed as AUC, and creatinine clearance indicates that, in addition to renal excretion, total clearance of PPX includes non-renal elimination. Some patients with impaired renal function may have increased PPX exposure due to reduced non-renal elimination. Since the CNS toxic effect of PPX is lower than that of ropivacaine, the clinical consequences of this effect during short-term treatment are considered insignificant. Studies in patients with end-stage renal disease undergoing regular dialysis have not been conducted.
Use in paediatric practice
The pharmacokinetics of ropivacaine are based on the analysis of pooled data from a patient population obtained during six studies involving 192 children aged 0 to 12 years.
In 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 hepatic function maturation; clearance normalised to body weight reaches a maximum at approximately 1–3 years. Clearance of unbound ropivacaine increases from 2.4 L/h/kg in neonates and 3.6 L/h/kg in 1-month-old infants to approximately 8–16 L/h/kg in children aged 6 months.
In addition, the volume of distribution of unbound ropivacaine, normalised to body weight, increases with age and reaches a maximum at 2 years of age. The volume of distribution of unbound ropivacaine increases from 22 L/kg in neonates and 26 L/kg in 1-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 1-month-old infants compared to 3 hours in older children.
The half-life of PPX is even longer: about 43 hours in neonates and 26 hours in 1-month-old infants compared to 15 hours in older children.
Due to immaturity of liver function, systemic exposure is higher in neonates and slightly higher in infants aged 1–6 months compared to older children. Dosage recommendations for prolonged epidural infusion partially compensate for this difference.
Clinical characteristics.
Indications.
Ropilong 7.5 mg/mL and 10 mg/mL is indicated in 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.
Contraindications.
- Hypersensitivity to ropivacaine or to any of the excipients;
- hypersensitivity to other amide-type local anesthetics;
- general contraindications associated with epidural or regional anesthesia, regardless of which local anesthetic is used;
- do not use for intravenous regional anesthesia;
- do not use for paracervical anesthesia in obstetrics;
- do not use for epidural anesthesia in patients with hypovolemia.
Interaction with other medicinal products and other forms of interaction.
Ropilong should be used with caution when administered concomitantly with drugs structurally related to local anesthetics, i.e., class IB antiarrhythmics such as lidocaine and mexiletine, since their toxic effects are additive. Concomitant administration of Ropilong with general anesthetics or opioids may potentiate the adverse effects of both agents.
Specific interaction studies between ropivacaine and class III antiarrhythmics (e.g., amiodarone) have not been conducted, but caution is recommended when co-administering (see also section "Special precautions for use").
Cytochrome P450 (CYP) 1A2 is involved in the formation of 3-hydroxy-ropivacaine, the major metabolite. In vivo, plasma clearance of ropivacaine was reduced by up to 77% when administered concomitantly with fluvoxamine, a selective and potent inhibitor of CYP1A2. Therefore, concomitant administration of potent CYP1A2 inhibitors such as fluvoxamine and enoxacin with ropivacaine 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 vivo, plasma clearance of ropivacaine was reduced by 15% when administered concomitantly with ketoconazole, a selective and potent inhibitor of CYP3A4. However, inhibition of this isoenzyme is unlikely to be of clinical significance.
In vitro, ropivacaine is a competitive inhibitor of CYP2D6, but it is unlikely to inhibit this isoenzyme at clinically achieved plasma concentrations.
Special precautions for use.
Regional anesthesia should always be administered by experienced personnel in a properly equipped facility. Equipment and medications necessary for monitoring and emergency resuscitation must be readily available.
Patients undergoing brachial plexus nerve block should be in optimal condition; an intravenous catheter should be inserted prior to performing the block. The responsible physician must take appropriate precautions to avoid intravascular injection of the drug (see section "Method of 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, which 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").
Care must be taken to avoid injecting the drug into inflamed tissues.
When administering Ropilong by intra-articular injection, caution is advised if recent extensive intra-articular trauma is suspected or if extensive open surfaces are present in the joint from surgical procedures, as this may accelerate absorption and lead to increased plasma concentrations of the drug.
Effect 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 receiving class III antiarrhythmic drugs (e.g., amiodarone) should be closely monitored. Furthermore, ECG monitoring may be required due to possible additive cardiac effects.
Rare cases of cardiac arrest have been reported during administration of ropivacaine for epidural anesthesia or peripheral nerve block, particularly after unintentional accidental intravascular injection in elderly patients and patients with concomitant heart disease. In some cases, resuscitation was difficult. In the event of cardiac arrest, prolonged resuscitation measures may be required to achieve a positive outcome.
Head and neck blocks
Certain procedures with 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 vessels, where there is an increased 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 undergoing epidural anesthesia, sudden and severe arterial hypotension may develop regardless of the type of local anesthetic used and for any reason (see section "Contraindications").
Patients with compromised general health
Patients with compromised general health due to advanced age or presence of compromising factors such as partial or complete 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 liver disease: due to slowed elimination, repeated doses may need to be reduced. Dose adjustment is generally not required 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, increase the risk of systemic toxicity.
This risk should also be considered if the patient's nutrition is inadequate or if the patient has been treated for hypovolemic shock.
Acute porphyria
Ropilong, solution for injection or infusion, may provoke porphyria; therefore, it should be prescribed to patients with acute porphyria only if no safe alternative is available.
Appropriate preventive measures should be taken for susceptible patients.
Chondrolysis
After the marketing of ropivacaine, cases of chondrolysis have been reported in patients who received prolonged infusion of the drug during intra-articular local anesthesia. Chondrolysis was most frequently reported involving 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 method of administration of Ropilong.
Long-term use of the drug
Long-term use of ropivacaine should be avoided in patients treated with potent CYP1A2 inhibitors such as fluvoxamine and enoxacin (see section "Interaction with other medicinal products and other forms of interaction").
Children
Due to the immaturity of certain organs and metabolic functions, neonates may require special attention. Wide fluctuations in plasma ropivacaine concentrations observed during clinical trials in neonates suggest an increased risk of systemic toxicity, especially during prolonged epidural infusion. Dosing recommendations for neonates are based on limited clinical data. In neonates, due to delayed elimination of the drug, regular monitoring is necessary for possible development of systemic toxicity (e.g., monitoring for signs of CNS toxicity, ECG parameters, peripheral oxygen saturation) and local neurotoxicity (e.g., prolonged recovery period), which should continue after the end of infusion.
Cases of using higher concentrations (more than 5 mg/mL) of the drug in children have not been documented.
- Safety and efficacy of ropivacaine at concentrations of 7.5 mg/mL and 10 mg/mL in children under 12 years of age have not been established.
- Safety and efficacy of ropivacaine at a concentration of 2 mg/mL for regional block in children under 12 years of age have not been established.
- Safety and efficacy of ropivacaine at a concentration of 2 mg/mL for peripheral nerve block in infants (under 1 year of age) have not been established.
Excipients
This medicinal product contains 0.148 mmol (or 3.4 mg) of sodium per 1 mL dose, i.e., practically sodium-free.
This medicinal product contains 14.8 mmol (or 340 mg) of sodium per 100 mL dose. Caution is advised when administering to patients on a sodium-controlled diet.
Use during pregnancy or breastfeeding.
Use during pregnancy
Apart from data on epidural administration of the drug in obstetric practice, sufficient data on use of the drug in pregnant women are lacking. Data from animal studies do not indicate a direct or indirect harmful effect of the drug on pregnancy, embryonal/fetal development, labor, or postnatal development.
Spinal administration of the drug during cesarean section has not been reported.
Use during 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 the direct anesthetic effect, may have a minor effect on mental function and coordination, even in the absence of evident CNS toxicity, and may temporarily impair motor activity and vigilance.
Method of Administration and Dosage
Ropilon should be administered only by physicians experienced in regional anesthesia or under their supervision.
To achieve an adequate level of anesthesia, the lowest possible effective 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 general condition.
Anesthesia for surgical procedures usually requires higher doses and higher concentrations than analgesia for acute pain relief, for which a concentration of 2 mg/mL is generally 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
| Indications |
Concentration (mg/mL) |
Volume (mL) |
Dose (mg) |
Onset (min) |
Duration (hr) |
| ANESTHESIA FOR SURGICAL PROCEDURES |
|||||
| Lumbar epidural anesthesia for surgical intervention |
7.5 mg/mL |
15–25 mL |
113–188 mg |
10–20 min |
3–5 hr |
| 10 mg/mL |
15–20 mL |
150–200 mg |
10–20 min |
4–6 hr |
|
| Lumbar epidural anesthesia for cesarean section |
7.5 mg/mL |
15–20 mL |
113–150 mg |
10–20 min |
3–5 hr |
| Thoracic epidural injection for postoperative analgesic block |
7.5 mg/mL |
5–15 mL depending on injection site |
38–113 mg |
10–20 min |
__ |
| Brachial plexus block |
7.5 mg/mL |
10–40 mL |
75–300 mg(1) |
10–25 min |
6–10 hr |
| Blockade of small nerves and infiltration anesthesia |
7.5 mg/mL |
1–30 mL |
7.5–225 mg |
1–15 min |
2–6 hr |
| ACUTE PAIN MANAGEMENT |
|||||
| Lumbar epidural administration |
|||||
| Bolus |
2 mg/mL |
10–20 mL |
20–40 mg |
10–15 min |
0.5–1.5 hr |
| Intermittent injections (supplemental doses), e.g. for labor analgesia |
2 mg/mL |
10–15 mL with intervals of at least 30 minutes |
20–30 mg |
__ |
__ |
| Continuous epidural infusion, e.g. for labor analgesia |
2 mg/mL |
6–14 mL/hr |
12–20 mg/hr |
__ |
__ |
| Thoracic epidural administration |
|||||
| Continuous infusion, e.g. for postoperative analgesia |
2 mg/mL |
6–14 mL/hr |
12–28 mg/hr |
__ |
__ |
| Peripheral nerve block and infiltration anesthesia |
2 mg/mL |
1–100 mL |
2–200 mg |
1–5 min |
2–6 hr |
| Intra-articular injection(3) (e.g., single dose in knee arthroscopy) |
7.5 mg/mL |
20 mL |
150 mg(2) |
|
2–6 hr |
| Peripheral nerve blocks (femoral or intercostal block) Continuous infusion or intermittent injections (e.g., for postoperative analgesia) |
2 mg/mL |
5–10 mL/hr |
10–20 mg/hr |
__ |
__ |
| The doses listed in Table 1 are required to achieve clinically acceptable blockade; they should be considered as recommended doses for adults. There is considerable individual variability in the onset and duration of effect. |
|||||
(3)Chondrolysis has been reported in patients receiving prolonged infusion for intra-articular local anesthesia following marketing authorization. Prolonged intra-articular infusion is not an approved route of administration for this drug. |
|||||
It is essential to exercise special caution to prevent accidental intravascular injections. Aspiration 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 Xylocaine with adrenaline. Accidental intravascular injection may cause, for example, a 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 requiring epidural block, single doses of ropivacaine up to 250 mg are used and are well tolerated.
For brachial plexus block, administration of 40 mL of Ropilon long with a concentration of 7.5 mg/mL may result in maximum plasma concentrations of ropivacaine in some patients approaching levels at which mild symptoms of CNS toxicity have been described. Therefore, doses exceeding 40 mL of Ropilon long with a concentration of 7.5 mg/mL (300 mg of 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 over 24 hours have been well tolerated in adult patients during anesthesia for surgical procedures 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 administering Ropilon long 10 mg/mL or 7.5 mg/mL, or after surgery by epidural bolus administration of Ropilon long 7.5 mg/mL. Analgesia is maintained by epidural infusion of Ropilon long 2 mg/mL. Clinical studies have demonstrated that an infusion rate of 6–14 mL (12–28 mg) per hour usually provides adequate analgesia for moderate to severe postoperative pain, with only mild and non-progressive motor block in most cases. The maximum duration of epidural blockade is 3 days. However, careful monitoring of analgesic effect is required to remove the catheter as soon as the pain condition allows. This technique significantly reduces the need for additional opioid analgesics.
Clinical studies have also been conducted in which ropivacaine 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 pain relief. Ropivacaine 2 mg/mL (6–14 mg/hour) provided adequate analgesia in most patients. The combination of ropivacaine with fentanyl provided better analgesia but was associated with undesirable opioid effects.
For cesarean section, epidural use of ropivacaine at concentrations exceeding 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 administering 300 mg of ropivacaine at a concentration of 7.5 mg/mL, and intercostal block by administering 225 mg of ropivacaine at a concentration of 7.5 mg/mL. Subsequent analgesia was maintained with ropivacaine at a concentration of 2 mg/mL. Infusion rates or intermittent injections of 10–20 mg/hour over 48 hours provided sufficient analgesia and were well tolerated.
Ropivacaine at doses of 7.5 and 10 mg/mL may cause systemic and CNS toxicity in children. Therefore, for use in pediatric patients, the lowest concentration (2 mg/mL) is more appropriate.
Dosing recommendations for peripheral nerve block in infants and children provide a methodological basis for use in children without serious underlying diseases. For children with serious medical conditions, lower doses and careful monitoring are recommended.
The use of ropivacaine in premature infants has not been documented.
Increased caution is essential to prevent accidental intravascular injections. Aspiration should be carefully performed before and during injection of the total dose. Vital functions of the patient should be closely monitored during drug administration. If signs of toxicity occur, drug administration 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 dose 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 control 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.
Instructions for use and disposal
Ropilon, injection solution, contains no preservatives and is intended for single use only. Any unused solution should be discarded. Unopened packaging should not be re-sterilized by autoclaving.
The medicinal product should be visually inspected before use. Only clear solution in undamaged packaging should be used.
Children.
The medicinal product is used in pediatric practice.
Overdose.
Toxicity
Seizures have been observed following accidental intravascular injections during brachial plexus block and other peripheral nerve blocks.
Systemic toxicity is not expected after spinal administration, as low doses are used. However, 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 affect the central nervous and cardiovascular systems. 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 slower increases in local anesthetic blood concentration.
Treatment
If signs of acute systemic toxicity occur, administration of local anesthetics should be immediately discontinued. CNS-related symptoms (seizures and CNS depression) must be promptly treated with appropriate respiratory support, maintenance of adequate ventilation, oxygenation, circulation, and administration of anticonvulsant agents. Oxygen should always be provided, and artificial ventilation should be performed if necessary. If seizures do not stop spontaneously within 15–20 seconds, intravenous thiopental sodium 1–3 mg/kg should be administered to ensure adequate lung ventilation, or intravenous diazepam 0.1 mg/kg (which acts more slowly). Prolonged seizures threaten the patient's breathing and oxygenation. Injection of a muscle relaxant (e.g., succinylcholine 1 mg/kg) creates favorable conditions for ensuring patient lung ventilation and oxygenation but requires experience in tracheal intubation and artificial ventilation.
In case of circulatory arrest, cardiopulmonary resuscitation should be initiated immediately. Maintaining adequate oxygenation, lung ventilation, circulation, and treatment of acidosis are of great importance.
In case of cardiac depression (low blood pressure / bradycardia), appropriate treatment should be considered, including intravenous fluid administration, vasopressors (e.g., intravenous ephedrine 5–10 mg, repeatable after 2–3 minutes), chronotropic and/or inotropic agents. When treating children, doses appropriate to their age and body weight should be used.
In cardiac arrest, achieving a positive outcome may require prolonged resuscitation efforts.
When treating symptoms of toxicity in children, doses appropriate to their age and body weight should be used.
Adverse reactions.
The adverse effect profile of the medicinal product Ropiong is similar to that of other long-acting local anesthetics of the amide type. A large number of symptoms have been recorded during clinical studies, 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 administration of the medicinal product are difficult to distinguish from physiological effects caused by nerve blockade 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 common adverse reactions, such as nausea, vomiting, and arterial hypotension, are very frequently observed during anesthesia and surgical procedures, and these adverse reactions arising from the clinical situation cannot be clearly differentiated from those caused by the administration of the medicinal product or resulting from the performance of the blockade.
The frequency of adverse reactions is classified as follows: 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 based on available data).
Table 2
| System organ |
Frequency |
Adverse reaction |
| Immune system |
Rare |
Allergic reactions (anaphylactic reactions, anaphylactic shock, angioedema and urticaria) |
| Psychiatric disorders |
Uncommon |
Anxiety |
| Nervous system |
Common |
Paraesthesia, dizziness, headache |
| Uncommon |
Symptoms of toxic effect on CNS (convulsions, tonic-clonic seizures, grand mal seizure, stroke, dyspnoea, pre-syncope, perioral paraesthesia, tongue numbness, hyperacusis, tinnitus, visual disturbances, dysarthria, muscle twitching, tremor)*, hypaesthesia |
|
| Unknown |
Dyskinesia, Horner's syndrome |
|
| Cardiac disorders |
Common |
Bradycardia, tachycardia |
| Rare |
Cardiac arrest, arrhythmias |
|
| Vascular disorders |
Very common |
Arterial hypotension |
| Common |
Arterial hypertension |
|
| Uncommon |
Syncope |
|
| Respiratory, thoracic and mediastinal disorders |
Uncommon |
Dyspnoea |
| Gastrointestinal disorders |
Very common |
Nausea |
| Common |
Vomitingb |
|
| Musculoskeletal and connective tissue disorders |
Common |
Back pain |
| Renal and urinary disorders |
Common |
Urinary retention |
| General disorders and administration site conditions |
Common |
Pyrexia, chills |
| Uncommon |
Hypothermia |
a Arterial hypotension is less common in children (> 1/100).
b Vomiting is very common in children (> 1/10).
* These symptoms usually occur as a result of accidental intravascular administration, overdose, or rapid absorption (see also section "Overdose").
Adverse reactions associated with the drug class
The adverse reactions listed below include complications related to 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 regional anesthesia regardless of the type of local anesthetic used.
After epidural administration of local anesthesia, particularly in pregnant women, cranial spread of the local anesthetic may sometimes cause Horner’s syndrome, characterized by miosis, ptosis, and anhidrosis. Symptoms resolve spontaneously after discontinuation of local anesthesia.
Total spinal block
Total spinal block may develop following accidental intrathecal administration of an epidural dose or use 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 and cardiovascular systems. 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 for use").
CNS symptoms are similar with all amide-type local anesthetics, whereas cardiac symptoms vary more in both quantitative and qualitative terms depending on the specific drug.
Toxic effects on the central nervous system
Toxic effects on the central nervous system (CNS) manifest as a stepwise progression of symptoms and signs with increasing severity. Initial symptoms include visual or auditory disturbances, perioral numbness, dizziness, mental clouding, tingling, and paresthesia. Dysarthria, muscle rigidity, and muscle twitching are more serious symptoms and may precede generalized seizures. These signs should not be mistaken for neurotic behavior. Subsequently, loss of consciousness and generalized tonic-clonic seizures may occur, 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 respiratory and metabolic acidosis, hyperkalemia, hypocalcemia, and hypoxia exacerbates and prolongs the toxic effects of local anesthetics.
Recovery depends on redistribution of the local anesthetic away from the CNS, followed by metabolism and excretion. Recovery is usually rapid, except when very large doses have been administered.
Toxic effects on the cardiovascular system
Toxic effects on the cardiovascular system are usually more severe. High systemic concentrations of local anesthetics may lead to arterial hypotension, bradycardia, arrhythmias, and even cardiac arrest. In volunteers, intravenous infusion of ropivacaine resulted in signs of conduction depression and contractile depression.
Signs of developing CNS toxicity usually precede cardiovascular toxicity, unless the patient is under general anesthesia or receiving strong sedative agents such as benzodiazepines or barbiturates.
Early signs of systemic toxicity from local anesthetics are usually difficult to detect in children, as they cannot adequately describe these symptoms (see also section "Special precautions for use").
Children
The frequency, type, and severity of adverse reactions 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 systemic toxicity from local anesthetics are usually difficult to detect in children, as they cannot adequately describe these symptoms (see also section "Special precautions for use").
Treatment of acute systemic toxicity
See section "Overdose".
Reporting suspected adverse reactions
Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua
Shelf life. 3 years.
Shelf life after first opening
From a microbiological standpoint, the medicinal product should be used immediately. If not used immediately, the duration and conditions of storage after opening are the responsibility of the user and should not exceed 24 hours at a temperature of 2 to 8 °C.
Storage conditions.
Store at temperatures not exceeding 25 °C in the original packaging. Do not freeze. Keep out of reach of children.
Incompatibilities.
Alkalinization of the solution may cause precipitation, as ropivacaine is poorly soluble at pH above 6.0.
Packaging.
10 ml in glass ampoules, 5 ampoules in a blister pack, 1 blister pack per cardboard box.
Prescription status. Prescription only.
Manufacturer.
TOV "Yuria-Pharm".
Manufacturer's address and location of operations.
108 Kobzarska Street, Cherkasy, Cherkasy Oblast, 18030, Ukraine. Tel.: (044) 281-01-01.