Ropilong
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROPILONG (ROPILONG)
Composition:
Active substance: ropivacaine;
1 ml of solution contains 2.12 mg of ropivacaine hydrochloride monohydrate, equivalent to 2 mg of ropivacaine hydrochloride;
Excipients: sodium chloride, concentrated hydrochloric acid, sodium hydroxide, water for injections.
Pharmaceutical form. Infusion 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 an amide-type local anaesthetic with both anaesthetic and analgesic effects. Surgical anaesthesia is achieved with higher doses, while lower doses produce sensory blockade (analgesia) with limited and non-progressive motor blockade.
The mechanism of action involves reversible reduction of the nerve fibre membrane permeability to sodium ions. As a result, the rate of depolarisation decreases and the excitation threshold increases. Ultimately, this 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]). See Table 1 in the section "Dosage and Administration" for details.
Pharmacodynamic effects. In vitro, ropivacaine demonstrated a lower negative inotropic effect than levobupivacaine and bupivacaine.
Assessment of cardiac 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 such changes occur at higher doses of ropivacaine and levobupivacaine than of bupivacaine.
Direct cardiovascular effects of local anaesthetics include slowed conduction, negative inotropy, and ultimately arrhythmia and cardiac arrest.
In a study in dogs, where 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 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 tolerated intravenous administration of ropivacaine at maximum tolerated doses very well, with expected central nervous system (CNS) symptoms occurring. A significantly lower potential for toxicity on the central nervous and cardiovascular systems was demonstrated compared to bupivacaine. CNS symptoms are similar with both drugs, 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 accompanying sympathetic blockade, although this is less pronounced in children.
Rapid onset of symptoms in the central nervous and cardiovascular systems occurs if 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 a 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
Ropivacaine demonstrates 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 in elimination 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 approximately 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 coefficient is approximately 0.4.
Ropivacaine is predominantly bound to plasma proteins, mainly 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, 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 between the pregnant woman and the foetus is achieved for 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 via aromatic hydroxylation to 3-hydroxy-ropivacaine (catalysed by cytochrome CYP1A2) and via 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-dose administration, but becomes the main metabolite after prolonged epidural infusion.
Elimination
Ropivacaine has intermediate and low hepatic extraction ratios. Therefore, its elimination rate should depend on the plasma concentration of unbound fractions. Postoperative increases in α1-acid glycoprotein lead 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, approximately 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 primarily 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 easily detectable concentrations.
A similar metabolite profile has been observed in children from 1 year of age.
Renal impairment has minimal 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 toxicity of PPX is lower than that of ropivacaine, the clinical consequences of this effect during short-term treatment are considered negligible. Studies in patients with end-stage renal failure undergoing regular dialysis have not been conducted.
Use in Paediatric Practice
The pharmacokinetics of ropivacaine are based on the analysis of pooled patient population data obtained from 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 age effect is interpreted in the context of 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. 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 6-month-old infants.
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: approximately 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. Dosing recommendations for prolonged epidural infusion partially compensate for this difference.
Clinical characteristics.
Indications.
- For use in adults and children aged 12 years and older for management of acute pain:
- prolonged epidural infusion or intermittent bolus injections for relief of postoperative pain or labor analgesia;
- peripheral nerve block;
- prolonged peripheral nerve block via continuous infusion or intermittent bolus injections, e.g., for relief of postoperative pain.
- For use in children aged 1 to 12 years for management of acute pain (during and after surgery):
- peripheral nerve block with single-dose administration.
- For use in children from birth to 12 years for caudal epidural block (during and after surgery):
- prolonged epidural infusion.
Contraindications.
- Hypersensitivity to ropivacaine or any of the excipients;
- hypersensitivity to other amide-type local anesthetics;
- general contraindications associated with epidural or regional anesthesia, regardless of the local anesthetic 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.
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 Ropilon with general anesthetics or opioids may potentiate adverse effects of both agents.
Specific interaction studies between ropivacaine and Class III antiarrhythmics (e.g., amiodarone) have not been conducted; however, caution is recommended when co-administering these agents (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 studies have shown that 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 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 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 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 performed by experienced personnel in a properly equipped facility. Equipment and medications necessary for monitoring and emergency resuscitation must 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 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 a high degree of 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 of the drug 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 Ropiong by 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.
Effects on the cardiovascular system
Epidural anesthesia may result in 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 under close surveillance. 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 blocks, particularly after unintentional accidental intravascular injection in elderly patients and patients with concomitant cardiac 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 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 administered to 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, regardless of the type of local anesthetic used, sudden and severe arterial hypotension may develop 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-dose 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
Ropiong, solution for injection or infusion, may provoke an attack of porphyria and therefore 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
Since the marketing of ropivacaine, cases of chondrolysis have been reported in patients who received prolonged intra-articular infusion of the drug during intra-articular local anesthesia. Most reports 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 Ropiong.
Long-term use
Prolonged 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 types of interactions").
Children
Due to organ and metabolic immaturity, 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 for possible systemic toxicity (e.g., monitoring for signs of CNS toxicity, ECG parameters, peripheral oxygen saturation) and local neurotoxicity (e.g., prolonged recovery period) is necessary and should continue after the end of infusion.
Cases of using higher concentrations (above 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 the use of the drug in pregnant women are lacking. Data from animal studies do not indicate direct or indirect harmful effects of the drug on pregnancy, embryonic/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 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.
Ropilon should be administered only by physicians experienced in regional anesthesia, or under their supervision.
To achieve adequate 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 listed below; dosage should be adjusted according to the extent of block and the patient's general 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
| 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 necessary to achieve clinically acceptable blockade; they should be considered as recommended doses for adults. There are significant individual variations in onset time and duration of effect. |
|||||
(3)Chondrolysis has been reported in patients receiving prolonged infusion for intra-articular local anesthetic administration following marketing authorization. Prolonged intra-articular infusion is not an approved route of administration for this drug. |
|||||
Special caution must be exercised to prevent accidental intravascular injection. 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. When administering epidurally, 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 must be immediately discontinued.
For epidural block during surgical procedures, single doses of up to 250 mg of ropivacaine are well tolerated.
For brachial plexus block by administration of 40 mL of Ropilon Long at a concentration of 7.5 mg/mL, maximum plasma concentrations of ropivacaine in some patients may approach levels at which mild symptoms of CNS toxicity have been described. Therefore, doses exceeding 40 mL of Ropilon Long 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 surgical procedures and for postoperative pain management. Good tolerability has also been observed in adults during prolonged epidural infusions administered postoperatively 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 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 generally provides adequate analgesia 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 in order to remove the catheter as soon as the pain condition permits. This approach allows a significant reduction in the need for additional opioid analgesics.
Clinical studies have also been conducted in which ropivacaine at a dose 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 at 2 mg/mL (6−14 mg/hour) provided adequate analgesia in most patients. The combination of ropivacaine with fentanyl provided improved analgesia but was associated with undesirable opioid-related effects.
For cesarean section, epidural administration of ropivacaine at concentrations exceeding 7.5 mg/mL or spinal administration has not been documented.
When performing prolonged peripheral nerve blocks 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 ropivacaine at a concentration of 7.5 mg/mL, and intercostal block by administration of 225 mg of ropivacaine at a concentration of 7.5 mg/mL. Subsequently, analgesia was maintained by administration of ropivacaine at a dose of 2 mg/mL. Infusion rates or intermittent injections of 10−20 mg/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
| Indications |
Concentration (mg/mL) |
Volume (mL/kg) |
Dose (mg/kg) |
| ACUTE PAIN MANAGEMENT (before and after surgical intervention) |
|||
| Caudal block in children aged 0–12 years Block below the T12 level in children with body weight up to 25 kg |
2 mg/mL |
1 mL/kg |
2 mg/kg |
| Continuous epidural infusion In children with body weight up to 25 kg |
|||
| 0–6 months Bolus dosea Infusion up to 72 hours |
2 mg/mL 2 mg/mL |
0.5–1 mL/kg 0.1 mL/kg/hour |
1–2 mg/kg 0.2 mg/kg/hour |
| 6–12 months Bolus dosea Infusion up to 72 hours |
2 mg/mL 2 mg/mL |
0.5–1 mL/kg 0.2 mL/kg/hour |
1–2 mg/kg 0.4 mg/kg/hour |
| 1–12 years Bolus doseb Infusion up to 72 hours |
2 mg/mL 2 mg/mL |
1 mL/kg 0.2 mL/kg/hour |
2 mg/kg 0.4 mg/kg/hour |
| Peripheral nerve block in children aged 1–12 years |
|||
| Continuous infusion Infusion up to 72 hours |
2 mg/mL |
0.1–0.3 mL/kg/hour |
0.2–0.6 mg/kg/hour |
| When administering the drug to children, the doses listed in Table 2 should be considered as recommendations. Individual variations may occur. Children with excessive body weight often require dose reduction based on ideal body weight. The volume of drug used for single-dose epidural anesthesia and for epidural bolus injections should not exceed 25 mL for any patient. |
|||
| a For thoracic epidural blocks, doses at the lower end of the dosing range are recommended, whereas for lumbar or caudal epidural blocks, doses at the upper end of the dosing range are recommended. b Recommended for lumbar epidural blocks. |
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Ropivacaine at concentrations of 7.5 and 10 mg/mL may produce systemic toxicity and central nervous system toxicity in children. Therefore, for use in these patients, the lowest concentration of the drug (2 mg/mL) is more appropriate.
Guidelines for dosing of ropivacaine for peripheral nerve block in infants and children provide a methodological basis for administration of the drug to children without serious underlying diseases. In children with serious underlying diseases, lower doses are recommended, along with careful monitoring.
The use of ropivacaine in premature infants has not been documented.
Great care must be taken to avoid accidental intravascular injection. Aspiration for blood should be carefully performed before and during injection of each dose. Vital functions of the patient should be closely monitored during administration. If signs of toxic effects occur, administration should be stopped immediately.
When calculated doses are used, 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 blockade. Doses of up to 3 mg/kg inclusive, using a ropivacaine concentration of 3 mg/mL, have been safely administered to children aged 4 years and older.
Experience with caudal blocks in children weighing more than 25 kg is limited.
Children
The medicinal product is used in pediatric practice.
Instructions for use and disposal
Ropilon, infusion solution, does not contain preservatives and is intended for single use only. Any unused solution should be discarded. Unopened packaging should not be subjected to repeated autoclaving.
Ropilon, infusion solution, is chemically and physically compatible with the following medicinal products:
| Concentration of the medicinal product Ropilon: 1–2 mg/ml |
|
| Additional drug |
Concentration* |
| Fentanyl citrate |
1–10 mcg/ml |
| Sufentanil citrate |
0.4–4 mcg/ml |
| Morphine sulfate |
20–100 mcg/ml |
| Clonidine hydrochloride |
5–50 mcg/ml |
* The concentration ranges shown in the table are broader than those used in clinical practice.
Epidural infusions of ropivacaine/sufentanil citrate, ropivacaine/morphine sulfate, and ropivacaine/clonidine hydrochloride have not been evaluated in clinical studies.
Prior to administration, the medicinal product should be visually inspected. Only clear solution in undamaged packaging should be used. From a microbiological standpoint, the mixture should be used immediately. If the prepared mixture is not used immediately, the storage duration and conditions are the responsibility of the user and should not exceed 24 hours at a temperature of 2 to 8 °C.
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 a low dose of the drug is used in this case. Intrathecal administration of a very high dose of the drug may lead to total spinal block, which in turn may result in severe cardiovascular depression and respiratory insufficiency.
Symptoms
Systemic toxic reactions primarily involve the central nervous and cardiovascular systems. Accidental intravascular injections of local anesthetics may cause immediate (within several seconds to several minutes) systemic toxic reactions. In cases of overdose, systemic toxicity manifests later (15−60 minutes after injection) due to a slower increase in the blood concentration of the local anesthetic.
Treatment
If signs of acute systemic toxicity occur, administration of local anesthetics should be immediately discontinued. Central nervous system symptoms (seizures and CNS depression) must be promptly treated with appropriate respiratory support, maintenance of adequate ventilation, oxygenation, circulation, and administration of an anticonvulsant agent. Oxygen should always be administered, and if necessary, artificial ventilation of the lungs should be performed. If seizures do not cease spontaneously within 15−20 seconds, the patient should receive intravenous sodium thiopental at a dose of 1−3 mg/kg to ensure adequate lung ventilation, or intravenous diazepam at 0.1 mg/kg (which acts significantly more slowly). Prolonged seizures threaten the patient's respiration and oxygenation. Injection of a muscle relaxant (e.g., succinylcholine at 1 mg/kg) creates more favorable conditions for ensuring patient lung ventilation and oxygenation but requires experience in tracheal intubation and artificial ventilation of the lungs.
In case of circulatory arrest, cardiopulmonary resuscitation should be initiated immediately. Maintaining adequate oxygenation, lung ventilation and circulation, as well as treatment of acidosis, are of great importance.
In case of cardiac depression (low blood pressure / bradycardia), appropriate treatment with intravenous fluids, a vasopressor (e.g., intravenous administration of ephedrine 5−10 mg, which may be repeated after 2−3 minutes), and/or a chronotropic and/or inotropic agent should be considered. When treating children, doses appropriate to their age and body weight should be used.
In case of 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 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 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; these adverse reactions resulting from the clinical situation cannot be clearly distinguished from those caused by the administration of the medicinal product or by the performance of the block.
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 (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); and frequency not known (cannot be estimated based on available data).
Table 3
| System of organs |
Frequency |
Adverse reaction |
| Immune system |
Rare |
Allergic reactions (anaphylactic reactions, anaphylactic shock, angioneurotic edema and urticaria) |
| Psychiatric disorders |
Uncommon |
Anxiety |
| Nervous system |
Common |
Paresthesia, dizziness, headache |
| Uncommon |
Symptoms of toxic effect on CNS (seizures, tonic-clonic seizures, grand mal seizure, stroke, dyspnea, pre-syncopal state, perioral paresthesia, tongue numbness, hyperacusis, tinnitus, visual disturbances, dysarthria, muscle twitching, tremor)*, hypoesthesia |
|
| 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 system, thoracic organs and mediastinum |
Uncommon |
Dyspnea |
| Gastrointestinal disorders |
Very common |
Nausea |
| Common |
Vomitingb |
|
| Musculoskeletal and connective tissue system |
Common |
Back pain |
| Urinary system |
Common |
Urinary retention |
| General disorders and administration site conditions |
Common |
Increased temperature, chills |
| Uncommon |
Hypothermia |
a 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 administration, 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 outcomes, have been associated with regional anesthesia regardless of the type of local anesthetic used.
Following epidural administration of local anesthesia, particularly in pregnant women, cranial spread of the local anesthetic may occasionally 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 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 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 represent a stepwise reaction, with symptoms and signs progressing in 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 respiratory compromise. 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 central nervous system, followed by its metabolism and excretion. Recovery is usually rapid unless very large doses have been administered.
Toxic effects on the cardiovascular system
Toxic effects on the cardiovascular system are generally 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 suppression.
Signs of developing toxic effects of local anesthetics on the central nervous system usually precede cardiovascular toxicity, unless the patient is under general anesthesia or under the influence of strong sedative agents such as benzodiazepines or barbiturates.
Early signs of systemic toxicity are generally difficult to detect in children, as they are unable to 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 are generally difficult to detect in children, as they are unable to adequately describe these symptoms (see also section "Special precautions for use").
Treatment of acute systemic toxicity
See section "Overdose".
Reporting suspected adverse reactions
Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or 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 storage conditions and duration 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 a temperature not exceeding 25 °C in the original packaging. Do not freeze. Keep out of reach of children.
Incompatibilities.
The medicinal product should not be mixed with other medicinal products except those specified in the section "Method of administration and dosage". Alkalinization of the solution may cause precipitation, as ropivacaine has poor solubility at pH above 6.0.
Packaging.
100 ml in glass vials, 1 vial in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
Yuria-Pharm LLC.
Date of last review.