Naropin for epidural anesthesia. Naropin: instructions for using the solution. Further information is provided upon request.

28.07.2020 Drugs

Instructions for use Naropin ®
The composition of the drug Naropin ®
Indications of the drug Naropin ®
Storage conditions of the drug Naropin ®
Shelf life of the drug Naropin ®

Release form, composition and packaging

solution for injection 2 mg / 1 ml: amp. 20 ml 5 Pcs.
Reg. No.: RK-LS-5-No. 012505 dated 06/18/2014 - Current

Injection transparent, colorless.

Excipients:

20 ml - polypropylene ampoules (1) - contoured cell packs (5) - cardboard packs.

solution for injection 10 mg / 1 ml: amp. 10 ml 5 Pcs.
Reg. No: RK-LS-5-No 012507 dated 06/18/2014 - Current

Injection transparent, colorless.

Excipients: sodium chloride, hydrochloric acid, sodium hydroxide (up to pH 4-6), water d / i.

solution for injection 7.5 mg / 1 ml: amp. 10 ml 5 Pcs.
Reg. No.: RK-LS-5-No. 012506 dated 06/18/2014 - Current

Injection transparent, colorless.

Excipients: sodium chloride, hydrochloric acid or sodium hydroxide (up to pH 4-6), water d / i.

10 ml - polypropylene ampoules (1) - contour cell packs (5) - cardboard packs.

Description of the medicinal product NAROPIN ® created in 2013 on the basis of instructions posted on the official website of the Ministry of Health of the Republic of Kazakhstan. Date of renovation: 02.03.2015

pharmachologic effect

Naropin ® - the first local anesthetic of the amide type long acting, which is a pure enantiomer. It has both anesthetic and analgesic effects. High doses of the drug are used for local anesthesia during surgery, low doses of the drug provide analgesia (sensory block) with minimal and non-progressive motor block. The duration and intensity of the blockade caused by ropivacaine is not affected by the addition of adrenaline. By reversibly blocking voltage-dependent sodium channels, it prevents the generation of impulses at the endings of sensory nerves and the conduction of impulses along nerve fibers.

Naropin ® can affect other excitable cell membranes (for example, in the brain and myocardium). If an excess amount of local anesthetic reaches the systemic circulation in a short period of time, signs of systemic toxicity may be manifested. Signs of toxicity from the central nervous system precede signs of toxicity from of cardio-vascular system, since they are observed at lower concentrations of the drug in the blood plasma.

The direct effect of local anesthetics on the heart includes conduction deceleration, negative inotropic effect and, in severe overdose, arrhythmias and cardiac arrest. Intravenous administration of high doses of Naropin® leads to the same effects on the cardiovascular system.

Indirect cardiovascular effects (lowering blood pressure, bradycardia) that can occur after epidural administration of ropivacaine are due to the resulting sympathetic blockade.

Pharmacokinetics

Plasma concentration of ropivacaine depends on the dose, route of administration and the degree of vascularization of the injection site. The pharmacokinetics of ropivacaine is linear, the maximum concentration (C max) is proportional to the administered dose. After epidural administration, ropivacaine is completely absorbed. Absorption is biphasic, the half-life (T 1/2) for the two phases is 14 minutes and 4 hours, respectively. The slowdown in the elimination of ropivacaine is determined by slow absorption, which explains the longer T 1/2 after epidural administration compared to intravenous administration.

The total plasma clearance of ropivacaine is 440 ml / min, the plasma clearance of unbound substances is 8 L / min, the renal clearance is 1 ml / min, the volume of distribution in the equilibrium state is 47 L, the hepatic extraction index is about 0.4, T 1/2 -1.8 h.

Ropivacaine strongly binds to blood plasma proteins (mainly with a1-acid glycoproteins), the unbound fraction of ropivacaine is about 6%. Ropivacaine crosses the placental barrier with rapid equilibration to an unbound fraction. The degree of binding to plasma proteins in the fetus is lower than in the mother, which entails a lower total concentration in the fetal blood plasma. Ropivacaine is extensively metabolized in the liver, mainly by aromatic hydroxylation to 3-hydroxy-ropivacaine by cytochrome P4501A2 and by N-dealkylation to PPX (N-depropylate ropivacaine - pipecoloxylidide) by CYP3A4.

About 37% of 3-hydroxy-ropivacaine, the main metabolite of ropivacaine, is excreted in the urine, both bound and unbound. Urinary excretion of PPX and other metabolites is less than 3% of the total dose.

With epidural infusion, the main metabolites PPX and 3-hydroxy-ropivacaine are excreted in the urine. The total plasma PPX concentration is about half of the total ropivacaine concentration, however, the unbound PPX concentration is 7-9 times higher than the unbound ropivacaine concentration with subsequent continuous epidural infusion up to 72 hours.

Renal dysfunction does not significantly affect the pharmacokinetics of ropivacaine. The renal clearance of PPX is significantly correlated with creatinine clearance. Lack of correlation
between total exposure, expressed in AUC, and creatinine clearance indicates that total PPX clearance includes extrarenal elimination in addition to renal excretion. In some patients with impaired renal function, there may be an increase in PPX exposure as a result of low renal clearance. Because of the reduced neurotoxicity of PPX compared to ropivacaine, the clinical effects are considered negligible for short-term use.

Evidence for racemization of ropivacaine in vivo absent.

Indications for use

Surgical anesthesia:

epidural block during surgical interventions, including caesarean section;
blockade of large nerves and nerve plexuses;
blockade of individual nerves and infiltration anesthesia.

prolonged epidural infusion or intermittent bolus administration, for example, to eliminate postoperative pain or labor pain relief;
blockade of individual nerves and infiltration;
prolonged blockade of peripheral nerves;
intra-articular injection.

Relief of acute pain syndrome in pediatrics:

caudal epidural block in newborns and children up to 12 years of age inclusive
blockade of peripheral nerves in children from 1 to 12 years of age inclusive
prolonged epidural infusion in newborns and children up to 12 years of age inclusive

Dosage regimen

Naropin ® should only be used by specialists with sufficient experience in performing regional anesthesia.

Adults and children over 12 years old

Drug concentration (mg / ml)		Solution volume (ml)	Dose (mg)	Beginning of action (min)	Duration of action (h)
Surgical anesthesia:
Lumbar epidural anesthesia
Surgical interference	7.5	15 - 25	113 - 188	10 - 20	3 - 5
Surgical interference	10.0	15 - 20	150 - 200	10 - 20	4 - 6
Cesarean section	7.5	15 - 20	113 - 150	10 - 20	3 - 5
Thoracic epidural anesthesia
Postoperative analgesic block	7.5	5 - 15	38 - 113	10 - 20	-
Large nerve plexus block
For example, a brachial plexus block	7.5	10 - 40	75 - 300	10 - 25	6 – 10
Conduction and infiltration anesthesia	7.5	1 - 30	7,5 - 225	1 - 15	2 - 6
Relief of acute pain syndrome:
Epidural administration at the lumbar level:
Bolus	2.0	10 - 20	20 - 40	10 - 15	0,5 – 1,.5
Periodic introduction (for example, for pain relief in labor)	2.0	10 – 15 (minimum interval -30 min)	20 - 30
Extended infusion for: - pain relief during labor	2.0	6 - 10 ml / h	12 - 20 mg / h	-	-
- postoperative pain relief	2.0	6 - 14 ml / h	12 - 28 mg / h	-	-
Peripheral nerve block
Femoral nerve block (infusion or injection)	2,0	5 - 10 ml / h	10– 20 mg / h	-	-
Epidural administration at the thoracic level
Extended infusion (for example, for postoperative pain relief)	2.0	6 - 14 ml / h	12 - 28 mg / h	-	-
Conductive block and infiltration	2.0	1 - 100	2 - 200	1 - 5	2 - 6
Intra-articular administration
Single injection for knee arthroscopy	7.5	20	150	-	2-6

The doses indicated in the table are considered necessary for a reliable blockade and should be considered as a guideline for use in adults. There may be individual variability in the onset and duration of action. The numbers represent the average range of expected dosages. Standard guidelines should be used for information on factors that influence the methods of performing individual blocks and on the requirements for specific patient groups.

The dosage for blocking large nerves should be adjusted depending on the site of administration and the condition of the patient. Interstellar and supraclavicular brachial plexus block may be associated with a higher incidence of severe adverse reactions, regardless of the local anesthetic (see also the section "Special instructions").

If Naropin was additionally used for other types of anesthesia, maximum dose should not exceed 225 mg.

To prevent the ingress of the anesthetic into the vessel, it is imperative to carry out an aspiration test before and during the administration of the drug. If you intend to use the drug in a high dose, it is recommended to administer a test dose - 3-5 ml of lidocaine with adrenaline. Inadvertent intravascular injection is recognized by a temporary increase in heart rate, and inadvertent intrathecal injection is recognized by signs of spinal block.

Before the introduction and during the administration of Naropin (which should be carried out slowly or by increasing the doses of the drug administered sequentially at a rate of 25-50 mg / min), it is necessary to carefully monitor the patient's vital functions and maintain verbal contact with him. A single injection of Naropin® at a dose of up to 250 mg for epidural blockade for surgical intervention was usually well tolerated by patients. If toxic symptoms appear, the drug should be discontinued immediately. With prolonged blockade by prolonged infusion or repeated bolus administration, the possibility of creating toxic concentrations of the anesthetic in the blood and local nerve damage should be taken into account. Introduction Naropin ® for 24 hours at a dose of up to 800 mg in total for surgical interventions and for postoperative pain relief, as well as prolonged epidural infusion after surgery at a rate of 28 mg / h for 72 hours is well tolerated by adult patients.

if an epidural catheter was not installed during surgery, after its installation, an epidural blockade Naropin ® (7.5 mg / ml) is performed. Analgesia is supported by an infusion of Naropin® (2 mg / ml). In most cases, for the relief of moderate to severe postoperative pain, infusion at a rate of 6-14 ml / h (12-28 mg / h) provides adequate analgesia with minimal non-progressive motor blockade (with this technique, a significant decrease in the need for opioid analgesics was observed) ... For postoperative pain relief, Naropin® (2 mg / ml) can be administered continuously as an epidural infusion for 72 hours without fentanyl or mixed with it (1-4 μg / ml). When using Naropin 2 mg / ml (6-14 ml / h), adequate pain relief was provided in most patients.

The use of Naropin ® at a concentration above 7.5 mg / ml for caesarean section has not been studied.

With prolonged peripheral blockade using continuous infusion or by repeated injections, the risk of reaching a toxic plasma concentration of the drug, as well as local nerve damage, should be taken into account.

Drug concentration (mg / ml)		Solution volume (ml / kg)	Dose (mg / kg)
Relief of acute pain syndrome (preoperative and postoperative):
Caudal epidural injection:
Blockade in the area below T 12 in children weighing up to 25 kg.	2,0	1	2
Peripheral nerve block in children from 1 to 12 years of age inclusive:
(for example, for ilio-inguinal nerve block)	5,0	0,6	3
Prolonged epidural infusion in children weighing up to 25 kg
Age from 0 to 6 months
Bolus *	2,0	0,5 - 1	1 - 2
Infusion up to 72 h	2,0	0.1ml / kg / h	0.2ml / kg / h
Age from 6 to 12 months
Bolus *	2,0	0,5 - 1	1 - 2
Infusion up to 72 h	2,0	0.2ml / kg / h	0.4ml / kg / h
Age from 1 to 12 years old inclusive
Bolus **	2,0	1	2
Infusion up to 72 h	2,0	0.2ml / kg / h	0.4ml / kg / h

* Smaller doses from the suggested interval are recommended for thoracic epidurals, while larger doses are recommended for lumbar or caudal epidurals.

The doses indicated in the table are considered sufficient to achieve a reliable blockade and are a guide to the use of the drug in pediatric practice... At the same time, there is individual variability in the rate of development of the block and its duration.

In overweight children, a gradual dose reduction is often required; in this case, it is necessary to be guided by the "ideal" weight of the patient. Standard guidelines should be used for information on factors that influence the methods of performing individual blocks and on the requirements for specific patient groups. The volume of the solution for caudal epidural administration and the volume of the bolus for the epidural administration should not exceed 25 ml for any patient.

To prevent inadvertent intravascular administration of anesthetic, a thorough aspiration test should be performed before and during administration of the drug. During the administration of the drug, it is necessary to carefully monitor the vital functions of the patient. If toxic symptoms appear, the drug should be discontinued immediately.

A single injection of ropivacaine at a dose of 2 mg / ml (at the rate of 2 mg / kg, solution volume 1 ml / kg) for postoperative caudal analgesia provides adequate analgesia below the T 12 level in most patients. Children over 4 years of age tolerate doses up to 3 mg / kg well. The volume of epidural solution administered at the caudal level can be adjusted to achieve different sensory block prevalence, as described in standard guidelines.

Regardless of the type of anesthesia, it is recommended to administer the calculated dose of the drug. The use of the drug at a concentration above 5 mg / ml, as well as the intrathecal use of Naropin® in children, has not been studied. The use of Naropin ® in premature infants has not been studied.

Side effects

Very often (> 1/10): hypotension nausea.

Often (> 1/100): paresthesia, dizziness, headache, bradycardia, tachycardia, hypertension, vomiting, delay in urination, reactions at the injection site (fever, chills, back pain).

Uncommon (> 1/1000): anxiety, signs of intoxication from the central nervous system (convulsions, major epileptic seizure, convulsions, light dizziness, perioral paresthesia, numbness of the tongue, hyperacusis, ringing in the ears, blurred vision, dysarthria, muscle twitching, tremor), hypesthesia, syncope, shortness of breath, general complications and reactions at the injection site (hypothermia).

Rarely (> 1/10000): cardiac arrest, arrhythmia, allergic reactions(anaphylactic shock, angioedema and urticaria).

Naropin ® can cause acute systemic toxic reactions when using high doses or with a rapid increase in blood concentration in case of accidental intravascular administration of the drug or its overdose.

Application for violations of liver function

Carefully the drug should be administered to patients with progressive liver cirrhosis.

Since Naropina is metabolized in the liver, caution should be exercised when using the drug in patients with severe liver disease; in some cases, due to delayed elimination, it may be necessary to reduce repeated doses of anesthetic.

Application for impaired renal function

The drug should be administered with caution to patients with chronic renal failure.

special instructions

Regional anesthesia should be performed by experienced professionals. Equipment is required and drugs for resuscitation measures. An intravenous catheter must be placed before large blockages are performed.

Personnel providing anesthesia should be appropriately trained and familiar with the diagnosis and treatment of potential side effects, systemic toxic reactions and other possible complications.

Epidural anesthesia can lead to a decrease in blood pressure and bradycardia. Introduction vasoconstrictor drugs or an increase in blood volume may reduce the risk of these side effects.

There are reports of isolated cases of cardiac arrest in elderly patients and in patients with concomitant cardiovascular diseases when using Naropin® for epidural anesthesia or peripheral nerve blocks, especially after accidental intravascular ingestion of the drug. In some cases, resuscitation measures were difficult. Cardiac arrest usually requires longer resuscitation. Since Naropina is metabolized in the liver, caution should be exercised when using the drug in patients with severe liver disease; in some cases, due to delayed elimination, it may be necessary to reduce repeated doses of anesthetic.

Hypotension should be promptly corrected by intravenous administration 5-10 mg ephedrine, s re-introduction, if necessary. The use of the drug in newborns requires taking into account the possible immaturity of organs and physiological functions, which is especially important with prolonged infusion. Naropina ® - may be porphyrinogenic and can be used in patients with acute porphyria only if there is no safer alternative.

There are reports of cases of chondrolysis in patients receiving postoperative intra-articular extended infusion. Most of these messages concerned shoulder joint... Due to the possibility of the influence of various factors and conflicting literature data, an exact causal relationship has not been established. Naropina ® is not indicated for prolonged intra-articular infusion.

Carefully:

the drug should be administered to weakened elderly patients or patients with severe concomitant diseases, such as heart block (sinoatrial, atrioventricular, intraventricular), progressive cirrhosis of the liver, severe chronic renal failure. For these patient groups, regional anesthesia is preferred.

Overdose

Symptoms: impaired vision and hearing, numbness around the mouth, dizziness, paresthesia, dysarthria, muscle hypertonia, muscle twitching, arrhythmias;

with the progression of intoxication - a decrease in blood pressure, bradycardia, arrhythmia, loss of consciousness, generalized convulsions, cardiac arrest.

Treatment: when the first signs of intoxication appear, the administration should be discontinued;

with the development of seizures, an adequate supply of oxygen is maintained with the help of an oxygen bag or mask, 100-120 mg of thiopental or 5-10 mg of diazepam is injected intravenously;

after intubation and initiation of mechanical ventilation, suxamethonium is administered. It is necessary to maintain optimal gas composition blood with simultaneous correction of acidosis.

Drug interactions

Possible summation of toxic effects while prescribing with other local anesthetics or drugs structurally similar to local anesthetics of the amide type.

The interaction of ropivacaine and class III antiarrhythmic drugs (for example, amiodarone) has not been specifically studied, but caution should be exercised when prescribing together.

The clearance of ropivacaine is reduced by 77% when administered together with fluvoxamine, which is a potent competitive inhibitor of cytochrome P4501A2. Thus, the simultaneous use of potent inhibitors of CYP1A2, such as fluvoxamine and enoxacin, with Naropin® can cause metabolic interactions that lead to an increase in the concentration of ropivacaine in the blood plasma. Therefore, patients on treatment with potent CYP1A2 inhibitors such as fluvoxamine and enoxacin should not be given long-term ropivacaine.

An increase in the pH of the solution above 6.0 can lead to the formation of a precipitate due to the poor solubility of ropivacaine under these conditions.

Compound

Active substance: ropivacaine; 1 ml ropivacaine hydrochloride monohydrate, which corresponds to ropivacaine hydrochloride 2 mg or 7.5 mg or 10 mg

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

Dosage form"type =" checkbox ">

Dosage form

Injection.

Basic physical and chemical properties: clear, colorless liquid.

Pharmacological group"type =" checkbox ">

Pharmacological group

Local anesthetic.

ATX code N01B B09.

Pharmacological properties"type =" checkbox ">

Pharmacological properties

Pharmacological.

Naropine contains ropivacaine, a pure enantiomer, which is an amide-type local anesthetic. Ropivacaine reversibly blocks the conduction of impulses along nerve fibers, suppressing the transport of sodium ions across nerve membranes. Similar effects can also be observed on the excitatory membranes of the brain and myocardium.

Ropivacaine has anesthetic and analgesic effects. With high doses, surgical anesthesia is achieved, while low doses result in sensory blockade (analgesia), accompanied by limited and non-progressive motor block. The duration and intensity of the blockade of ropivacaine is not improved by the addition of epinephrine.

pharmacodynamic effects

Ropivacaine in vitro had less negative inotropic effect than levobupivacaine and bupivacaine.

Determination of the effect on cardiac activity, carried out in vivo in several animal studies, showed that ropivacaine has a lower cardiac toxicity than bupivacaine. This difference was both qualitative and quantitative.

Ropivacaine causes less expansion of the QRS complex than bupivacaine, and changes occur with higher doses of ropivacaine and levobupivacaine than bupivacaine.

The direct cardiovascular effects of local anesthetics include slow conduction, negative inotropism, and ultimately arrhythmias and cardiac arrest.

After ropivacaine administration, healthy volunteers receiving intravenous infusions showed significantly less potential for central nervous system and cardiovascular toxicity than after bupivacaine administration. CNS symptoms are similar in these drugs, but when bupivacaine is used, they occur at lower doses and plasma concentrations, and also have a longer duration.

Indirect cardiovascular effects (arterial hypotension, bradycardia) can develop after epidural block, depending on the degree of concomitant sympathetic block, which, however, is less pronounced in children.

When a large amount of the drug enters the bloodstream, symptoms from the central nervous and cardiovascular systems rapidly develop.

Pharmacokinetics.

Ropivacaine has a chiral center and is available as the pure S - (-) - enantiomer. Ropivacaine is a highly lipid-soluble compound. The pKa value of ropivacaine is 8.1, and the partition coefficient is 141 (25 ° C n-octanol / phosphate buffer at

pH 7.4). All metabolites have a local anesthetic effect, but are significantly less active and have a shorter duration of action than ropivacaine.

absorption

The concentration of ropivacaine in blood plasma depends on the dose of the drug, the type of blockade and vascularization at the injection site. Ropivacaine demonstrates linear pharmacokinetics, that is, the maximum plasma concentration is proportional to the dose of the drug.

Ropivacaine demonstrates complete and biphasic absorption from the epidural space; the half-life of the two phases is approximately 14 minutes and 4:00, respectively. Slow absorption is a rate-limiting factor for ropivacaine and explains why the terminal half-life after epidural administration is longer than after drug administration.

distribution

Ropivacaine binds in blood plasma mainly with α 1 -oxidized glycoproteins; the unbound fraction is about 6%. After administration, the steady state volume of distribution of ropivacaine is 47 liters. After prolonged epidural infusion, an increase in the total concentration of ropivacaine and PPX in blood plasma was observed, which depended on the postoperative increase in the levels of α 1 -acid glycoprotein. The increase in the concentration of unbound, pharmacologically active ropivacaine in blood plasma was significantly less than the increase in the concentration of total ropivacaine in blood plasma. The average concentration of unbound PPX was approximately 7-9 times higher than the average concentration of unbound ropivacaine after prolonged epidural infusion of up to 72 hours, inclusive.

Ropivacaine easily crosses the placenta and an equilibrium state is achieved with respect to unbound ropivacaine between mother and fetus. The degree of binding to blood plasma proteins in the fetus is less than in the mother, which leads to a decrease in the total concentration of the drug in the blood plasma of the fetus.

metabolism

Ropivacaine is metabolized in the liver mainly by aromatic hydroxylation to 3-hydroxy-ropivacaine (catalyzed with the participation of cytochrome CYP1A2) and by N-dealkylation to PPH (catalyzed with the participation of cytochrome CYP3A4). PPX of the active metabolite. The threshold for CNS toxic plasma concentrations of unbound PPX in rats is about 12 times higher than that for unbound ropivacaine. PPX is a metabolite, is of little importance after the use of single doses of the drug, however, after prolonged epidural infusion, it is the main metabolite.

Metabolites are excreted in the urine. Only about 1% of a single dose of ropivacaine is excreted unchanged as ropivacaine. The average value of the total clearance of ropivacaine is about 440 ml / min, the clearance of unbound ropivacaine is

8 l / min, and renal clearance - 1 ml / min. The terminal elimination half-life is 1.8 hours after drug administration, and the hepatic intermediate extraction coefficient is approximately 0.4.

Impairment of renal function has little or no effect on the pharmacokinetics of ropivacaine. Renal clearance of PPX has a significant relationship with creatinine clearance. The lack of correlation between exposures of the total composition and its unbound fraction, expressed as AUC and creatinine clearance, indicate that the total clearance of PPX includes, in addition to renal excretion, non-renal excretion. Some patients with impaired renal function may exhibit elevated level exposure to PPH resulting from low nonrenal clearance. Since the toxic effect on the central nervous system is lower for PPH compared to ropivacaine, the clinical consequences of such exposure during short-term treatment are considered to be negligible.

Application in pediatric practice

The pharmacokinetics of ropivacaine are based on an analysis of data for a pooled patient population obtained in six studies that included 192 children aged 0 to 12 years.

In the first years of life, the clearance of unbound ropivacaine and PPH depends on the body weight and age of the child. The effect of age is interpreted in terms of maturation of liver function; clearance normalized according to body weight reaches a maximum of about

1-3 years. The clearance of unbound ropivacaine increases from 2.4 L / h / kg in neonates and from 3.6 L / h / kg in infants at 1 month of age, according to approximately

8-16 l / h / kg for children from 6 months.

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

The half-life of ropivacaine is longer - 5-6 hours in newborns and monthly infants compared to 3:00 in older children.

The half-life of PPX is even longer - about 43 hours in newborns and

26 hours in monthly babies compared to 15 hours in older children.

Depending on the underdevelopment of liver function, systemic exposure is higher in newborns and slightly higher in infants aged 1-6 months compared to older children. Dosage recommendations for long-term epidural infusion partially compensate for this difference.

Indications

Naropina 7.5 mg / ml and 10 mg / ml

For adults and children over 12 years of age for anesthesia during surgery:
epidural anesthesia for surgical procedures, including cesarean section;
blockade of large nerves;
blockade of peripheral nerves.

Naropina 2 mg / ml

For adults and children over 12 years of age for the relief of acute pain:
long-term epidural infusion or intermittent bolus injections to relieve postoperative pain or to relieve labor pain;
blockade of peripheral nerves;
continued blockade of peripheral nerves by continuous infusion or periodic painful injections, for example, to relieve postoperative pain.
For infants 1 year of age and children under 12 years of age for acute pain relief (during and after surgery):
peripheral blockade with a single injection of the drug
for neonates, infants 1 year of age and children under 12 years of age for caudal epidural block (during and after surgery):
long-term epidural infusion.

Contraindications

Hypersensitivity to ropivacaine or any of the excipients.

Hypersensitivity to local anesthetics of the amide type.

General contraindications associated with epidural or regional anesthesia, regardless of whether a 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 together with drugs that are structurally similar to local anesthetics, that is, antiarrhythmic drugs of the IS class, such as lidocaine and mexiletine, since their toxic effects are additive. The simultaneous use of the drug Naropin with general anesthetics or opioids can enhance the adverse effects of each other.

Specific studies of interactions between local anesthetics and class III antiarrhythmics (eg, amiodarone) have not been conducted, but caution is advised in this case.

Cytochrome P450 (CYP) lA2 is involved in the formation of 3-hydroxy-ropivacaine, the main metabolite. In vivo, the clearance of ropivacaine decreased by up to 77% inclusively when used simultaneously with fluvoxamine, a selective and potent inhibitor of CYP1A2. Thus, the simultaneous use of potent inhibitors of CYP1A2, such as fluvoxamine and enoxacin, with this drug can cause metabolic interactions, resulting in an increase in the concentration of ropivacaine in the blood plasma. So, should be avoided long-term use ropivacaine in patients are concomitantly treated with potent CYP1A2 inhibitors.

In vivo, the clearance of ropivacaine decreased by 15% when used simultaneously with ketoconazole, a selective and potent inhibitor of CYP3A4. However, suppression of this enzyme is probably of no clinical significance.

In vitro, ropivacaine is a competitive inhibitor of CYP2D6, but it does not appear to inhibit this isoenzyme when used at concentrations that have been achieved in plasma in a clinical setting.

Application features

Regional anesthesia should always be performed by experienced personnel in an appropriately equipped room. Equipment and drugs required for monitoring and emergency resuscitation should be readily available.

Patients undergoing shoulder block nerve plexus should be in optimal condition; a catheter should be inserted into the patient prior to the blockade. The responsible physician must take necessary measures precautions to avoid intravascular administration of the drug, and be appropriately trained and familiar with the diagnosis and treatment of side effects, systemic toxicity and other complications. One of these complications is the accidental injection of the drug into the subarachnoid space, which can lead to the development high degree spinal blockade with apnea and arterial hypotension. The development of seizures most often occurs after the blockade of the brachial plexus and epidural blockade, may be the result of either accidental intravascular injection of the drug or the result of rapid absorption of the drug from the injection site.

The use of an excessive dose of the drug injected into the subarachnoid space can lead to general spinal blockade.

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

When administering the drug Naropin by intra-articular injection, it is recommended to be careful in case of suspicion of a recent extensive intra-articular injury or in the presence of extensive open surfaces in the joint formed during surgical procedures, this can accelerate absorption and lead to the appearance of increased concentrations in blood plasma.

Effects on the cardiovascular system

Patients who are being treated with class III antiarrhythmic drugs (eg, amiodarone) should be closely monitored. In addition, the need for ECG monitoring in such patients should be considered due to the possibility of additive cardiac effects.

There are rare reports of cases of cardiac arrest during the use of the drug Naropin for epidural anesthesia or blockade of peripheral nerves, especially after unintentional accidental intravascular administration of the drug in elderly patients and in patients with concomitant heart disease. In some cases, resuscitation was complicated. In the event of cardiac arrest, prolonged resuscitation may be necessary to achieve a positive result.

Head and neck blockages

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

Large blockages of peripheral nerves

Large peripheral nerve blocks may require the use of large volumes of local anesthetic in highly vascularized areas, often obscuring large vessels, where there is an increased risk of intravascular injection and / or rapid systemic absorption, which can lead to high concentrations in blood plasma.

hypersensitivity

The possibility of developing cross-hypersensitivity should be taken into account when using the drug with other local anesthetics of the amide type.

hypovolemia

Patients with hypovolemia during epidural anesthesia, regardless of the type of local anesthetic used, may develop sudden and severe arterial hypotension for any reason.

Patients with weakened general condition health

Patients with a weakened general health condition through elderly age and due to the presence of such compromising factors as partial or complete blockade cardiac conduction, progressive liver disease, or severe renal impairment require special attention, although regional anesthesia is often indicated in such patients.

Patients with impaired liver and kidney function

Ropivacaine is metabolized in the liver, therefore, the drug should be used with caution in patients with severe liver disease - due to the slow elimination of the drug from the body, it may be necessary to reduce repeated doses. There is no need to change the dose for patients with impaired renal function if the drug is used for a single dose or short-term treatment.

Acidosis and decreased plasma protein concentrations, often seen in patients with chronic renal failure, may increase the risk of systemic toxicity.

This risk should also be taken into account in malnourished patients and in patients treated for hypovolemic shock.

acute porphyria

A solution of the drug Naropin for injection and infusion can provoke the development of porphyria, therefore it should be prescribed to patients with acute porphyria only in the absence of a safe alternative.

chondrolysis

After the release of the drug on the market, there were reports of the development of chondrolysis in patients who received a long-term infusion of the drug during intra-articular local anesthesia. In most cases, the development of chondrolysis involving the shoulder joint has been reported. Due to the presence of a number of contributing causes and conflicting scientific data on the mechanism of action of ropivacaine, a causal relationship has not been established. Long-term intra-articular infusion is not an approved indication for the use of Naropin.

Excipients with a specific action / effect

This is medicine contains no more than 3.7 mg sodium per ml. This should be taken into account in patients who are on a diet that controls sodium levels.

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.

Due to the immaturity of certain organs and functions, newborns may require special attention. Large fluctuations in the concentration of ropivacaine in blood plasma observed during clinical research in neonates, suggest that there may be an increased risk of systemic toxicity in this age group, especially with prolonged epidural infusion. Recommended doses for neonates are based on limited clinical data. In newborns, due to the slow elimination of the drug from the body when using ropivacaine, it is necessary to regularly monitor the possibility of developing systemic toxicity (for example, by monitoring signs of toxic effects on the central nervous system, ECG indicators, monitoring the saturation of peripheral oxygen) and local neurotoxicity (for example, a long recovery period) which should be extended after the end of the infusion.

Cases of using higher concentrations (more than 5 mg / ml) of the drug in children have not been reported.

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

Safety and efficacy of using ropivacaine at a dose of 2 mg / ml for regional blockade in children<12 лет не установлены.

Safety and efficacy of ropivacaine 2 mg / ml for peripheral nerve block in infants<1 года не установлены.

Application during pregnancy or lactation

pregnancy

In addition to data on epidural administration of the drug when used in obstetric practice, there are no sufficient data on the use of the drug in pregnant women. Data obtained from animal studies does not indicate direct or indirect harmful effects in relation to pregnancy, embryonic / intrauterine development, childbirth or postpartum development.

There have been no reports of spinal drug administration during cesarean section.

Breastfeeding. Currently, it remains unknown how ropivacaine penetrates into breast milk.

The ability to influence the reaction rate when driving vehicles or other mechanisms. Any data is missing. Depending on the dose, local anesthetics may have little effect on mental function and coordination, even in the absence of obvious toxic effects on the central nervous system, and may also temporarily impair motor activity and vigilance.

Method of administration and dosage

Naropin is administered only by doctors with experience in anesthesia, or by junior medical personnel under their supervision. To achieve a sufficient degree of anesthesia, it is necessary to use the lowest possible dose of the drug.

Before starting treatment, it is necessary to test for individual sensitivity.

Adults and children over 12 years old

Surgical anesthesia usually requires high doses and higher concentrations than analgesia for acute pain relief, 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 over 12 years old

Indications

	Concentration (mg / ml)	Volume (ml)	Dose (mg)	Onset of action (min)	Duration of action (h)
Surgical anesthesia
Lumbar epidural injection for surgical intervention	7.5 mg / ml 10 mg / ml	15-25 ml 15-20 ml	113-188 mg 150-200 mg	10-20 minutes 10-20 minutes	3-5 h 4-6 h
Lumbar epidural injection for caesarean section	7.5 mg / ml	15-20 ml	113-150 mg	10-20 minutes	3-5 h
Thoracic epidural injection for postoperative analgesic blockade	7.5 mg / ml	5-15 ml depending on the injection level	38-113 mg	10-20 minutes	__
Brachial plexus block	7.5 mg / ml	10-40 ml	75-300 mg 1)	10-25 minutes	6-10 h
Blockade of small and medium nerves and infiltration anesthesia	7.5 mg / ml	1-30 ml	7.5-225 mg	1-15 minutes	2-6 h
Relief of acute PAIN
Lumbar epidural administration
bolus	2 mg / ml	10-20 ml	20-40 mg	10-15 minutes	0.5-1.5 h
Intermittent injections (additional doses), for example, for pain relief during labor	2 mg / ml	10-15 ml at intervals of at least 30 minutes	20-30 mg	__	__
Long-term infusion, such as for postoperative pain relief or pain relief during labor	2 mg / ml	6-14 ml / h	12-28 mg / h	__	__
Thoracic epidural administration
Long-term infusion, e.g. for postoperative pain relief	2 mg / ml	6-14 ml / h	12-28 mg / h	__	__
Peripheral nerve block and infiltration anesthesia	2 mg / ml	1-100 ml	2-200 mg	1-5 minutes	2-6 h
Intra-articular injection 3) (eg, single dose for knee arthroscopy)	7.5 mg / ml	20 ml	150 mg 2)	__	2-6 h
Peripheral nerve blocks (femoral or myjdrabin blockade) Long-term infusion or intermittent injections (eg, for postoperative pain relief)	2 mg / ml	5-10 ml / h	10-20 mg / h	__	__

Doses given in the table are required to provide a clinically acceptable block; they should be considered the recommended dosage for adults.

There are significant individual fluctuations in the onset time and duration of the effect.

1) The dose for the blockade of the nerve plexus should be adjusted depending on the place of administration of the drug and the patient's condition. An increased incidence of serious adverse reactions may be observed with mydrabin block and supraclavicular brachial plexus blocks, regardless of the type of local anesthetic used.

2) When an additional dose of ropivacaine is administered using any other technique, the same patient should not exceed a total dose of 225 mg.

3) After the release of the drug on the market, there were reports of the development of chondrolysis in patients receiving long-term infusion for intra-articular local anesthesia. Long-term intra-articular infusion is not an approved indication for the drug.

It is important to take special care to prevent accidental intravascular injection. A thorough aspiration test is recommended before and during the total dose injection. The total dose should be administered slowly, at a rate of 25-50 mg / min, or in separate doses, constantly monitoring the patient's condition. For epidural administration, it is recommended to administer a test dose of 3-5 ml of xylocaine adrenaline. Inadvertent intravascular injection can cause, for example, a short-term increase in heart rate, and inadvertent intrathecal injection can lead to signs of spinal blockade. If symptoms of intoxication occur, the administration of the drug should be stopped immediately.

When conducting epidural block during surgical interventions, use single doses of up to 250 mg of ropivacaine, which are well tolerated.

With blockade of the brachial plexus by introducing 40 ml of the drug Naropin with a concentration of 7.5 mg / ml, the maximum concentration of ropivacaine in some patients may approach the level at which mild symptoms of toxic effects of the drug on the central nervous system were described. Therefore, it is not recommended to use doses exceeding 40 ml of the drug Naropin with a concentration of 7.5 mg / ml (300 mg of ropivacaine).

When carrying out prolonged infusion or repeated painful injections, the risk of toxic plasma concentrations or damage to the local nerve should be taken into account. Total doses of up to 675 mg of ropivacaine administered within 24 hours were well tolerated by adult patients during surgical anesthesia and postoperative pain relief. Good tolerance has also been observed in adults with long-term epidural infusions given after surgery for 72 hours at an infusion rate of up to 28 mg / h. In a limited number of patients, the administration of higher doses of the drug (up to 800 mg / day) was accompanied by the appearance of a relatively small number of adverse reactions.

Relief of postoperative pain: blockade is carried out before surgery by administering Naropin 10 mg / ml or 7.5 mg / ml after surgery by epidural bolus administration of 7.5 mg / ml Naropin. Maintain analgesia with an epidural infusion of the drug Naropin 2 mg / ml. Clinical studies have shown that infusion at a rate of 6-14 ml (12-28 mg) per hour usually provides satisfactory anesthesia for moderate to severe postoperative pain, with only mild and non-progressive motor block in most cases. The maximum duration of an epidural block is 3 days. However, careful monitoring of the analgesic effect of the drug should be carried out in order to remove the catheter as soon as the pain condition allows it. This technique can significantly reduce the need for additional use of opioid analgesics.

Clinical studies were also conducted in which Naropina at a dose of 2 mg / ml was used alone or in combination with fentanyl (1-4 μg / ml) for 72 hours as an epidural infusion for postoperative pain relief. Naropina 2 mg / ml

(6-14 mg / h) provided adequate pain relief in most patients. The combination of the drug Naropin with fentanyl provided better pain relief, but caused the occurrence of opioid side effects.

For caesarean section, the epidural use of ropivacaine at a concentration of more than

7.5 mg / ml spinal use not documented.

When carrying out a long-term blockade of peripheral nerves by continuous infusion or repeated injections, the risk of reaching a toxic concentration of the drug in the blood plasma or causing local neurological damage should be taken into account. In clinical studies, blockade of the femoral nerve before surgery was achieved by administering 300 mg of Naropin at a concentration of 7.5 mg / ml, and mizhdrabinchasta blockade by injecting 225 mg of Naropin at a concentration of 7.5 mg / ml. Further, analgesia was maintained by the administration of the drug Naropin at a dose of 2 mg / ml. The infusion rate or intermittent injections of 10-20 mg per hour for 48 hours provided sufficient analgesia and was well tolerated.

Children under 12 years old

Table 2. Children under 12 years old

	concentration (Mg / ml)	Volume (Ml / kg)	dose (Mg / kg)
Relief of acute PAIN (Before and after surgery)
Caudal block in children 0-12 years old Blockade below the T12 level, in children weighing up to 25 kg inclusive	2 mg / ml	1 ml / kg	2 mg / kg
Long-term epidural infusion In children weighing up to 25 kg inclusive
0-6 months Bolus dose a)	2 mg / ml 2 mg / ml	0.5-1 ml / kg 0.1 ml / kg / h	1-2 mg / kg 0.2 mg / kg / h
6-12 months Bolus dose a) Infusion lasting up to 72 hours	2 mg / ml 2 mg / ml	0.5-1 ml / kg 0.2 ml / kg / h	1-2 mg / kg 0.4 mg / kg / h
1-12 years old Bolus dose b) Infusion lasting up to 72 hours	2 mg / ml 2 mg / ml	1 ml / kg 0.2 ml / kg / h	2 mg / kg 0.4 mg / kg / h
Peripheral nerve block 1-12 years old
long-term infusion	2 mg / ml	0.1-0.3 ml / kg / h	0.2-0.6 mg / kg / h
Infusion lasting up to 72 hours

When using the drug in children, the doses given in the table should be considered as recommendations. There are cases of individual variation. Overweight children often need a gradual dose reduction calculated based on ideal body weight. The volume of the drug for conducting caudal epidural block with a single injection of the drug and the volume of the drug for conducting epidural block when painful doses of the drug are administered should not exceed 25 ml for any patient.

The use of ropivacaine in doses of 7.5 and 10 mg / ml in children can lead to systemic toxic effects and the effect of the drug on the central nervous system. Thus, a low concentration level (2 mg / ml) is more acceptable for use in such patients.

The dosage guidelines for peripheral blockade in infants and children provide a methodological basis for using the drug in children without serious illness. For children with serious illnesses, the use of lower doses of the drug and careful monitoring is recommended.

The use of ropivacaine in premature infants has not been documented.

It is important to take more care to prevent accidental intravascular injection. A thorough aspiration test is recommended before and during the total dose injection. During the administration of the drug, the vital functions of the patient should be closely monitored. If signs of toxic effects occur, the administration of the drug should be discontinued immediately.

Caudal epidural injection of ropivacaine at a dose of 2 mg / mL provides adequate postoperative analgesia below the T12 level in most patients when the dose

2 mg / kg is administered in a volume of 1 ml / kg. The volume of the caudal epidural injection can be adjusted to achieve control over the spread of sensory blockade. Doses up to 3 mg / kg inclusive with a ropivacaine concentration of 3 mg / ml were safely used in children aged 4 years and older.

The experience of using caudal blockades in children weighing more than 25 kg is limited.

Children. The drug is used in pediatric practice.

Overdose

toxicity

After accidental intravascular injections during brachial plexus blockade and other peripheral blockade, there have been cases of trial.

After spinal use, systemic toxicity is not expected to develop, since a low dose of the drug is used in this case. Intrathecal administration of a very high dose of the drug can lead to total spinal blockade, which in turn will lead to suppression of the cardiovascular system and the development of respiratory failure.

symptoms

Systemic toxic reactions are mainly related to the central nervous system and the cardiovascular system. The appearance of such reactions is due to the high concentration of local anesthetics in the blood, which may be due to accidental intravascular administration of the drug, overdose, or extremely rapid absorption from highly vascularized areas.

CNS symptoms are similar for all amide-type local anesthetics, while cardiac symptoms are more dependent on the type of drug, both quantitatively and qualitatively.

Accidental intravascular injection of local anesthetics can cause immediate (seconds to minutes) systemic toxicity. In case of overdose, systemic toxicity appears later (15-60 minutes after injection) through a slower increase in the concentration of local anesthetic in the blood.

If signs of acute systemic toxicity occur, the use of local anesthetics should be discontinued immediately, and treatment should be directed to the rapid cessation of symptoms from the central nervous system (trial and depression of the central nervous system) in order to maintain oxygenation and blood circulation. Oxygen should always be provided and, if necessary, artificial respiration should be provided. If the seizures do not stop spontaneously after 15-20 seconds, the patient should be given intravenous sodium thiopental at a dose of 1-3 mg / kg to ensure adequate ventilation, or diazepam 0.1 mg / kg IV (acting much slower). Prolonged seizures threaten the patient's breathing and oxygenation. Injection of a muscle relaxant (for example, suxamethonium at a dose of 1 mg / kg) creates favorable conditions for patient ventilation and oxygenation, but requires experience in tracheal intubation and mechanical ventilation.

In case of circulatory arrest, measures for cardiopulmonary resuscitation should be started immediately. Maintaining proper oxygenation, ventilation and circulation, and treating acidosis are vital.

In case of depression of cardiac function (drop in blood pressure / bradycardia), consideration should be given to the appointment of appropriate treatment with the introduction of a liquid, a vasopressor agent (for example, the introduction of ephedrine at a dose of 5-10 mg, which can be repeated after 2-3 minutes) and / or an inotrope.

In case of cardiac arrest, achieving a positive result may require lengthy resuscitation measures.

When treating symptoms of toxicity in children, doses appropriate for their age and body weight should be used.

Adverse Reactions

The side effect profile of Naropin is similar to that of other long acting amide-type local anesthetics. During clinical trials, a large number of symptoms have been recorded that can develop regardless of the type of local anesthetic used, and also often represent physiological effects resulting from nerve blockade and the development of the clinical situation. Side effects caused by the use of the drug are difficult to distinguish from physiological effects caused by nerve blocks and sympathetic blockages, as well as events caused directly during the puncture with a needle (for example, spinal hematoma, headache, appeared after puncture of the dural space, meningitis and epidural abscess ). Many of the most commonly reported adverse reactions, such as nausea, vomiting and hypotension, are very common during anesthesia and surgical procedures, and these adverse reactions resulting from the development of the clinical situation cannot be distinguished from adverse reactions caused by the use of a drug or appeared as a result of the blockade.

Adverse reactions are listed in the table with the following frequency.

Adverse reactions are reflected within each organ system with the following frequency: very often (≥ 1/10); often (from ≥ 1/100 to<1/10); нечасто (от ≥ 1/1000 до <1/100); редко (от ≥ 1/10000 до <1/1000); очень редко (<1/10000).

Table 1. Adverse reactions during perineural and epidural administration of the drug.

organ system	frequency	unwanted effect
mental disorders	infrequently	anxiety
From the nervous system	often	Paresthesia, dizziness, headache
	infrequently	Symptoms of toxic effects on the central nervous system (convulsions, major epileptic seizure, attacks, light dizziness, perioral paresthesia, numbness of the tongue, hyperacusis, ringing in the ears, visual impairment, dysarthria, muscle convulsive movements, tremor) * hypesthesia
cardiac disorders	often	Bradycardia, tachycardia
	seldom	Cardiac arrest, arrhythmias
From the vascular system	Often	Arterial hypotension a
	often	arterial hypertension
	infrequently	fainting
From the respiratory system, chest and mediastinal organs	infrequently	dyspnea
From the digestive system	Often	nausea
	often	vomiting b
From the kidneys and urinary tract	often	urinary retention
Systemic disorders and complications at the injection site	often	Fever, chills, back pain
	infrequently	hypothermia
	seldom	Allergic reactions (anaphylactic reactions, angioedema and urticaria)

* These symptoms usually result from inadvertent intravascular administration of the drug, overdose or rapid absorption (see also the Overdose section).

a Hypotension is less common and occurs in children (> 1/100).

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

Adverse reactions to the drug, grouped by classes:

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

neurological complications

Spinal cord neuropathy and dysfunction (eg, anterior spinal artery syndrome, arachnoiditis, cauda equina syndrome), which can rarely lead to irreversible consequences, have been associated with spinal and epidural anesthesia, regardless of the type of local anesthetic used.

Total spinal block

Total spinal blockade can develop with accidental intrathecal administration of an epidural dose or with a very large spinal dose of the drug. The effects of systemic overdose and accidental intravascular injection can be serious.

Central nervous system toxicity

The toxic effect on the central nervous system is a phased reaction with symptoms and signs, accompanied by an increase in severity. At first, symptoms such as mild dizziness, perioral paresthesia, numbness of the tongue, hyperacusis, ringing in the ears and visual impairment are observed. Dysarthria, muscle stiffness, and muscle twitching are more serious symptoms and may be the onset of generalized seizures. These signs should not be mistaken for neurotic behavior. After this, loss of consciousness and a large epileptic seizure can occur, which can last from a few seconds to several minutes. During seizures, oxygen deficiency and hypercapnia rapidly develop due to increased muscle activity and insufficient gas exchange in the lungs. In severe cases, respiratory arrest may even develop. The development of acidosis, hyperkalemia, hypocalcemia and oxygen deficiency increases and lengthens the toxic effects of local anesthetics.

Recovery depends on the metabolism of the local anesthetic and its distribution outside the central nervous system. This happens quickly, unless the drug has been injected in very large quantities.

Toxic effects on the cardiovascular system

Toxic effects on the cardiovascular system are usually the cause of the development of a more serious situation. As a result of the action of high systemic concentrations of local anesthetics, arterial hypotension, bradycardia, arrhythmia and even cardiac arrest can develop. The volunteers developed signs of conduction suppression and contraction as a result of ropivacaine infusion.

Signs of the development of toxic effects of the drug on the central nervous system, as a rule, are the precursors of the effect of the drug on the cardiovascular system. Prodromal CNS symptoms may not occur in patients receiving a general anesthetic drug or under the influence of strong sedatives such as benzodiazepines or barbiturates.

Storage conditions

Store at a temperature not exceeding 30 ° C. Do not freeze. Keep out of the reach of children.

Directions for use, disposal behavior

Naropina, solution for injection, does not contain preservatives and is intended for single use only. The rest of the solution should be disposed of. An open infusion bag can be applied within 24 hours. Unopened packaging should not be autoclaved again. If sterile from the outside of the ampoule or infusion bags are required, a blister pack should be chosen.

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

The mixture is chemically and physically stable for 30 days at a temperature not exceeding 30 ° C. When preparing the mixture in the ward, it should be used immediately due to the risk of microbial contamination. When preparing the mixture on a LAF table in a clean area, the ui can be stored for a maximum of 24 hours at a temperature of 2-8 ° C. purity.

Incompatibility

Not known.

Package

For 2 mg / ml - 100 ml in a container, 1 container in a blister, 5 blisters in a cardboard box.

For 7.5 mg / ml 10.0 mg / ml - 10 ml in an ampoule, 1 ampoule in a blister, 5 blisters in a cardboard box.

Dosage Form: & nbsp

injection

Compound:

Active substance: ropivacaine hydrochloride monohydrate corresponding to 2.0 mg, 7.5 mg and 10.0 mg ropivacaine hydrochloride.

Excipients: sodium chloride 8.6 mg, 7.5 mg and 7.1 mg, respectively, 2 M sodium hydroxide solution and / or 2 M hydrochloric acid solution to adjust the pH to 4.0 - 6.0, water for injection to 1 , 0 ml.

Description:

Transparent colorless solution.

Characteristic

The solution of the drug Naropin® is a sterile isotonic aqueous solution, does not contain preservatives and is intended for single use only. pKa of ropivacaine 8.1; distribution coefficient - 141 (n-octanol / phosphate buffer pH 7.4 at 25 ° C).

Pharmacotherapeutic group:Local anesthetic ATX: & nbsp

N.01.B.B Amides

N.01.B.B.09 Ropivacaine

Pharmacodynamics:

Ropivacaine is the first long-acting amide-type local anesthetic that is a pure enantiomer. It has both anesthetic and analgesic effects. High doses of ropivacaine are used for local anesthesia in surgical procedures, while low doses of the drug provide analgesia (sensory block) with minimal and non-progressive motor block. The duration and intensity of the blockade caused by ropivacaine is not affected by the addition of epinephrine. By reversibly blocking voltage-gated sodium channels, it prevents the generation of impulses at the endings of sensory nerves and the conduction of impulses along nerve fibers.

Like other local anesthetics, it can affect other excitable cell membranes (for example, in the brain and myocardium). If an excess amount of local anesthetic reaches the systemic circulation within a short period of time, signs of systemic toxicity may occur. Signs of toxicity from the central nervous system precede signs of toxicity from the cardiovascular system, since they are observed at lower concentrations of ropivacaine in plasma (see section "Overdose"). The direct effect of local anesthetics on the heart includes conduction deceleration, negative inotropic effect and, in severe overdose, arrhythmias and cardiac arrest. Intravenous administration of high doses of ropivacaine has the same effects on the heart.

Intravenous infusion of ropivacaine in healthy volunteers has been shown to be well tolerated.

Indirect cardiovascular effects (lowering blood pressure, bradycardia) that can occur after epidural administration of ropivacaine are due to the resulting sympathetic blockade.

Pharmacokinetics:

The concentration of ropivacaine in blood plasma depends on the dose, route of administration and the degree of vascularization of the injection site. The pharmacokinetics of ropivacaine is linear, the maximum concentration (C max) is proportional to the administered dose.

After epidural administration, it is completely absorbed. Absorption is biphasic, the half-life (T 1/2) for the two phases is, respectively, 14 minutes and 4 hours. The slowdown in the elimination of ropivacaine is determined by slow absorption, which explains the longer T 1/2 after epidural administration compared with intravenous administration.

The total plasma clearance of ropivacaine is 440 ml / min, the plasma clearance of unbound substances is 8 l / min, the renal clearance is 1 ml / min, the volume of distribution in the equilibrium state is 47 l, the hepatic extraction index is about 0.4, T 1/2 is 1.8 including intensively binds to blood plasma proteins (mainly with a 1-acid glycoproteins), the unbound fraction of ropivacaine is about 6%. Long-term epidural infusion of ropivacaine leads to an increase in the total content of the drug in the blood plasma, which is due to an increase in the content of acidic glycoproteins in the blood after surgery, while the concentration of the unbound, pharmacologically active form of ropivacaine in the blood plasma changes to a much lesser extent than the total concentration of ropivacaine.

Ropivacaine crosses the placental barrier with a rapid equilibration of the unbound fraction. The degree of binding to blood plasma proteins in the fetus is less than in the mother, which leads to lower concentrations of ropivacaine in the fetal plasma compared to the total concentration of ropivacaine in the mother's blood plasma. actively metabolized in the body, mainly by aromatic hydroxylation. 3-hydroxyropivacaine (conjugated + unconjugated) is found in blood plasma. 3-hydroxy and 4-hydroxypi-caine have a weaker local anesthetic effect than ropivacaine.

After intravenous administration, 86% of ropivacaine is excreted in the urine and only about 1% of the drug excreted in the urine is excreted unchanged. About 37% of 3-hydroxyropivacaine, the main metabolite of ropivacaine, is excreted in the urine mainly in conjugated form.

1-3% of ropivacaine is excreted in the urine in the form of the following metabolites: 4-hydroxyropivacaine, N-dealkylated metabolites and 4-hydroxy-dealkylated ropivacaine. There is no evidence of racemization of ropivacaine in vivo.

Indications:

Surgical anesthesia:

Epidural block during surgery, including cesarean section;

Blockade of large nerves and nerve plexuses;

Blockade of individual nerves and infiltration anesthesia. Relief of acute pain syndrome:

Prolonged epidural infusion or intermittent bolus infusion, for example, to relieve postoperative pain or pain relief during labor;

Blockade of individual nerves and infiltration anesthesia;

Prolonged peripheral nerve blockade;

Intra-articular injection.

Relief of acute pain syndrome in pediatrics:

Caudal epidural block in newborns and children under 12 years of age inclusive;

Extended epidural infusion in newborns and children up to 12 years of age inclusive.

Contraindications:

Hypersensitivity to the components of the drug.

Known hypersensitivity to local anesthetics of the amide type.

Carefully:

Weakened elderly patients or patients with severe concomitant diseases, such as blockade of intracardiac conduction of II and III degrees (sinoatrial, atrioventricular, intraventricular), progressive liver disease, severe hepatic failure, severe chronic renal failure, in the treatment of hypovolemic shock. For these patient populations, regional anesthesia is often preferred. When carrying out "large" blockades in order to reduce the risk of developing severe adverse events, it is recommended to preliminarily optimize the patient's condition, as well as adjust the dose of anesthetic. Caution should be exercised when injecting local anesthetics in the head and neck region due to the possible increased incidence of serious side effects. With intra-articular administration of the drug, caution should be exercised if there is a suspicion of recent extensive joint injury or surgery with the opening of extensive joint surfaces, due to the possibility of increased absorption of the drug and a higher concentration of the drug in plasma.

Particular attention should be paid when using the drug in children under 6 months of age due to the immaturity of organs and functions.

Pregnancy and lactation:

Pregnancy

There was no evidence of the effect of ropivacaine on fertility and reproductive function, as well as teratogenic effects. No studies have been conducted to assess the possible effect of ropivacaine on fetal development in women.

Naropin® can be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus (in obstetrics, the use of the drug for anesthesia or analgesia is well justified).

Studies of the effect of the drug on reproductive function were carried out in animals. In studies on rats, it had no effect on fertility and reproduction in two generations. When the maximum doses of ropivacaine were administered to pregnant rats, an increase in offspring mortality was observed in the first three days after birth, which may be explained by the toxic effect of ropivacaine on the mother, leading to a violation of the maternal instinct.

Lactation

The excretion of ropivacaine or its metabolites in breast milk has not been studied. Based on experimental data, the dose given to newborns is estimated to be 4% of the dose given to the mother (milk concentration / plasma drug concentration). The total dose of ropivacaine exposed to a baby during breastfeeding is significantly less than the dose that can enterfetus with the introduction of an anesthetic to the mother during childbirth. If it is necessary to use the drug during breastfeeding, the ratio of the potential benefits to the mother and the possible risk to the baby should be considered.

Method of administration and dosage:

Naropin® should only be used by specialists with sufficient experience in local anesthesia, or under their supervision.

Adults and children over 12 years old:

In general, surgical anesthesia requires higher doses and more concentrated drug solutions than when using an anesthetic for pain relief. When using an anesthetic for pain relief, a dose of 2 mg / ml is usually recommended. For intra-articular administration, a dose of 7.5 mg / ml is recommended.

The doses indicated in Table 1 are considered sufficient to achieve a reliable blockade and are indicative when using the drug in adults, since there is individual variability in the rate of blockade development and its duration.

The data in Table 1 is an indicative guide to the dosage of the drug for the most commonly used blockades. The selection of the dose of the drug should be based on clinical experience, taking into account the physical condition of the patient.

Concentration

Volume

Dose

Start

Duration

ation

solution

(mg)

actions

ness

Surgical anesthesia:

Epidural anesthesia at the lumbar level:

Surgical interventions

15-25

113-188

10-20

10,0

15-20

150-200

10-20

Cesarean section

15-20

113-150

10-20

Thoracic epidural anesthesia:

Postoperative

anesthetic block

and surgical interventions

5-15

38-113

10-20

Large nerve plexus blockade:

For example, a brachial plexus block

10-40

75 - 300*

10-25

6-10

Conduction and infiltration anesthesia

1-30

7,5 - 225

1 -15

Relief of acute pain syndrome:

Epidural administration at the lumbar level:

Bolus

10-20

20-40

10-15

0,5 - 1,5

Periodic introduction

(for example, for

pain relief

childbirth)

10-15 (minimum

interval - 30 min)

20-30

Extended infusion for:

Labor pain relief

6-10 ml / h

12-20 mg / h

After

surgical pain relief

6-14 ml / h

12 - 28 mg / h

Peripheral nerve block:

For example, blockade

femoral nerve or

interstitial

blockade

(extended

infusion or

repeated

injection)

5-10 ml / h

10-20 mg / h

Epidural administration at the thoracic level:

Extended infusion

(for example, for

postoperative

Wow

pain relief)

6-14 ml / h

12-28 mg / h

Wire block and infiltration anesthesia

1 -100

2-200

Intra-articular administration

Arthroscopy

knee

joint **

150***

* The dose for blockade of large nerve plexuses should be selected in accordance with the site of administration and the condition of the patient. Interstellar and supraclavicular brachial plexus blockade can be associated with a high incidence of serious adverse reactions, regardless of the local anesthetic used.

** Cases of chondrolysis have been reported with postoperative prolonged intra-articular infusion of local anesthetics. Naropin® should not be used for prolonged intra-articular infusion.

*** If Naropin® was additionally used for other types of anesthesia, the maximum dose should not exceed 225 mg.

To familiarize yourself with the factors affecting the method of performing individual blocks, and with the requirements for specific groups of patients, standard guidelines should be used.

To prevent the ingress of the anesthetic into the vessel, it is imperative to carry out an aspiration test before and during the administration of the drug. If you intend to use the drug in a high dose, it is recommended to introduce a trial dose - 3-5 ml of lidocaine with epinephrine. Inadvertent intravascular injection is recognized by a temporary increase in heart rate, and inadvertent intrathecal injection is recognized by signs of spinal block. If toxic symptoms appear, the drug should be discontinued immediately.

Before the introduction and during the administration of the drug Naropin® (which should be carried out slowly or by increasing the doses of the drug administered sequentially at a rate of 25-50 mg / min), it is necessary to carefully monitor the vital functions of the patient and maintain verbal contact with him.

A single dose of ropivacaine up to 250 mg for epidural block for surgical intervention is usually well tolerated by patients. With blockade of the brachial plexus using 40 ml of Naropin® 7.5 mg / ml, the maximum plasma concentrations of ropivacaine in some patients can reach a value characterized by mild symptoms of toxicity from the central nervous system. Therefore, the use of a dose higher than 40 ml of Naropin® 7.5 mg / ml (300 mg ropivacaine) is not recommended.

With prolonged blockade by prolonged infusion or repeated bolus administration, the possibility of creating toxic concentrations of the anesthetic in the blood and local nerve damage should be taken into account. The administration of ropivacaine for 24 hours at a dose of up to 800 mg in total for surgical interventions and for postoperative pain relief, as well as prolonged epidural infusion after surgery at a rate of up to 28 mg / h for 72 hours is well tolerated by adult patients. To relieve postoperative pain, the following scheme of drug use is recommended: if an epidural catheter was not installed during surgery, after its installation, an epidural blockade with a bolus injection of Naropin® (7.5 mg / ml) is performed. Analgesia is supported by an infusion of Naropin® (2 mg / ml). In most cases, to relieve moderate to severe postoperative pain, infusion at a rate of 6-14 ml / h (12-28 mg / h) provides adequate analgesia with minimal non-progressive motor blockin opioid analgesics).

For postoperative pain relief, Naropin® (2 mg / ml) can be administered continuously as an epidural infusion for 72 hours without fentanyl or in combination with it (1-4 μg / ml). When using the drug Naropin® 2 mg / ml (6-14 ml / hour), adequate pain relief was provided in most patients. The combination of the drug Naropin® and fentanyl led to an improvement in pain relief, while causing the side effects inherent in narcotic analgesics.

The use of the drug Naropin® at a concentration above 7.5 mg / ml for cesarean section has not been studied.

	Drug concentration (mg / ml)	Solution volume (ml / kg)	Dose (mg / kg)
Relief of acute pain syndrome (intraoperative and postoperative):
Caudal epidural administration:
Blockade in the area below Th XII in children weighing up to 25 kg.

Extended epidural infusion in children weighing up to 25 kg,
Age from 0 to 6 months
Bolus *		0,5-1
Infusion up to 72 hours		0.1 ml / kg / h	0.2 mg / kg / h
Age 6 to 12 months
Bolus *		0,5-1
Infusion up to 72 hours		0.2 ml / kg / h	0.4 mg / kg / h
Age from 1 to 12 years old inclusive
Bolus **
Infusion up to 72 hours		0.2 ml / kg / h	0.4 mg / kg / h

* Smaller doses of the suggested interval are recommended for thoracic epidurals, while larger doses are recommended for lumbar or caudal epidurals.

The doses indicated in Table 2 are guidelines for the use of the drug in pediatric practice. At the same time, there is individual variability in the rate of development of the block and its duration.

In overweight children, a gradual dose reduction is often required; in this case, it is necessary to be guided by the "ideal" body weight of the patient. For background information on the factors that influence the methods of performing individual blocks and on the requirements for specific groups of patients, refer to specialized guidelines. The volume of the solution for caudal epidural administration and the volume of the bolus for the epidural administration should not exceed 25 ml for any patient.

A single injection of ropivacaine at a dose of 2 mg / ml (based on 2 mg / kg solution volume of 1 ml / kg) for postoperative caudal analgesia provides adequate analgesia below the level Th XII in most patients. Children over 4 years of age tolerate doses up to 3 mg / kg well. The volume of epidural solution infused at the caudal level can be adjusted to achieve different sensory block prevalence, as described in specific guidelines. Regardless of the type of anesthesia, bolus administration of the calculated dose of the drug is recommended.

The use of the drug at a concentration above 5 mg / ml, as well as the intrathecal use of the drug Naropin® in children, has not been studied. The use of the drug Naropin® in premature infants has not been studied.

Solution instructions

The solution does not contain preservatives and is intended for single use only. Any amount of solution left in the container after use must be destroyed.

An unopened container of solution must not be autoclaved.

Unopened blister pack ensures sterility of the outer surfacecontainer and is preferred for use in conditions requiring sterility.

Side effects:

Adverse reactions to Naropin® are similar to those to other local anesthetics of the amide type. They should be distinguished from the physiological effects arising from blockade of sympathetic nerves with epidural anesthesia, such as lowering blood pressure, bradycardia, or effects associated with the technique of drug administration, such as local nerve damage, meningitis, post-dural puncture headache, epidural abscess.

Side Effects of Local Anesthetics

From the central and peripheral nervous system

Possible neuropathy and dysfunction of the spinal cord (anterior spinal artery syndrome, arachnoiditis, cauda equina syndrome), usually associated with the technique of regional anesthesia, and not with the action of the drug.

Complete spinal block can occur as a result of inadvertent intrathecal administration of an epidural dose.

Serious complications are possible in case of systemic overdose and inadvertent intravascular administration of the drug (see the "Overdose" section).

Acute systemic toxicity

Naropin® can cause acute systemic toxic reactions when using high doses or with a rapid increase in its concentration in the blood in case of accidental intravascular administration of the drug or its overdose (see the section "Pharmacological properties" and "Overdose").

Most common side effects

Various side effects of the drug were reported, the vast majority of which were associated not with the effect of the anesthetic used, but with the technique of regional anesthesia.

The most common (> 1%) side effects were the following, which were regarded as of clinical significance, regardless of whether a causal relationship was established with the use of anesthetic: lowering blood pressure (BP) *, nausea, bradycardia, vomiting, paresthesia , fever, headache, urinary retention, dizziness, chills, increased blood pressure, tachycardia, hypesthesia, anxiety. The frequency of occurrence of undesirable effects is presented as follows:

Very often (> 1/10); Often (> 1/100,< 1/10); Нечасто (> 1/1000, < 1/100); Редко (> 1/10 000, < 1/1 000); Очень редко (< 1/10 000), включая отдельные сообщения.

Often	From the side of the cardiovascular system: lowering blood pressure * From the gastrointestinal tract (GIT): nausea
Often	From the nervous system: paresthesia, dizziness, headache From the side of the cardiovascular system: bradycardia, tachycardia, increased blood pressure From the side of the gastrointestinal tract: vomiting ** From the genitourinary system: urinary retention General: back pain, chills, fever
Infrequently	From the nervous system: anxiety, symptoms of toxicity from the central nervous system (convulsions, large seizures, paresthesia in the perioral zone, dysarthria, numbness of the tongue, visual impairment, ringing in the ears, hyperacusis, tremor, muscle cramps), hypesthesia From the vascular system: fainting From the respiratory system: shortness of breath, difficulty breath General: hypothermia
Seldom	From the cardiovascular system: arrhythmia, cardiac arrest General: allergic reactions (anaphylacticreactions, angioedema, urticaria)

* A decrease in blood pressure is common in children.

** Vomiting is very common in children.

Overdose:

Acute systemic toxicity

Cases of seizures have been observed with accidental intravascular injection during nerve plexus blockade or other peripheral blockade. If the epidural dose is incorrectly administered intrathecally, a complete spinal block may occur.

Inadvertent intravascular injection of anesthetic can cause an immediate toxic reaction.

In case of an overdose during regional anesthesia, symptoms of a systemic toxic reaction appear on a delayed basis 15-60 minutes after injection due to a slow increase in the concentration of local anesthetic in the blood plasma. Systemic toxicity is primarily manifested by symptoms of the central nervous system (CNS) and cardiovascular system (CVS). These reactions are caused by high concentrations of local anesthetic in the blood, which can result from (accidental) intravascular administration, overdose, or extremely high adsorption from highly vascularized areas.

CNS reactions are similar for all amide-type local anesthetics, while cardiovascular reactions are more dependent on the drug administered and its dose.

central nervous system

Manifestations of systemic toxicity from the central nervous system develop gradually: first, visual disturbances, numbness around the mouth, numbness of the tongue, hyperacusis, ringing in the ears, and dizziness appear. Dysarthria, tremors, and muscle twitching are more serious manifestations of systemic toxicity and may precede the onset of generalized seizures (these signs should not be confused with the patient's neurotic behavior). With the progression of intoxicationloss of consciousness, seizures lasting from several seconds to several minutes, accompanied by respiratory failure, rapid development of hypoxia and hypercapnia due to increased muscle activity and inadequate ventilation can be observed. In severe cases, respiratory arrest may even occur. The resulting acidosis, hyperkalemia, hypocalcemia increase the toxic effects of the anesthetic.

Subsequently, due to the redistribution of the anesthetic from the central nervous system and its subsequent metabolism and excretion, a fairly rapid recovery of functions occurs, unless a large dose of the drug has been administered.

The cardiovascular system

Cardiovascular disorders are signs of more serious complications. A decrease in blood pressure, bradycardia, arrhythmia and, in some cases, even cardiac arrest can occur due to a high systemic concentration of local anesthetics. In rare cases, cardiac arrest is not accompanied by previous CNS symptoms. In studies on volunteers, intravenous infusion of ropivacaine led to inhibition of conduction and contractility of the heart muscle. Symptoms from the cardiovascular system are usually preceded by manifestations of toxicity from the central nervous system, which can be overlooked if the patient is under the influence of sedatives (benzodiazepines or barbiturates) or under general anesthesia.

In children, early signs of systemic toxicity of local anesthetics are sometimes more difficult to detect due to the difficulty children have in describing symptoms or when regional anesthesia is used in conjunction with general anesthesia.

Acute toxicity treatment

At the first signs of acute systemic toxicity, you should immediately

stop drug administration.

When seizures and symptoms of CNS depression appear, the patient needs adequate treatment, the purpose of which is to maintain oxygenation, stop seizures, and maintain the activity of the cardiovascular system. Oxygenation with oxygen should be provided, and, if necessary, the transition to artificial ventilation of the lungs. If after 15-20 seconds the seizures do not stop, anticonvulsants should be used: sodium thiopental 1-3 mg / kg IV (provides rapid relief of seizures) or 0.1 mg / kg IV (the action develops more slowly compared to the action thiopental sodium). Suxamethonium 1 mg / kg quickly relieves convulsions, but its use requires intubation and mechanical ventilation.

When the activity of the cardiovascular system is inhibited (lowering blood pressure, bradycardia), intravenous administration of 5-10 mg of ephedrine is necessary, if necessary, repeat the administration after 2-3 minutes. If circulatory failure or cardiac arrest develops, standard resuscitation measures should be started immediately. It is vital to maintain optimal oxygenation, ventilation and blood circulation, and to correct acidosis. If cardiac arrest occurs, longer resuscitation may be required.

When treating systemic toxicity in children, it is necessary to adjust the dose according to the age and body weight of the patient.

Interaction:

Possible summation of toxic effects while prescribing with other local anesthetics or drugs structurally similar to local anesthetics of the amide type.

The clearance of ropivacaine is reduced to 77% when used simultaneously with fluvoxamine, which is a potent competitive inhibitor of the isoenzyme CYP 1 A 2, due to the possibility of a similar interaction, long-term use of Naropin® should be avoided in the presence of fluvoxamine.

An increase in the pH of the solution above 6.0 can lead to the formation of a precipitate due to the poor solubility of ropivacaine under these conditions.

A solution of Naropin® in plastic infusion bags is chemically and physically compatible with the following drugs:

Naropin concentration: 1-2 mg / ml
Added solution	Concentration
Fentanyl	1.0-10.0 μg / ml
Morphine	20.0 - 100.0 μg / ml

Despite the fact that the resulting mixtures retain chemical and physical stability for 30 days at a temperature not exceeding 30 ° C, based on the data on microbiological purity, the resulting mixtures of solutions should be used immediately after preparation.

Special instructions:

Anesthesia should be performed by experienced professionals. The availability of equipment and drugs for resuscitation is required. An intravenous catheter should be placed before large blocks are performed. Personnel providing anesthesia should be appropriately trained and familiar with the diagnosis and treatment of possible side effects, systemic toxic reactions and other possible complications (see Overdose section).

A complication of unintentional subarachnoid injection can be a spinal block with respiratory arrest and a decrease in blood pressure. Seizures occur more frequently with brachial plexus block and epidural block, probably due to accidental intravascular injection or rapid absorption at the injection site. Peripheral nerve blocks may require the introduction of a large volume of local anesthetic in areas with a large number of vessels, often near large vessels, which increases the risk of intravascular injection and / or rapid systemic absorption, which can lead to high plasma concentrations of the drug. Certain local anesthetic procedures, such as head and neck injections, may have an increased incidence of serious side effects, regardless of the type of local anesthetic used. Care must be taken to prevent injection into the area of inflammation.

Caution should be exercised when administering the drug to patients with grade II and III intracardiac conduction blockade, patients with severe renal failure, elderly and debilitated patients.

There are reports of rare cases of cardiac arrest when using the drug Naropin® for epidural anesthesia or blockade of peripheral nerves, especially after accidental intravascular administration of the drug, in elderly patients and in patients with concomitant cardiovascular diseases. In some cases, resuscitation measures were difficult. Cardiac arrest usually requires longer resuscitation. Since Naropin® is metabolized in the liver, caution should be exercised when using the drug in patients with severe liver disease; in some cases, due to delayed elimination, it may be necessary to reduce repeated doses of anesthetic.

Usually, in patients with renal insufficiency, when the drug is administered once or when the drug is used for a short period of time, there is no need to adjust the dose. However, acidosis and a decrease in the concentration of proteins in the blood plasma, which often develop in patients with chronic renal failure, may increase the risk of systemic toxic effects of the drug (see section "Dosage and Administration"). The risk of systemic toxicity is also increased when using the drug in patients with low body weight and patients with hypovolemic shock.

Epidural anesthesia can lead to a decrease in blood pressure and bradycardia. The introduction of vasoconstrictor drugs or an increase in the volume of circulating blood can reduce the risk of these side effects. It is necessary to promptly correct the decrease in blood pressure by intravenous administration of 5-10 mg of ephedrine, with. the need to repeat the introduction.

With intra-articular administration of the drug, caution should be exercised if there is a suspicion of recent extensive joint injury or surgery with the opening of extensive joint surfaces, due to the possibility of increased absorption of the drug and a higher concentration of the drug in plasma. Patients receiving therapy with class III antiarrhythmic drugs (for example, amiadorone) should be closely monitored, ECG monitoring is recommended due to the risk of increased cardiovascular effects. Long-term use of the drug Naropin® should be avoided in patients taking powerful inhibitors of the isoenzyme CYP1A2 (such as, and enoxacin).

You should take into account the possibility of cross-hypersensitivity, while using the drug Naropin® with other local anesthetics of the amide type.

Patients on a sodium-restricted diet should take the sodium content of the preparation into account.

The use of the drug in newborns requires taking into account the possible immaturity of organs and physiological functions of newborns. The clearance of the unbound fraction of ropivacaine and pipeloxylidine (PPK) depends on the body weight and age of the child in the first years of life. The influence of age is expressed in the development and maturity of liver function, the clearance reaches its maximum value at the age of about 1-3 years. The half-life of ropivacaine is 5-6 hours in neonates and children aged 1 month compared to 3 hours in older children. Due to the insufficient development of liver functions, the systemic exposure of ropivacaine is higher in newborns, moderately higher in children from 1 to 6 months compared with older children. Significant differences in neonatal plasma concentrations of ropivacaine found in clinical studies suggest an increased risk of systemic toxicity in this group of patients, especially with prolonged epidural infusion.

When using ropivacaine in neonates, monitoring of systemic toxicity (control of signs of toxicity from the central nervous system, ECG, monitoring of blood oxygenation) and local neurotoxicity is necessary, which should be continued after the end of the infusion due to the slow elimination of the drug in neonates.

The use of the drug at a concentration above 5 mg / ml, as well as the intrathecal use of the drug Naropin® in children, has not been studied.

Naropin® has the potential to cause porphyria and can only be used in patients diagnosed with acute porphyria if there is no safer alternative. In case of hypersensitivity of patients, the necessary precautions should be taken.

Cases of chondrolysis have been reported with postoperative prolonged intra-articular infusion of local anesthetics. In most of the cases described, the infusion was carried out into the shoulder joint. A causal relationship with the use of anesthetics has not been established. Naropin® should not be used for prolonged intra-articular infusion.

Impact on the ability to drive vehicles. Wed and fur .:In addition to the analgesic effect, Naropin® may have a weak transient effect on motor function and coordination. Given the profile of the side effects of the drug, care must be taken when driving vehicles and performing other potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions. Release form / dosage:

Solution for injection 2 mg / ml, 7.5 mg / ml and 10 mg / ml.

Package:

Solution for injection 2 mg / ml:

20 ml each in sealed polypropylene ampoules. Each ampoule is placed in a blister strip packaging. 5 blister strip packs with instructions for use in a cardboard box with first opening control.

100 ml or 200 ml in polypropylene containers (bags), sealed with a butyl rubber stopper and a leaf-shaped aluminum plate. Polypropylene containers (bags) are individually packed in a blister made of polypropylene / paper. 5 blisters in a cardboard box with instructions for use.

Solution for injection 7.5 mg / ml and 10 mg / ml:

10 ml in sealed polypropylene ampoules. Each ampoule is placed in a blister strip packaging. 5 blister strip packs with instructions for use in a cardboard box with first opening control.

Storage conditions:Store at a temperature not exceeding 30 ° C. Do not freeze. Keep out of the reach of children. Shelf life: 3 years. Do not use after the expiration date printed on the package. Terms of dispensing from pharmacies: On prescription Registration number: P N014458 / 01 Registration date: 27.01.2010 / 27.03.2017 Expiration date: Indefinite Marketing Authorization Holder:Aspen Pharma Trading Limited Manufacturer: & nbsp Representative office: & nbsp Aspen Health LLC Date of information update: & nbsp 27.05.2018 Illustrated instructions

Description

Transparent colorless solution.

Characteristic

Pharmacotherapeutic group

local anesthetic

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics

Intravenous infusion of ropivacaine in healthy volunteers has been shown to be well tolerated.

Indirect cardiovascular effects (lowering blood pressure, bradycardia) that can occur after epidural administration of ropivacaine are due to the resulting sympathetic blockade.

Pharmacokinetics

After epidural administration, ropivacaine is completely absorbed. Absorption is biphasic, the half-life (T1 / 2) for the two phases is 14 minutes and 4 hours, respectively. The slowdown in the elimination of ropivacaine is determined by slow absorption, which explains the longer T1 / 2 after epidural administration compared to intravenous administration.

The total plasma clearance of ropivacaine is 440 ml / min, the plasma clearance of unbound substances is 8 l / min, the renal clearance is 1 ml / min, the volume of distribution at steady state is 47 l, the hepatic extraction rate is about 0.4, T1 / 2 is 1.8 h Ropivacaine intensively binds to blood plasma proteins (mainly α 1-acid glycoproteins), the unbound fraction of ropivacaine is about 6%. Long-term epidural infusion of ropivacaine leads to an increase in the total content of the drug in the blood plasma, which is due to an increase in the content of acidic glycoproteins in the blood after surgery, while the concentration of the unbound, pharmacologically active form of ropivacaine in the blood plasma changes to a much lesser extent than the total concentration of ropivacaine ...

Ropivacaine is extensively metabolized in the body, mainly by aromatic hydroxylation. 3-hydroxyropivacaine (conjugated + unconjugated) is found in blood plasma. 3-hydroxy and 4-hydroxyropivacaine have a weaker local anesthetic effect than ropivacaine.

After intravenous administration, 86% of ropivacaine is excreted in the urine and only about
1% of the drug excreted in the urine is excreted unchanged. About 37% 3-
hydroxyropivacaine, the main metabolite of ropivacaine, is excreted in the urine
predominantly in conjugated form.

INDICATIONS

Surgical anesthesia:

- epidural block during surgical interventions, including cesarean section;

- blockade of large nerves and nerve plexuses;

- blockade of individual nerves and infiltration anesthesia.

Relief of acute pain syndrome:

- prolonged epidural infusion or intermittent bolus administration, for example,

to eliminate postoperative pain or pain relief during labor;

- blockade of individual nerves and infiltration anesthesia;

- prolonged blockade of peripheral nerves;

- intra-articular injection.

Relief of acute pain syndrome in pediatrics:

- caudal epidural block in newborns and children under 12 years of age

inclusive;

- prolonged epidural infusion in newborns and children under 12 years of age

inclusive.

CONTRAINDICATIONS

Hypersensitivity to the components of the drug.

Known hypersensitivity to local anesthetics of the amide type.

Carefully

debilitated elderly patients or patients with severe
concomitant diseases such as blockade of intracardiac conduction II and
III degrees (sinoatrial, atrioventricular, intraventricular), progress
major liver diseases, severe hepatic impairment, severe
chronic renal failure, in the treatment of hypovolemic shock. For
In these patient populations, regional anesthesia is often preferred. At
carrying out "large" blockades in order to reduce the risk of developing severe
adverse events, it is recommended to preliminarily optimize the condition
the patient, and also adjust the dose of anesthetic.

Care should be taken when injecting local anesthetics into the head and
neck, due to the possible increased incidence of serious side effects.

Particular attention should be paid when using the drug in children under 6 months of age due to the immaturity of organs and functions.

APPLICATION DURING PREGNANCY AND DURING BREASTFEEDING

Pregnancy

Studies of the effect of the drug on reproductive function were carried out in animals. In studies in rats, ropivacaine had no effect on fertility and reproduction in two generations. When the maximum doses of ropivacaine were administered to pregnant rats, an increase in offspring mortality was observed in the first three days after birth, which may be explained by the toxic effect of ropivacaine on the mother, leading to a violation of the maternal instinct.

Lactation

The excretion of ropivacaine or its metabolites in breast milk has not been studied. Based on experimental data, the dose of the drug given to the newborn is assumed to be 4% of the dose given to the mother (concentration of drug in milk / drug concentration in plasma). The total dose of ropivacaine exposed to a baby during breastfeeding is significantly less than the dose that can enter
fetus with the introduction of an anesthetic to the mother during childbirth. If it is necessary to use the drug during breastfeeding, the ratio of the potential benefits to the mother and the possible risk to the baby should be considered.

Method of administration and dosage

Naropin® should only be used by specialists with sufficient experience in local anesthesia, or under their supervision.

Adults and children over 12 years old

In general, for anesthesia during surgery, higher
doses and more concentrated solutions of the drug than when using an anesthetic for the purpose of pain relief. When using an anesthetic for pain relief, a dose of 2 mg / ml is usually recommended. For intra-articular administration, a dose of 7.5 mg / ml is recommended.

** Cases of chondrolysis have been reported with postoperative prolonged intra-articular infusion of local anesthetics. Naropin® should not be used for prolonged intra-articular infusion. The dose for blockade of large nerve plexuses should be selected in accordance with the injection site and the patient's condition. Interstellar and supraclavicular brachial plexus blockade can be associated with a high incidence of serious adverse reactions, regardless of the local anesthetic used.

*** If Naropin® was additionally used for other types of anesthesia, the maximum dose should not exceed 225 mg.

To familiarize yourself with the factors affecting the method of performing individual blocks, and with the requirements for specific groups of patients, standard guidelines should be used.

To prevent the ingress of the anesthetic into the vessel, it is imperative to carry out an aspiration test before and during the administration of the drug. If you intend to use the drug in a high dose, it is recommended to introduce a trial dose - 3-5 ml of lidocaine with epinephrine. Inadvertent intravascular injection is recognized by a temporary increase in heart rate, and inadvertent intrathecal injection is recognized by signs of spinal block. If toxic symptoms appear, the drug should be discontinued immediately.

To relieve postoperative pain, the following scheme of drug use is recommended: if an epidural catheter was not installed during surgery, after its installation, an epidural blockade with a bolus injection of Naropin® (7.5 mg / ml) is performed. Analgesia is supported by an infusion of Naropin® (2 mg / ml). In most cases, for the relief of moderate to severe postoperative pain, an infusion at a rate of 6-14 ml / h (12-28 mg / h) provides adequate analgesia with minimal non-progressive motor blockade (when using this technique, a significant decrease in the need for opioid analgesics was observed ).

The use of the drug Naropin® at a concentration above 7.5 mg / ml for cesarean section has not been studied.

* Smaller doses of the suggested interval are recommended for thoracic epidurals, while larger doses are recommended for lumbar or caudal epidurals.

The volume of the solution for caudal epidural administration and the volume of the bolus for the epidural administration should not exceed 25 ml for any patient.

A single injection of ropivacaine at a dose of 2 mg / ml (at the rate of 2 mg / kg, solution volume 1 ml / kg) for postoperative caudal analgesia provides adequate analgesia below the ThXII level in most patients. Children over 4 years of age tolerate doses up to 3 mg / kg well. The volume of epidural solution infused at the caudal level can be adjusted to achieve different sensory block prevalence, as described in specific guidelines. Regardless of the type of anesthesia, bolus administration of the calculated dose of the drug is recommended.

Instructionsonapplicationsolution

The solution does not contain preservatives and is intended for single use only. Any amount of solution left in the container after use must be destroyed.

An unopened container of solution must not be autoclaved. An unopened blister pack maintains sterility on the outside of the container and is preferred for use where sterility is required.

SIDE EFFECT

Side Effects of Local Anesthetics

Withpartiescentralandperipheralnervoussystems

Complete spinal block can occur as a result of inadvertent intrathecal administration of an epidural dose.

Serious complications are possible in case of systemic overdose and inadvertent intravascular administration of the drug (see the "Overdose" section).

Sharpsystemictoxicity

Naropin® can cause acute systemic toxic reactions when used
high doses or with a rapid increase in its concentration in the blood in case of accidental
intravascular administration of the drug or its overdose (see section

"Pharmacological properties" and "Overdose").

Mostoftenmeetingcollateraleffects

Various side effects of the drug were reported, the vast majority of which were associated not with the effect of the anesthetic used, but with the technique of regional anesthesia.

The most common (> 1%) side effects were the following, which were regarded as of clinical significance, regardless of whether a causal relationship was established with the use of anesthetic: lowering blood pressure (BP) *, nausea, bradycardia, vomiting, paresthesia , fever, headache, urinary retention, dizziness, chills, increased blood pressure, tachycardia, hypesthesia, anxiety. The incidence of undesirable effects is presented as follows: Very often (> 1/10); Often (> 1/100,< 1/10); Нечасто (> 1/1000, < 1/100); Редко (> 1/10 000, < 1/1 000); Очень редко (< 1/10 000), включая отдельные сообщения.

* A decrease in blood pressure is common in children. ** Vomiting is very common in children.

OVERDOSE

Sharpsystemictoxicity

Cases of seizures have been observed with accidental intravascular injection during nerve plexus blockade or other peripheral blockade.

If the epidural dose is incorrectly administered intrathecally, a complete spinal block may occur.

Inadvertent intravascular injection of anesthetic can cause an immediate toxic reaction.

Systemic toxicity is primarily manifested by symptoms of the central nervous system (CNS) and cardiovascular system (CVS). These reactions are caused by high concentrations of local anesthetic in the blood, which can result from (accidental) intravascular administration, overdose, or extremely high adsorption from highly vascularized areas.

CNS reactions are similar for all amide-type local anesthetics, while cardiovascular reactions are more dependent on the drug administered and its dose.

Centralnervoussystem

Manifestations of systemic toxicity from the central nervous system develop gradually: first, visual disturbances, numbness around the mouth, numbness of the tongue, hyperacusis, ringing in the ears, and dizziness appear. Dysarthria, tremors, and muscle twitching are more serious manifestations of systemic toxicity and may precede the onset of generalized seizures (these signs should not be confused with the patient's neurotic behavior). With the progression of intoxication, loss of consciousness may occur, seizures lasting from several seconds to several minutes, accompanied by respiratory failure, the rapid development of hypoxia and hypercapnia due to increased muscle activity and inadequate ventilation. In severe cases, respiratory arrest may even occur. The resulting acidosis, hyperkalemia, hypocalcemia increase the toxic effects of the anesthetic.

Cordially- vascularsystem

Treatmentacutetoxicity

When the first signs of acute systemic toxicity appear, the drug should be discontinued immediately.

When seizures and symptoms of CNS depression appear, the patient needs adequate treatment, the purpose of which is to maintain oxygenation, stop seizures,
maintaining the activity of the cardiovascular system. Oxygenation with oxygen should be provided, and, if necessary, the transition to artificial ventilation of the lungs. If after 15-20 seconds the seizures do not stop, anticonvulsants should be used: sodium thiopental 1-3 mg / kg IV (provides rapid relief of seizures) or diazepam 0.1 mg / kg IV (the effect develops more slowly compared with the action of sodium thiopental). Suxamethonium 1 mg / kg quickly relieves convulsions, but its use requires intubation and mechanical ventilation.

With the suppression of the activity of the cardiovascular system (lowering blood pressure, bradycardia)
intravenous administration of 5-10 mg of ephedrine is necessary, if necessary after 2-
Repeat the introduction for 3 minutes. When circulatory failure develops or stops
cardiac arrest, standard resuscitation should be initiated immediately.

It is vital to maintain optimal oxygenation, ventilation and blood circulation, and to correct acidosis. If cardiac arrest occurs, longer resuscitation may be required.

When treating systemic toxicity in children, it is necessary to adjust the dose according to the age and body weight of the patient.

INTERACTION WITH OTHER DRUGS AND OTHER FORMS OF DRUG INTERACTIONS

Possible summation of toxic effects while prescribing with other local anesthetics or drugs structurally similar to local anesthetics of the amide type.

The clearance of ropivacaine decreases to 77% when used simultaneously with fluvoxamine, which is a potent competitive inhibitor of the CYP1A2 isoenzyme; due to the possibility of a similar interaction, long-term use of Naropin should be avoided in the presence of fluvoxamine.

An increase in the pH of the solution above 6.0 can lead to the formation of a precipitate due to the poor solubility of ropivacaine under these conditions.

A solution of Naropin® in plastic infusion bags is chemically and physically compatible with the following drugs:

SPECIAL INSTRUCTIONS

Anesthesia should be performed by experienced professionals. It is obligatory to have equipment and medicines for resuscitation measures. An intravenous catheter should be placed before large blocks are performed.
Personnel providing anesthesia must be appropriate
is well prepared and familiar with the diagnosis and treatment of possible side effects, systemic toxic reactions and other possible complications (see Overdose section).

Certain local anesthetic procedures, such as head and neck injections, may have an increased incidence of serious side effects, regardless of the type of local anesthetic used. Care must be taken to prevent injection into the area of inflammation.

Caution should be exercised when administering the drug to patients with grade II and III intracardiac conduction blockade, patients with severe renal failure, elderly and debilitated patients.

In some cases, resuscitation measures were difficult. Cardiac arrest usually requires longer resuscitation.

Since Naropin® is metabolized in the liver, caution should be exercised when using the drug in patients with severe liver disease; in some cases, due to delayed elimination, it may be necessary to reduce repeated doses of anesthetic.

Usually, in patients with renal insufficiency, when the drug is administered once or when the drug is used for a short period of time, there is no need to adjust the dose. However, acidosis and a decrease in the concentration of proteins in the blood plasma, which often develop in patients with chronic renal failure, may increase the risk of systemic toxic effects of the drug (see section "Dosage and Administration"). The risk of systemic toxicity is also increased with the use of the drug in patients with low body weight and patients with hypovolemic shock.

Patients receiving therapy with class III antiarrhythmic drugs (for example, amiadorone) should be closely monitored, ECG monitoring is recommended due to the risk of increased cardiovascular effects.

Long-term use of the drug Naropin® should be avoided in patients taking potent inhibitors of the isoenzyme CYP1A2 (such as fluvoxamine and enoxacin).

Consideration should be given to the possibility of cross-hypersensitivity with the simultaneous use of Naropin® with other local anesthetics of the amide type.

Patients on a sodium-restricted diet should take the sodium content of the preparation into account.

The use of the drug in newborns requires taking into account the possible immaturity of organs and physiological functions of newborns. The clearance of the unbound fraction of ropivacaine and pipeloxylidine (PPK) depends on the body weight and age of the child in the first years of life. The influence of age is expressed in the development and maturity of liver function, the clearance reaches its maximum value at the age of about 1-3 years. The half-life of ropivacaine is 5-6 hours in neonates and children aged 1 month compared to 3 hours in older children. Due to the insufficient development of liver functions, the systemic exposure of ropivacaine is higher in newborns, moderately higher in children from 1 to 6 months compared to older children. Significant differences in neonatal plasma concentrations of ropivacaine found in clinical studies suggest an increased risk of systemic toxicity in this group of patients, especially with prolonged epidural infusion. Recommended doses for neonates are based on limited clinical data.

The use of the drug at a concentration above 5 mg / ml, as well as the intrathecal use of the drug Naropin® in children, has not been studied.

INFLUENCE ON THE ABILITY TO DRIVE VEHICLES AND OTHER MECHANISMS

In addition to the analgesic effect, Naropin® may have a mild transient
influence on motor function and coordination. Given the profile of the side effects of the drug, care must be taken when driving vehicles and performing other potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions.

RELEASE FORM

Solution for injection 2 mg / ml, 7.5 mg / ml and 10 mg / ml.

Solution for injection 2 mg / ml:

20 ml each in sealed polypropylene ampoules. Each ampoule is placed in a blister strip packaging. 5 blister strip packs with instructions for use in a cardboard box with first opening control.

TERMS OF HOLIDAY

On prescription.

COMPANY MANUFACTURER

Solution for injection 2 mg / ml, 7.5 mg / ml, 10 mg / ml (ampoules):
AstraZeneca AB, SE-151 85 Södertalje, Sweden;

Solution for injection 2 mg / ml (bags):
AstraZeneca Petit Ltd, Australia, 10-14 Cartoum Road, North Ryde, NSW 2113

Further information is provided upon request.

Representative office of AstraZeneca UK Limited, UK in Moscow and AstraZeneca Pharmaceuticals LLC

125284 Moscow, st. Begovaya d. 3, building 1

Instructions for use Naropin ®
The composition of the drug Naropin ®
Indications of the drug Naropin ®
Storage conditions of the drug Naropin ®
Shelf life of the drug Naropin ®

Release form, composition and packaging

solution for injection 20 mg / 10 ml: amp. 5 pieces.

Injection transparent, colorless.

Excipients:

solution for injection 40 mg / 20 ml: amp. 5 pieces.
Reg. No: 7457/05/10 dated 02.11.2010 - Expired

Injection transparent, colorless.

Excipients: sodium chloride, hydrochloric acid or sodium hydroxide (up to pH 4-6), water d / i.

solution for injection 75 mg / 10 ml: amp. 5 pieces.
Reg. No: 7457/05/10 dated 02.11.2010 - Expired

Injection transparent, colorless.

Excipients: sodium chloride, hydrochloric acid or sodium hydroxide (up to pH 4-6), water d / i.

10 ml - polypropylene ampoules (5) - contoured cell packaging (1) - cardboard packs.

solution for injection 100 mg / 10 ml: amp. 5 pieces.
Reg. No: 7457/05/10 dated 02.11.2010 - Expired

Injection transparent, colorless.

Excipients: sodium chloride, hydrochloric acid or sodium hydroxide (up to pH 4-6), water d / i.

10 ml - polypropylene ampoules (5) - contoured cell packaging (1) - cardboard packs.

solution for injection 150 mg / 20 ml: amp. 5 pieces.
Reg. No: 7457/05/10 dated 02.11.2010 - Expired

Injection transparent, colorless.

Excipients: sodium chloride, hydrochloric acid or sodium hydroxide (up to pH 4-6), water d / i.

20 ml - polypropylene ampoules (5) - contoured cell packs (1) - cardboard packs.

solution for injection 200 mg / 20 ml: amp. 5 pieces.
Reg. No: 7457/05/10 dated 02.11.2010 - Expired

Injection transparent, colorless.

Excipients: sodium chloride, hydrochloric acid or sodium hydroxide (up to pH 4-6), water d / i.

20 ml - polypropylene ampoules (5) - contoured cell packs (1) - cardboard packs.

Description of the medicinal product NAROPIN ® created in 2011 on the basis of instructions posted on the official website of the Ministry of Health of the Republic of Belarus. Updated date: 23.04.2012

pharmachologic effect

Ropivacaine is the first long-acting amide-type local anesthetic that is a pure enantiomer. It has both anesthetic and analgesic effects. High doses of the drug are used for local
anesthesia during surgery, low doses of the drug provide analgesia (sensory block) with minimal and non-progressive motor block.
The duration and intensity of the blockade caused by ropivacaine is not affected by the addition of adrenaline. By reversibly blocking voltage-dependent sodium channels, it prevents the generation of impulses at the endings of sensory nerves and the conduction of impulses along nerve fibers.

Like other local anesthetics, it can affect other excitable cell membranes (for example, in the brain and myocardium). If an excess amount of local anesthetic reaches the systemic circulation within a short period of time, signs of systemic toxicity may occur. Signs of toxicity from the central nervous system precede signs of toxicity from the cardiovascular system, since they are observed at lower plasma concentrations of the drug. The direct effect of local anesthetics on the heart includes conduction deceleration, negative inotropic effect and, in severe overdose, arrhythmias and cardiac arrest. IV administration of high doses of ropivacaine leads to the same effects on the heart.

Intravenous infusion of ropivacaine was shown to healthy volunteers to be well tolerated.

Indirect cardiovascular effects (lowering blood pressure, bradycardia) that can occur after epidural administration of ropivacaine are due to the resulting sympathetic blockade.

Pharmacokinetics

Plasma concentration of ropivacaine depends on the dose, route of administration and the degree of vascularization of the injection site. Pharmacokinetics of ropivacaine is linear, C max is proportional to the administered dose.

After epidural administration, ropivacaine is completely absorbed. Absorption is biphasic, T 1/2 for two phases is, respectively, 14 minutes and 4 hours. The slowdown in the elimination of ropivacaine is determined by slow absorption, which explains the longer T 1/2 after epidural administration compared with intravenous administration.

The total plasma clearance of ropivacaine is 440 ml / min, the plasma clearance of unbound substances is 8 l / min, the renal clearance is 1 ml / min, the Vd at steady state is 47 liters, the hepatic extraction index is about 0.4, T 1/2 is 1.8 hours. Ropivacaine is intensive binds to blood plasma proteins (mainly α1-acid glycoproteins), the unbound fraction of ropivacaine is about 6%. Long-term epidural infusion of ropivacaine leads to an increase in the total content of the drug in the blood plasma, which is due to an increase in the level of acidic glycoproteins in the blood after surgery, while the concentration of the unbound, pharmacologically active form of the drug in the blood plasma changes to a much lesser extent than the total concentration of the drug.

Ropivacaine crosses the placental barrier with a rapid equilibration of the unbound fraction. The degree of binding to blood plasma proteins in the fetus is less than in the mother, which leads to lower concentrations of the drug in the fetal plasma compared to the total concentration of the drug in the mother's blood plasma. Ropivacaine is extensively metabolized in the body, mainly by aromatic hydroxylation. 3-hydroxy-ropivacaine (conjugated + unconjugated) is found in blood plasma. 3-hydroxy and 4-hydroxyropivacaine have a weaker local anesthetic effect than ropivacaine.

After intravenous administration, 86% of ropivacaine is excreted in the urine and only about 1% of the drug excreted in the urine is excreted unchanged. About 37% of 3-hydroxy-ropivacaine, the main metabolite of ropivacaine, is excreted in the urine, mainly in conjugated form.

1-3% of ropivacaine is excreted in the urine as the following metabolites:

4-hydroxy-ropivacaine, N-dealkylated metabolites, and 4-hydroxy-dealkylated ropivacaine.

There is no evidence of racemization of ropivacaine in vivo.

Indications for use

Surgical anesthesia:

epidural block during surgery, including cesarean section;
blockade of large nerves and nerve plexuses;
blockade of individual nerves and infiltration anesthesia.

Relief of acute pain syndrome:

extended epidural infusion or intermittent bolus administration.

For postoperative pain relief or labor pain relief:

blockade of individual nerves and infiltration;
prolonged blockade of peripheral nerves;
intra-articular injection.

Dosage regimen

Naropin should only be used by specialists with sufficient experience in performing regional anesthesia, or under their supervision.

Adults and children over 12 years old:

In general, anesthesia for surgical procedures (eg, epidurals) requires higher doses and more concentrated solutions of the drug. For pain relief (for example, an epidural for pain relief), lower doses and concentrations of the drug are recommended. The doses indicated in the table are considered sufficient to achieve a reliable blockade and are indicative when using the drug in adults, since there is individual variability in the rate of block development and its duration. The table below is an indicative guide to the dosage of the drug for the most commonly used blockades. The selection of the dose of the drug should be based on clinical experience, taking into account the physical status of the patient.

	Drug concentration (mg / ml)	Solution volume (ml)	Dose (mg)	Onset of action (min)	Duration of action (h)
Surgical anesthesia:
Epidural anesthesia at the lumbar level:
Surgical interventions	7.5 10.0	15-25 15-20	113-188 150-200	10-20 10-20	3-5 4-6
Cesarean section	7.5	15-20	113-150	10-20	3-5
Thoracic epidural anesthesia:
Postoperative analgesic block	7.5	5-15	38-113	10-20	-
Large nerve plexus blockade:
For example, a brachial plexus block	7.5	10-40	75-300	10-25	6-10
Conduction and infiltration anesthesia	7.5	1-30	7.5-225	1-15	2-6
Relief of acute pain syndrome:
Epidural administration at the lumbar level:
Bolus	2.0	10-20	20-40	10-15	0.5-1.5
Intermittent administration (eg, for pain relief in labor)	2.0	10-15 (minimum interval -30 min)	20-30	-	-
Extended infusion for - pain relief during labor - postoperative pain relief	2.0 2.0	6-10 ml / h 6-14 ml / h	12-20 mg / h 12-28 mg / h
Peripheral nerve block:
Femoral nerve block (infusion or injection)	2.0	5-10 ml / h	10-20 mg / h	-	-
Epidural administration at the thoracic level:
Extended infusion, e.g. for postoperative pain relief)	2.0	6-14 ml / h	12-28 mg / h	-	-
Conductive block and infiltration	2.0	1-100	2-200	1-5	2-6
Intra-articular administration
Knee arthroscopy	7,5	20	150*	-	2-6

* - if Naropin was additionally used for other types of anesthesia, the maximum dose should not exceed 225 mg.

To familiarize yourself with the factors affecting the method of performing individual blocks, and with the requirements for specific groups of patients, standard guidelines should be used.

Before preventing the ingress of the anesthetic into the vessel, it is imperative to carry out an aspiration test before and during the administration of the drug. If you intend to use the drug in a high dose, it is recommended to administer a test dose - 3-5 ml of lidocaine with adrenaline. Inadvertent intravascular injection is recognized by a temporary increase in heart rate, and inadvertent intrathecal injection is recognized by signs of spinal block.

Before and during the administration of Naropin (which should be carried out slowly or by increasing the sequentially administered doses of the drug at a rate of 25-50 mg / min), it is necessary to carefully monitor the patient's vital functions and maintain verbal contact with him. If toxic symptoms appear, the drug should be discontinued immediately.

A single dose of ropivacaine up to 250 mg for epidural block for surgical intervention was generally well tolerated by patients. With prolonged blockade by prolonged infusion or repeated bolus administration, the possibility of creating toxic concentrations of the anesthetic in the blood and local nerve damage should be taken into account. The introduction of ropivacaine for 24 hours at a dose of up to 800 mg in total for surgical interventions and for postoperative pain relief, as well as prolonged epidural infusion after surgery at a rate of 28 mg / h for 72 hours is well tolerated by adult patients.

if an epidural catheter was not installed during surgery, after its installation, epidural blockade with Naropin (7.5 mg / ml) is performed. Analgesia is supported by an infusion of Naropin (2 mg / ml). In most cases, for the relief of moderate to severe postoperative pain, an infusion at a rate of 6-14 ml / h (12-28 mg / h) provides adequate analgesia with minimal non-progressive motor blockade (when using this technique, a significant decrease in the need for opioid analgesics was observed ). For postoperative pain relief, Naropin (2 mg / ml) can be administered continuously as an epidural infusion for 72 hours without fentanyl or mixed with it (1-4 μg / ml). When using Naropin 2 mg / ml (6-14 ml / h), adequate pain relief was provided in most patients. The combination of Naropin and fentanyl resulted in improved pain relief, while causing the side effects associated with opioids. The use of Naropin at a concentration above 7.5 mg / ml for caesarean section has not been studied.

The doses indicated in the table are considered sufficient to achieve a reliable blockade and are indicative when using the drug in children, since there is individual variability in the rate of block development and its duration. In overweight children, a gradual dose reduction is often required; in this case, it is necessary to be guided by the "ideal" weight of the patient. Standard guidelines should be used for information on factors that influence the methods of performing individual blocks and on the requirements for specific patient groups.

Due to the lack of a sufficient number of clinical observations, it is not recommended to use Naropin in children under 1 year of age.

Solution instructions

The solution does not contain preservatives and is intended for single use only. Any amount of solution remaining in the container after use must be destroyed.

An unopened container of solution must not be autoclaved.

An unopened blister pack maintains sterility on the outside of the container and is preferred for use where sterility is required.

Side effects

Adverse reactions to Naropin are similar to reactions to other local anesthetics of the amide type and, if used correctly (no overdose or intravascular administration), are very rare. They should be distinguished from the physiological effects that occur due to blockade of sympathetic nerves in the presence of epidural anesthesia, for example, a decrease in blood pressure, bradycardia.

Serious complications are possible with systemic overdose and unintentional intravascular administration of the drug.

Allergic reactions: allergic reactions (in the most severe case - anaphylactic shock) are rare.

From the side of the central and peripheral nervous system: possible neuropathy and dysfunction of the spinal cord (anterior spinal artery syndrome, arachnoiditis, cauda equina syndrome) are usually associated with the technique of regional anesthesia, and not with the action of the drug.

Acute systemic toxicity: naropin can cause acute systemic toxic reactions when high doses are used or with a rapid increase in blood concentration in case of accidental intravascular administration of the drug or its overdose.

Most common side effects

Various side effects of the drug were reported, the overwhelming majority of which were associated not with the effect of the anesthetic used, but with the technique of regional anesthesia.

The most common side effects (> 1%) reported were the following, which were judged to be of clinical significance, regardless of whether a causal relationship was established with the use of the anesthetic:

lowering blood pressure, nausea, bradycardia, vomiting, paresthesia, fever, headache, urinary retention, dizziness, chills, increased blood pressure, tachycardia, hypoesthesia, anxiety.

Clinical trial data:

very frequent (> 1/10), frequent (> 1/100), less frequent (> 1/1000), rare (<1/1000) побочные эфекты.

very common - hypotension.

From the gastrointestinal tract: very frequent - nausea;

frequent - vomiting.

From the nervous system: frequent - paresthesia, dizziness, headache;

less frequent - anxiety, symptoms of toxicity from the central nervous system (convulsions, dysarthria, numbness of the tongue, ringing in the ears, tremors, muscle weakness, hypoesthesia, paraesthesia).

On the part of the cardiovascular system: frequent - bradycardia, tachycardia, hypertension;

less frequent - syncope;

rare - cardiac arrhythmia, myocardial infarction.

From the genitourinary system: frequent - urinary retention.

From the respiratory system: less frequent - shortness of breath, shortness of breath.

General: frequent - back pain, chills, fever;

less frequent - hypothermia;

rare - allergic reactions, angioedema, urticaria.

Contraindications for use

hypersensitivity to local anesthetics of the amide type;
children's age (up to 1 year) due to the lack of clinical data.

Carefully: the drug should be administered to weakened elderly patients or patients with severe concomitant diseases, such as heart block (sinoatrial, atrioventricular, intraventricular), progressive cirrhosis of the liver, severe chronic renal failure. For these patient groups, regional anesthesia is preferred. When carrying out large blockades in order to reduce the risk of developing severe adverse events, it is recommended to preliminarily optimize the patient's condition, as well as adjust the dose of anesthetic.

Application during pregnancy and lactation

Naropin can be used during pregnancy only if it is justified by the clinical situation (in obstetrics, the use of the drug for anesthesia or analgesia is well justified).

Studies of the effect of the drug on reproductive function were carried out in animals. In studies in rats, ropivacaine had no effect on fertility and reproduction in two generations. When the maximum doses of the drug were administered to pregnant rats, an increase in offspring mortality was observed in the first three days after birth, which may be explained by the toxic effect of ropivacaine on the mother, leading to a violation of the maternal instinct.

Teratogenicity studies in rabbits and rats have not revealed side effects of ropivacaine on organogenesis or early fetal development. Also, in the course of perinatal and postnatal studies on rats receiving the maximum tolerated dose of the drug, there were no side effects on late stages of fetal development, labor, lactation, viability or on the growth of offspring. In the course of perinatal and postnatal comparative studies of ropivacaine with bupivacaine, it was shown that, in contrast to ropivacaine, the toxic effect of bupivacaine was observed at significantly lower doses of the drug and at lower concentrations of unbound bupivacaine in the blood.

The excretion of ropivacaine or its metabolites in breast milk has not been studied. Based on experimental data, the dose given to newborns is estimated to be 4% of the dose given to the mother (milk concentration / plasma drug concentration). The total dose of ropivacaine exposed to a baby during breastfeeding is significantly less than the dose that can enter the fetus when an anesthetic is administered to the mother during childbirth.

If it is necessary to use the drug during breastfeeding, the ratio of the potential benefits to the mother and the possible risk to the baby should be considered.

Application for violations of liver function

Carefully the drug should be administered to patients with progressive liver cirrhosis.

Application for impaired renal function

Carefully the drug should be administered to patients with severe chronic renal failure.

special instructions

Regional anesthesia should be performed by experienced professionals. The availability of equipment and drugs for resuscitation is required. An IV catheter should be placed before major blockages are performed.

Personnel providing anesthesia should be appropriately trained and familiar with the diagnosis and treatment of potential side effects, systemic toxicity, and other potential complications.

Certain local anesthetic procedures, such as head and neck injections, can cause serious side effects, regardless of the type of local anesthetic used. Epidural anesthesia can lead to a decrease in blood pressure and bradycardia. The introduction of vasoconstrictor drugs or an increase in the volume of circulating blood can reduce the risk of these side effects.

There are reports of isolated cases of myocardial infarction in elderly patients and in patients with concomitant cardiovascular diseases when using Naropin for epidural anesthesia or peripheral nerve blockade, especially after accidental intravascular ingestion of the drug. In some cases, resuscitation measures were difficult. The development of myocardial infarction, as a rule, requires more prolonged resuscitation measures.

Since Naropin is metabolized in the liver, caution should be exercised when using the drug in patients with severe liver disease; in some cases, due to delayed elimination, it may be necessary to reduce repeated doses of anesthetic.

Hypotension should be promptly corrected by intravenous administration of 5-10 mg of ephedrine, repeated if necessary.

Influence on the ability to drive vehicles and control mechanisms

Depending on the dose, local anesthetics can have little effect on mental function and coordination, even in the absence of toxic manifestations from the central nervous system, and can temporarily disrupt motor function and reduce attention.

Overdose

Acute systemic toxicity

Inadvertent intravascular injection of anesthetic can cause an immediate toxic reaction.

In case of an overdose during regional anesthesia, C max of the drug in the blood plasma can be achieved more than 1-2 hours after administration, depending on the place of administration of the drug, and therefore the appearance of signs of toxicity may be delayed. Systemic toxicity may present with central nervous and cardiovascular symptoms.

central nervous system

Manifestations of systemic toxicity from the central nervous system are discrete:

first, visual and hearing disorders, numbness around the mouth, dizziness, tingling sensation, paresthesia appear. Dysarthria, increased muscle tone, and muscle twitching are more serious manifestations of systemic toxicity and may precede the onset of generalized seizures (these signs should not be confused with the patient's neurotic behavior). With the progression of intoxication, loss of consciousness may occur, seizures lasting from several seconds to several minutes, accompanied by respiratory failure, the rapid development of hypoxia and hypercapnia due to increased muscle activity. In severe cases, respiratory arrest may even occur. Respiratory and metabolic acidosis increase the toxic effects of the anesthetic.

Subsequently, due to the redistribution of the anesthetic from the central nervous system and its subsequent metabolism and excretion, a fairly rapid restoration of functions occurs, unless a large dose of the drug has been administered.

The cardiovascular system

Cardiovascular disorders are signs of more serious complications. A decrease in blood pressure, bradycardia, arrhythmia and, in some cases, even cardiac arrest can occur due to a high systemic concentration of local anesthetics. In studies on volunteers, intravenous infusion of ropivacaine led to inhibition of the conduction and contractility of the heart muscle. Symptoms from the cardiovascular system are usually preceded by manifestations of toxicity from the central nervous system, which can be overlooked if the patient is under the influence of sedatives (benzodiazepines or barbiturates) or under general anesthesia.

Acute toxicity treatment

When the first signs of acute systemic toxicity appear, the drug should be discontinued immediately.

When seizures appear, the patient needs treatment, the purpose of which is to maintain oxygenation, stop seizures, and maintain the activity of the cardiovascular system. Oxygenation with oxygen, and, if necessary, artificial ventilation of the lungs (using a bag or mask) should be provided. If after 15-20 seconds the seizures do not stop, anticonvulsants should be used:

sodium thiopental 100-150 mg i.v. (provides quick relief of seizures) or 5 diazepam 5-10 mg i.v. (the action develops more slowly compared to the action of hyopental). Suxamethonium quickly relieves seizures, but when using it, the patient must be intubated and artificial lung ventilation must be performed.

When the activity of the cardiovascular system is inhibited (hypotension, bradycardia), it is necessary to administer 5-10 mg of ephedrine intravenously, if necessary, repeat the administration after 2-3 minutes. In cardiac arrest, standard resuscitation should be initiated immediately. It is vital to maintain optimal oxygenation, ventilation and blood circulation, and to correct acidosis.

With the development of myocardial infarction, longer resuscitation measures may be required.

Drug interactions

Possible summation of toxic effects while prescribing with other local anesthetics or drugs structurally similar to local anesthetics of the amide type.

The clearance of bupivacaine is reduced by 30% when coadministered with fluvoxamine, which is a strong competitive inhibitor of cytochrome P450 1A2, due to the possibility of a similar interaction, long-term use of Naropin should be avoided in the presence of fluvoxamine.

An increase in the pH of the solution above 6.0 can lead to the formation of a precipitate due to the poor solubility of ropivacaine under these conditions.