Naropin - instructions for use, dose, side effects, contraindications

Drug solution Naropin® is a sterile isotonic aqueous solution, contains no preservatives and is intended for single use only. pKa of ropivacaine 8.1; the partition coefficient is 141 (n-acrylic / 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 a long-acting local anesthetic of the amide type, which is a pure levorotatory enantiomer. Has both anesthetic and analgesic effect.High concentrations of ropivacaine are used for local anesthesia during surgical interventions. In low concentrations causes a sensory block (analgesia) with a minimal and non-progressive motor block. Reversibly blocking the potential-dependent sodium channels, prevents the generation of pulses in the endings of the sensory nerves and impulses along nerve fibers. Like other local anesthetics, it can affect other excitable cell membranes (for example, in the brain and myocardium), and signs of systemic toxicity are possible. Getting in excessive amounts in the systemic blood stream, can have a depressing effect on the central nervous system and myocardium (reduces excitability, automatism and conductivity). Signs of toxicity from the central nervous system (see the section "Overdose") precede signs of toxicity from the cardiovascular system, as observed at lower concentrations of ropivacaine in plasma. Naropin® has a wide therapeutic range (the range between doses that have therapeutic and toxic effects).In vivo studies in animals, it has been shown that ropivacaine has a less toxic effect on the myocardium compared with bupivacaine. Indirect cardiovascular effects (decrease in blood pressure, bradycardia), which can occur after epidural administration of ropivacaine, are due to the emerging sympathetic blockade.

The onset and duration of anesthesia with Naropin® depends on the concentration and site of administration of the drug. The duration and intensity of the blockade caused by ropivacaine, the addition of epinephrine is virtually unaffected.

Pharmacokinetics:

The concentration of ropivacaine in the blood plasma depends on the dose, the route of administration and the degree of vascularization of the injection site. The pharmacokinetics of ropivacaine is linear, the maximum concentration (Cmax) is proportional to the administered dose. After epidural administration ropivacaine completely absorbed into the blood. Absorption is biphasic in nature. The half-life (T_1/2) for each phase is, respectively, 14 minutes and 4 hours. The slowing down of 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 the unbound substance 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 hours.

Ropivacaine binds intensely to blood plasma proteins (mainly with alpha 1-acid glycoproteins), the unbound fraction of ropivacaine is about 6%.

Long-term epidural infusion of ropivacaine after surgery 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, while the concentration of unbound, pharmacologically active form of ropivacaine in blood plasma varies much less than the total concentration of ropivacaine.

Ropivacaine penetrates well through the placental barrier with rapid achievement of equilibrium over the unbound fraction. The degree of binding to blood plasma proteins in the fetus is less than that of the mother, which leads to lower concentrations of ropivacaine in fetal plasma compared to the total concentration in the blood plasma of the mother.

Ropivacaine is actively metabolized in the body,mainly by aromatic hydroxylation (major metabolites: 3-hydroxypropvacaine, 4-hydroxypropyvacaine, N-dealkylated metabolites and 4-hydroxydecyl-alkylated ropivacaine). 3-Hydroxy-hydroxypivacaine (conjugated and unconjugated) is found in the blood plasma. 3-hydroxy and 4-hydroxyropivacaine have a weaker local anesthetic effect compared to ropivacaine. After intravenous administration, 86% of ropivacaine is excreted in the urine (1% - unchanged). About 37% of 3-hydroxyropivacaine, the main metabolite of ropivacaine, is excreted in urine (mainly in conjugated form).

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

Indications:

Anesthesia during surgical interventions:

- Intratelal blockade.

Kupirovanie acute pain in pediatrics:

- Blockade of peripheral nerves in children from 1 to 12 years of age, inclusive.

Contraindications:Known hypersensitivity to local anesthetics of the amide type.Due to the lack of sufficient clinical observations, the use of Naropin® in children younger than 1 year is not recommended, as is the intrathecal administration of the drug.

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 diseases, severe hepatic insufficiency, severe chronic renal failure, hypovolemic shock therapy, pregnancy, lactation. For these groups of patients, regional anesthesia is preferable, when carrying out large blockages in order to reduce the risk of developing severe adverse events, it is recommended to pre-optimize the patient's condition and also adjust the dose of anesthetic.

Patients on a diet with sodium restriction must take into account the sodium content in the preparation.

Pregnancy and lactation:

Pregnancy

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

Naropin® can be used during pregnancy only if the expected benefit to the mother exceeds the potential risk to the fetus.

Lactation

The isolation of ropivacaine or its metabolites with breast milk has not been studied. Based on the experimental data, the dose of the drug to the newborn is presumably 4% of the dose given to the mother (ie, the total dose of ropivacaine affecting the baby during breastfeeding is significantly less than the dose that can be given to the newborn when the mother's anesthetic is administered childbirth). If you need to use the drug during breastfeeding, consider the ratio of potential benefits to the mother and the possible risk to the baby.

Dosing and Administration:

The drug is used for epidural, spinal, infiltration and conduction anesthesia.

Naropin® should only be used by specialists with sufficient experience in conducting regional anesthesia, or under their supervision, with the availability of equipment and medications forresuscitation measures. Prior to the execution of large blockades, intravenous catheters should be installed.

Naropin® is administered slowly or by increasing sequential doses of the drug at a rate of 25-50 mg / min.

To prevent the anesthetic from entering the vessel, an aspiration test should be performed. A random intravascular injection is recognized by a temporary increase in the heart rate. The table is an indicative guide to the dosing of the drug for carrying out an intrathecal blockade. When choosing a dose of the drug should be based on clinical experience, taking into account the physical condition of the patient.

Recommendations for dosing of Naropin® for adults:

	Konzen(mg / ml)	Volume of solution (ml)	Dose (mg)	Start of action (min)	DatesThe action ())




Anesthesia in surgical interventions:

Intrathecal blockade:
Surgical interventions	5,0	3 -4	15-20	1-5	2-6

Recommendations for dosing the drug Naropin® for children from 1 year:

	Concentrationration of the drug (mg / ml)	Scope solution (ml / kg)	Dose (mg / kg)




Coping with acute pain syndrome (intraoperative and postoperative):


Blockade of peripheral nerves in children from 1 to 12 years of age inclusive:
(eg, for blockade of the ilio-inguinal nerve)	5,0	0,6	3

The doses indicated in the table are considered sufficient to achieve a reliable blockade and are indicative for the use of the drug in adults, since there is an individual variability in the speed of the developed block and its duration.

For anesthesia with caesarean section, the intrathecal route of ropivacaine administration has not been studied. To familiarize with the factors influencing the method of execution of individual blockades, and with the requirements for specific groups of patients, standard guidelines should be used. The use of concentrations above 5 mg / ml in children, as well as intrathecal administration of any drug concentrations, has not been studied.

Instructions for use of the solution

The solution does not contain preservatives and is intended for single use only. Any amount of solution left in the container after use should be destroyed. The unopened container with the solution must not be autoclaved.The unopened blister pack provides sterility of the outer surface of the infusion container and is preferred for use in conditions requiring sterility. In view of the lack of sufficient clinical observations not It is recommended to use Naropin® in children under the age of 1 year.

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

Side effects inherent in local anesthetics

From the central and peripheral nervous system

Possible neuropathy and impaired spinal cord function (anterior spinal artery syndrome, arachnoiditis, horse tail syndrome), are usually associated with the technique of conducting regional anesthesia, and not with the action of the drug.As a result of a random intrathecal injection of the epidural dose, a complete spinal block can occur.

Serious complications are possible with systemic overdose and unintentional intravascular administration of the drug (see section "Overdose").

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 with accidental intravascular administration of the drug or its overdose (see section "Pharmacological properties" and "Overdose"). The most common side effects

Various side effects of the drug were reported, the vast majority of which was not due to the effect of the anesthetic used, but to the technique of conducting regional anesthesia.

Most often (> 1%), the following side effects were noted, which were regarded as having clinical significance, regardless of whether a causal relationship was established with the use of an anesthetic: lowering blood pressure (BP), nausea, bradycardia, vomiting, paresthesia, fever, headache,delayed urination, dizziness, chills, increased blood pressure, tachycardia, hypesthesia, anxiety. The frequency of undesirable effects is as follows:

Very often (> 1/10); Often (> 1/100, <1/10); Infrequently (> 1/1000, <1/100); Rarely (> 1/10 000, <1/1 000); Very rarely (<1/10 000), including individual messages.

Often	From the cardiovascular system: a decrease in blood pressure * From the gastrointestinal tract (GIT): nausea
Often	From the side of the nervous system: paresthesia, dizziness, headache From the cardiovascular system: bradycardia, tachycardia, increased blood pressure From the gastrointestinal tract: vomiting ** On the part of the genitourinary system: retention of urination General: back pain, chills, fever
Infrequently	From the nervous system: anxiety, symptoms of toxicity from the side of the central nervous system (convulsions, large seizures, paresthesia in the perioral zone, dysarthria, numbness of the tongue, visual impairment, ringing in the ears, hyperacus, tremor, muscle cramps), hypoesthesia From the side of the vascular system: a syncope From the respiratory system: shortness of breath, shortness of breath General: hypothermia
Rarely	From the cardiovascular system: arrhythmia, cardiac arrest General: allergic reactions (anaphylactic reactions, angioedema, hives)

* Decrease in blood pressure occurs in children often.

** Vomiting is very common in children.

Overdose:

Acute Systemic Toxicity

In case of accidental intravascular injection, blockages of nerve plexuses or other peripheral blockades were accompanied by seizures. In the case of an incorrect injection of an epidural dose of an anesthetic intrathecally, a complete spinal block may occur.

A random intravascular injection of an anesthetic can cause an immediate toxic reaction.

In case of an overdose during the regional anesthesia, the symptoms of a systemic toxic reaction appear in a delayed manner 15-60 min after the injection due to a slow increase in the local anesthetic concentration in the blood plasma. Systemic toxicity, in the first place, is manifested by symptoms from 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 injection, overdose or exceptionally high adsorption from highly vascularized areas. CNS reactions are similar for all local anesthetics of the amide type, 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 there are visual disturbances, numbness around the mouth, numbness of the tongue, hyperacusis, ringing in the ears, dizziness. Dysarthria, tremor and muscle twitching are more serious manifestations of systemic toxicity and may precede the appearance of generalized seizures (these signs should not be mistaken for the patient's neurotic behavior). With the progression of intoxication, loss of consciousness, seizures of a duration of several seconds to several minutes, accompanied by a violation of breathing, rapid development of hypoxia and hypercapnia due to increased muscle activity and inadequate ventilation can occur.In severe cases, even stopping breathing may occur. Emerging acidosis, hyperkalemia, hypocalcemia increases the toxic effects of anesthetic.

Subsequently, because of the redistribution of 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

Disorders from the cardiovascular system are signs of more serious complications. Decrease in blood pressure, bradycardia, arrhythmia and, in some cases, even cardiac arrest may occur due to the high systemic concentration of local anesthetics. In rare cases, cardiac arrest is not accompanied by a previous symptomatology of the CNS. 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 sedated (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 difficulties experienced by children in describing symptoms, or in the case of regional anesthesia combined with general anesthesia.

Acute Toxicity Treatment

When the first signs of acute systemic toxicity appear, discontinue the drug immediately.

When there are seizures and symptoms of CNS depression, the patient needs adequate treatment, whose goal is to maintain oxygenation, arrest seizures, maintain the cardiovascular system. It is necessary to provide oxygenation by oxygen, and if necessary - transition to artificial ventilation of the lungs. If after 15-20 seconds of seizures do not stop, anticonvulsants should be used: thiopental sodium 1-3 mg / kg IV (ensures rapid arrest 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 cures seizures, but requires intubation and artificial ventilation of the lungs.

When oppressing the cardiovascular system (lowering blood pressure, bradycardia), intravenous injection of 5-10 mg of ephedrine is necessary, and if necessary, repeat after 2-3 minutes. With the development of circulatory insufficiency or cardiac arrest, standard resuscitation should begin immediately. It is vitally important to maintain optimal oxygenation, ventilation and circulation of blood, and also to correct acidosis. Heart failure may require longer resuscitation.

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 with simultaneous use with other local anesthetics or preparations structurally similar to local anesthetics of the amide type.

The clearance of ropivacaine is reduced to 77% with simultaneous application with fluvoxamine (a powerful competitive inhibitor of the isoenzyme CYP1A2); Because of the possibility of similar interactions, prolonged use of Naropin® should be avoided with fluvoxamine.

An increase in the pH of the solution above 6.0 can lead to the formation of precipitate (lower solubility of ropivacaine).

Special instructions:

Anesthesia should be conducted by experienced specialists. It is necessary to have equipment and medicines for resuscitation. Before starting large blockades, an intravenous catheter should be installed.

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 section "Overdose").

Complication of unintentional subarachnoidal administration may be a spinal block with respiratory arrest and a decrease in blood pressure. Seizures develop more often with blockade of the brachial plexus and epidural block, probably due to accidental intravascular injection or rapid absorption at the injection site.

Execution of peripheral nerve blockages may require the injection of a large volume of local anesthetic into 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.Some procedures associated with the use of local anesthetics, such as injections in the head and neck, may be accompanied by 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.

Care should be taken when administering the drug to patients with blockade of intracardiac conductance of II and III degrees, patients with severe renal failure, elderly and weakened patients.

There have been reports of rare cases of cardiac arrest with Naropin® for epidural anesthesia or peripheral nerve blockages, especially after accidental intravascular drug administration in elderly patients and in patients with concomitant cardiovascular diseases. In some cases, resuscitation was difficult. Heart failure, as a rule, requires more prolonged 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 because ofdelayed elimination, it may be necessary to reduce re-injected doses of anesthetic.

Usually, in patients with renal insufficiency, when administering the drug once or when using the drug for a short period of time, it is not necessary to adjust the dose. However, acidosis and a decrease in the concentration of proteins in the blood plasma, often developing in patients with chronic renal failure, may increase the risk of systemic toxic effects of the drug. The risk of systemic toxicity is also increased when the drug is used 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 vasoconstrictors or an increase in the volume of circulating blood can reduce the risk of such side effects. It is necessary to correct the BP reduction in a timely manner by intravenous injection of 5-10 mg of ephedrine, if necessary, the administration can be repeated.

Patients receiving treatment with antiarrhythmic drugs of the III class (for example, amiadorin) should be closely monitored, ECG monitoring is recommended in connection with the risk of increasing cardiovascular effects.Avoid prolonged use of the drug Naropin® in patients taking potent inhibitors of the CYP1A2 isoenzyme (such as, fluvoxamine and enoxacin).

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

Patients on a diet with sodium restriction must take into account the sodium content in the preparation.

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

Naropin® is potentially capable of causing porphyria and can be used in patients diagnosed with acute porphyria only in cases where there is no safer alternative. In the case of hypersensitivity patients should take the necessary precautions.

Effect on the ability to drive transp. cf. and fur:In addition to the analgesic effect, Naropin® can 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 hazardousActivities that require increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Solution for injection 5 mg / ml.

Packaging:

10 ml in sealed ampoules made of polypropylene. Each ampoule is placed in a contour mesh package.

5 contour mesh packages with instructions for use in a cardboard bundle with the control of the first opening.

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 expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LS-001984

Date of registration:02.09.2011 / 22.03.2017

Expiration Date:Unlimited

The owner of the registration certificate:Aspen Pharma Trading LimitedAspen Pharma Trading Limited

Manufacturer: & nbsp

ASTRAZENECA, AB Sweden

Representation: & nbspAspen Hells Ltd.Aspen Hells Ltd.

Information update date: & nbsp13.06.2018

Illustrated instructions

Instructions

Naropin® (Naropin®)