Naropin of 5 mg/ml

General characteristics. Structure:

Active agent: a ropivakaina a hydrochloride the monohydrate corresponding a ropivakaina to a hydrochloride of 5,0 mg.
Excipients: sodium chloride of 8,0 mg, sodium hydroxide and/or Acidum hydrochloricum for finishing рН to 4,0 – 6,0, water for injections to 1,0 ml.
Description
Transparent colourless solution.
Characteristic
Solution of the drug Naropin® represents sterile isotonic aqueous solution, does not contain preservatives and is intended only for single use. rka of a ropivakain 8,1; a distribution coefficient – 141 (n-okanol/fosfatny the buffer рН 7,4 at 25C).

Pharmacological properties:

Pharmacodynamics. Ropivakain – it is long the operating local anesthetic of amide type, being a pure left-handed enantiomer. Possesses the action both anesthetizing, and anesthetizing. High concentration of a ropivakain are applied to local anesthesia at surgical interventions. In low concentration calls the touch block (analgesia) with the minimum and not progressing motor block. Reversibly blocking potentsialzavisimy natrium channels, interferes with generation of impulses in the terminations of sensory nerves and to carrying out impulses on nerve fibrils. As well as other local anesthetics can exert impact on other excitable cellular membranes (for example, in a brain and a myocardium), at the same time manifestation of signs of system toxicity is possible. Getting in excess quantities to a system blood stream, can have the oppressing effect on the central nervous system and a myocardium (reduces excitability, automatism and conductivity). Toxicity signs from the central nervous system (see the section "Overdose") precede toxicity signs from cardiovascular system as are observed at lower concentration of a ropivakain in plasma. Наропин® has broad therapeutic range (range between the doses having therapeutic and toxic effect). In the researches in vivo on animals it is shown what ропивакаин has smaller toxic effect on a myocardium in comparison with bupivacaine. Indirect cardiovascular effects (decrease in the ABP, bradycardia) which can arise after epidural introduction of a ropivakain are caused by the arising sympathetic blockade.
The beginning and duration of anesthesia the drug Naropin® depend on concentration and an injection site of drug. Addition of Epinephrinum practically does not influence duration and intensity of the blockade caused ropivakainy.

Pharmacokinetics. Concentration of a ropivakain in a blood plasma depends on a dose, a way of introduction and degree of vascularization of area of an injection. The pharmacokinetics of a ropivakain linear, maximum concentration (Cmax) is proportional to the entered dose. After epidural introduction ропивакаин it is completely absorbed in blood. Absorption has two-phase character. The elimination half-life (T1/2) for each phase makes, respectively, 14 min. and 4 h. Delay of elimination of a ropivakain is defined by slow absorption that explains longer T1/2 after epidural introduction in comparison with intravenous administration.
The general plasma clearance of a ropivakain – 440 ml/min., plasma clearance of untied substance - 8 l/min, renal clearance - 1 ml/min., distribution volume in an equilibrium state - 47 l, an indicator of hepatic extraction about 0,4, T1/2-1,8 of h.
Ropivakain intensively contacts proteins of a blood plasma (mainly with alfa1-acid glycoproteins), the untied fraction of a ropivakain makes about 6%.
Long epidural infusion of a ropivakain after surgeries leads to increase in the general content of drug in a blood plasma that is caused by increase in maintenance of acid glycoproteins in blood, at the same time concentration untied, pharmacological an active form of a ropivakain in a blood plasma changes in much smaller degree, than the general concentration of a ropivakain.
Ropivakain well gets through a placental barrier with bystry achievement of balance on untied fraction. Extent of linkng with proteins of a blood plasma at a fruit is less, than at mother that results in lower concentration of a ropivakain in fruit plasma in comparison with the general concentration in a blood plasma of mother.
Ropivakain is actively metabolized in an organism, mainly, by an aromatic hydroxylation (the main metabolites: 3-gidroksiropivakain, 4-gidroksiropivakain, N-dezalkilirovannye metabolites and 4-gidroksidezalkilirovanny ропивакаин). 3-gidroksiropivakain (conjugated and not conjugated) it is found in a blood plasma. 3 hydroxies and 4-gidroksiropivakain possess weaker mestnoanestezirushchy action in comparison with ropivakainy.
After intravenous administration of 86% of a ropivakain it is removed with urine (1% - in is invariable - number a look). About 37% of a 3-gidroksiropivakain, the main metabolite of a ropivakain, are removed with urine (preferential in the conjugated form).
1-3% of a ropivakain are removed with urine in the form of the following metabolites: 4-gidroksiropivakaina, N-dezalkilirovannykh of metabolites and 4-gidroksidezalkilirovanny ropivakain.
There are no data on racemization of a ropivakain of in vivo.

Indications to use:

• Intrathecal blockade
Anesthesia at surgical interventions:
• Blockade of peripheral nerves at children from 1 to 12 summer age inclusive
Stopping of an acute pain syndrome in pediatrics.

Route of administration and doses:

Drug is used for epidural, spinal, infiltration and conduction anesthesia.
Наропин® it has to be used only by the specialists having sufficient experience of carrying out regional anesthesia or under their observation, in the presence of the equipment and medicines for holding resuscitation actions. Prior to performance of big blockade intravenous catheters have to be established.
Наропин® enter slowly or by increase in the drug doses entered consistently with speed of 25-50 mg/min.
For prevention of hit of anesthetic it is necessary to carry out aspiration test to a vessel surely. Accidental intravascular introduction is distinguished on temporary increase in heart rate. The provided table is the indicative guide to a drug dosing for carrying out intrathecal blockade. At selection of a dose of drug it is necessary to be based on clinical experience taking into account a physical condition of the patient.
Recommendations about a drug dosing of Naropin® for adults:
                                Kontsentra-         Volume of solution                      of Doza Nachalo Dlitel-
                                tion of drug     (ml)                       (ml)          of action       nost
                                (mg/ml)                                                                  (min.)            of action
                                                                                                                                     (hour)
Anesthesia at surgical interventions:
Intrathecal blockade:
Surgical
interventions                                                    5,0 3 - 4 15 - 20          1 - 5              2 - 6

Recommendations about a drug dosing of Naropin® for children of the 1st year:
                                             Concentration      Volume                 Dose
                                             drug              of solution             (ml/kg)
                                             (mg/ml)                   (ml/kg)
Stopping of an acute pain syndrome (intraoperative and postoperative):
Blockade of peripheral nerves at children from 1 to 12 summer age inclusive:
(for example, for blockade
ilioinguinal nerve)                       5,0 0,6                           3

The doses specified in the table are considered sufficient for achievement of reliable blockade and are approximate when using drug at adults as there is an individual variability of speed of development of the block and its duration.
For anesthesia at Cesarean section the intrathecal way of introduction of a ropivakain was not studied.
For acquaintance with the factors influencing a method of performance of separate blockade and with requirements imposed to specific groups of patients it is necessary to use the standard managements.
Concentration use higher than 5 mg/ml at children, and also intrathecal introduction of any concentration of drug is not studied.
Application instructions of solution
Solution does not contain preservatives and is intended only for single use. Any amount of the solution which remained in a container after use has to be destroyed.
The opened container with solution has to be autoclaved.
Not opened blister packaging provides sterility of an external surface of an infusional container and is preferable to use in the conditions demanding sterility.
In view of lack of enough clinical observations it is not recommended to apply Naropin® at children aged up to 1st year.

Features of use:

Anesthesia has to be carried out by experienced specialists. Existence of the equipment and medicines for holding resuscitation actions is obligatory. Prior to performance of big blockade the catheter has to be established intravenously.
The personnel providing anesthesia performance have to be appropriately prepared and familiar with diagnosis and treatment of possible side effects, system toxic reactions and other possible complications (see the section "Overdose").
The spinal block with an apnoea and decrease in the ABP can be a complication of inadvertent subarachnoidal introduction. Spasms develop more often at blockade of a brachial plexus and epidural blockade probably owing to accidental intravascular introduction or bystry absorption in the place of an injection.
Performance of blockade of peripheral nerves can demand introduction of large volume of local anesthetic to zones with a large number of vessels, often near large vessels that increases risk of intravascular introduction and/or bystry system absorption that can result in high concentration of drug in plasma.
Some procedures connected using local anesthetics such as injections in the head and a neck, can be followed by the increased frequency of development of serious side effects, regardless of type of the applied local anesthetic. It is necessary to be careful for prevention of an injection to the area of an inflammation.
It is necessary to be careful at administration of drug to patients with blockade of endocardiac conductivity II and III degrees, to patients with a heavy renal failure, to the elderly and weakened patients.
There are messages on exceptional cases of a cardiac standstill at use of the drug Naropin® for epidural anesthesia or blockade of peripheral nerves, especially after accidental intravascular administration of drug, for elderly patients and for patients with the accompanying cardiovascular diseases.
In some cases resuscitation actions were difficult. The cardiac standstill, as a rule, demands longer resuscitation actions.
As Naropin® is metabolized in a liver, it is necessary to show care at use of drug for patients with a serious illness of a liver; in certain cases because of the slowed-down elimination there can be a need of reduction of repeatedly entered anesthetic doses.
Usually at patients with a renal failure at administration of drug once or when using drug during a short span it is not required to adjust a dose. However the acidosis and decrease in concentration of proteins in a blood plasma which are often developing at patients with a chronic renal failure can increase risk of systemic toxic action of drug. The risk of system toxicity is also increased at use of drug for patients with an underweight of a body and patients with hypovolemic shock.
Epidural anesthesia can lead to decrease in the ABP and bradycardia. Administration of vasoconstrictive drugs or increase in volume of the circulating blood can reduce risk of development of similar side effects. It is necessary to adjust timely decrease in the ABP by intravenous administration of 5-10 mg of ephedrine, if necessary introduction can be repeated.
The patients receiving therapy by antiarrhytmic drugs III of a class (for example, amiadorony) have to be under careful observation, ECG monitoring in connection with risk of strengthening of cardiovascular effects is recommended.
It is necessary to avoid prolonged use of the drug Naropin® at the patients accepting powerful inhibitors of an isoenzyme CYP1A2 (such as, флувоксамин and эноксацин).
It is necessary to consider a possibility of cross hypersensitivity at simultaneous use of the drug Naropin® with other local anesthetics of amide type.
The patients who are on a diet with sodium restriction need to take into account the content of sodium in drug.
Use of drug in concentration is higher than 5 mg/ml, and also intrathecal use of the drug Naropin® for children was not investigated.
Наропин® it is potentially capable to cause a porphyria and the acute porphyria only in cases can be applied at patients with the diagnosis if there is no safer alternative. In case of hypersensitivity of patients necessary precautionary measures have to be taken. INFLUENCE ON ABILITY to MANAGE VEHICLES AND OTHER MECHANISMS
In addition to analgeziruyushchy effect, Naropin® can exert weak tranzitorny impact on motive function and coordination. Considering a profile of side effects of drug, it is necessary to be careful at control of vehicles and performance of other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

Undesirable reactions to Naropin® are similar to reactions to other local anesthetics of amide type. They should be distinguished from the physiological effects arising because of blockade of sympathetic nerves against the background of epidural anesthesia such as, a lowering of arterial pressure, bradycardia, or the effects connected with technology of administration of drug such as, local injury of a nerve, meningitis, a post-puncture headache, epidural abscess.
From the central and peripheral nervous system
Side effects inherent in local anesthetics
Neuropathy and dysfunction of a spinal cord (syndrome of a front spinal artery, arachnoiditis, syndrome of a horse tail) are possible, are usually connected with technology of carrying out regional anesthesia, but not with effect of drug.
The full spinal block can result from accidental intrathecal introduction of an epidural dose.
Serious complications at system overdose and inadvertent intravascular administration of drug are possible (see the section "Overdose").
Acute system toxicity
Наропин® can cause acute system toxic reactions when using high doses or at bystry increase in its concentration in blood at accidental intravascular administration of drug or its overdose (see the section "Pharmacological Properties" and "Overdose").
The most often found side effects
It was reported about various side effects of drug which vast majority was connected not with influence of the used anesthetic, and with technology of carrying out regional anesthesia.
Most often (> 1%) noted the following side effects which were regarded as whether having clinical value regardless of that relationship of cause and effect was established with anesthetic use: lowering of arterial pressure (ABP) *, nausea, bradycardia, vomiting, paresthesia, fervescence, headache, urination delay, dizziness, fever, increase in arterial pressure, tachycardia, hypesthesia, concern.
Frequency of emergence of undesirable effects is presented as follows:
Very often (> 1/10); Often (> 1/100, <1/10); Infrequently (> 1/1000, <1/100); Seldom (> 1/10 000, <1/1 000); Very seldom (<1/10 000), including separate messages.
Very often
From cardiovascular system: decrease in the ABP *
From the digestive tract (DT): nausea
Often
From a nervous system: paresthesia, dizziness, headache
From cardiovascular system: bradycardia, tachycardia, increase in the ABP
From a GIT: vomiting **
From urinogenital system: urination delay
The general: dorsodynia, fever, fervescence
Infrequently
From a nervous system: concern, toxicity symptoms from TsNS (spasms, big convulsive attacks, paresthesias in a circumoral zone, a dysarthtia, numbness of language, a vision disorder, a ring in ears, a hyperacusia, a tremor, muscular spasms), a hypesthesia
From vascular system: syncope
From respiratory system: an asthma, the complicated breath
The general: hypothermia
Seldom
From cardiovascular system: arrhythmia, cardiac standstill
The general: allergic reactions (anaphylactic reactions, Quincke's disease, small tortoiseshell).
* Decrease in the ABP occurs at children often.
** Vomiting occurs at children very often.

Interaction with other medicines:

Summing of toxic effects at simultaneous use with other local anesthetics or drugs structurally similar to local anesthetics of amide type is possible.
The clearance of a ropivakain decreases to 77% at simultaneous use with fluvoksaminy (a powerful competitive inhibitor of an isoenzyme of CYP1A2); because of a possibility of similar interaction it is necessary to avoid prolonged use of the drug Naropin® against the background of action of a fluvoksamin.
Increase рН solution above 6,0 can give to formation of precipitated calcium superphosphate (decrease in solubility of a ropivakain).

Contraindications:

The known hypersensitivity to local anesthetics of amide type.
In view of lack of enough clinical observations use of the drug Naropin® for children is not recommended intrathecal administration of drug is younger than the 1st year, and also.
With care: the weakened elderly patients or patients with serious associated diseases, such as blockade of endocardiac conductivity II and III degrees (sinuatrial, atrioventricular, intra ventricular), the progressing liver diseases, a heavy liver failure, a heavy chronic renal failure, at therapy of hypovolemic shock, pregnancy, the lactation period. For these groups of patients regional anesthesia is preferable, when carrying out big blockade for the purpose of decrease in risk of development of the heavy adverse phenomena it is recommended to optimize previously a condition of the patient, and also to correct an anesthetic dose.
The patients who are on a diet with sodium restriction need to take into account the content of sodium in drug.
PREGNANCY AND LACTATION
Pregnancy
Influence of a ropivakain on fertility and reproductive function, and also its teratogenic action is not revealed. Researches on assessment of possible action of a ropivakain on fetation at women were not conducted.
Наропин® it is possible to apply at pregnancy only if the expected advantage for mother surpasses potential risk for a fruit.
Lactation
Allocation of a ropivakain or its metabolites with breast milk was not studied. Proceeding from experimental data, the drug dose received by the newborn presumably makes 4% of a dose, the entered mother (i.e. the general dose of a ropivakain influencing the child when breastfeeding is much less than a dose which can be received by the newborn at administration of anesthetic of mother at childbirth). In need of use of drug during chest feeding it is necessary to consider a ratio of potential advantage for mother and possible risk for the baby.

Overdose:

Acute system toxicity
At accidental intravascular introduction when carrying out blockade of neuroplexes or other peripheral blockade cases of developing of spasms were observed.
In case of the wrong introduction of an epidural dose of anesthetic emergence of the full spinal block is intratekalno possible.
Accidental intravascular administration of anesthetic can cause immediate toxic reaction.
At overdose during regional anesthesia symptoms of system toxic reaction appear in the delayed order in 15-60 min. after an injection because of slow increase in concentration of local anesthetic in a blood plasma. System toxicity, first of all, is shown by symptoms from the central nervous system (CNS) and cardiovascular system (CCC). These reactions are caused by high concentration of local anesthetic in blood which can arise owing to (accidental) intravascular introduction, overdose or exclusively high adsorption from strongly vaskulyarizirovanny areas. Reactions from TsNS are similar for all local anesthetics of amide type while reactions from cardiovascular system more depend on the administered drug and its dose.
Central nervous system
Manifestations of system toxicity from the central nervous system develop gradually: at first there are visual disturbances, numbness around a mouth, numbness of language, a hyperacusia, a ring in ears, dizziness. The dysarthtia, a tremor and muscular twitchings are more serious manifestations of system toxicity and can precede emergence of generalized spasms (these signs should not be accepted to neurotic behavior of the patient). When progressing intoxication the loss of consciousness, attacks of spasms lasting from several seconds up to several minutes which are followed by breath disturbance, bystry development of a hypoxia and a hypercapnia because of the increased muscular activity and inadequate ventilation can be observed. In hard cases there can even come the apnoea. The arising acidosis, a hyperpotassemia, a hypocalcemia strengthen toxic effects of anesthetic.
Afterwards, because of redistribution of anesthetic from TsNS and its subsequent metabolism and excretion, there is rather bystry recovery of functions if the high dose of drug was only not entered.
Cardiovascular system
Frustration from cardiovascular system are signs of more serious complications. Decrease in the ABP, bradycardia, arrhythmia and, in some cases, even a cardiac standstill can arise owing to high system concentration of local anesthetics. In rare instances the cardiac standstill is not followed by the previous symptomatology from TsNS. In researches on volunteers intravenous infusion of a ropivakain led to oppression of conductivity and sokratitelny ability of a cardiac muscle. Symptoms from cardiovascular system are usually preceded by manifestations of toxicity from TsNS which can be not noticed if the patient is under the influence of sedatives (benzodiazepines or barbiturates) or under the general anesthesia.
At children it is sometimes more difficult to reveal precursory symptoms of system toxicity of local anesthetics owing to the difficulties experienced by children at the description of symptoms or in case of use of regional anesthesia in combination with the general anesthesia.
Treatment of acute toxicity
At emergence of the first signs of acute system toxicity it is necessary to stop administration of drug immediately.
At emergence of spasms and symptoms of oppression of TsNS sick adequate treatment which purpose is oxygenation maintenance, stopping of spasms, maintenance of activity of cardiovascular system is required. It is necessary to provide oxygenation with oxygen, and if necessary – transition to artificial ventilation of the lungs. If 15-20 seconds of a spasm later do not stop, it is necessary to use anticonvulsants: thiopental of sodium of 1-3 mg/kg in/in (provides bystry stopping of spasms) or diazepam of 0,1 mg/kg in/in (action develops more slowly in comparison with effect of thiopental of sodium). Succinylcholine of 1 mg/kg quickly stops spasms, but at its use the intubation and artificial ventilation of the lungs is required.
At oppression of activity of cardiovascular system (decrease in the ABP, bradycardia) intravenous administration of 5-10 mg of ephedrine is necessary, if necessary in 2-3 min. to repeat introduction. At development of circulator insufficiency or a cardiac standstill it is necessary to begin standard resuscitation actions immediately. It is vital to support optimum oxygenation, ventilation and blood circulation, and also to adjust acidosis. At a cardiac standstill longer resuscitation actions can be required.
At therapy of system toxicity at children it is necessary to adjust doses according to age and body weight of the patient.

Storage conditions:

To store at a temperature not above 30 °C. Not to freeze. To store in the places not available to children. Period of validity 3 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Solution for injections of 5 mg/ml. On 10 ml in the soldered ampoules from polypropylene. Each ampoule is placed in a blister strip packaging.
5 blister strip packagings with the application instruction in a cardboard pack with control of the first opening.