Markain

General characteristics. Structure:

Active ingredient: bupivacaine a hydrochloride monohydrate of 5,28 mg that corresponds to 5,0 mg of bupivacaine of a hydrochloride;
Excipients: sodium chloride of 8,0 mg, sodium hydroxide of 2 mol/l or Acidum hydrochloricum of 2 mol/l to рН 4, water for injections to 1,0 ml.
Description: transparent colourless solution.

Pharmacological properties:

Pharmacodynamics. Local anesthetic of long action of amide type, is 4 times stronger than lidocaine. Reversibly blocks carrying out an impulse on nerve fibril due to influence on natrium channels. Has hypotensive effect, slows down heart rate. The postoperative analgesia is supported during 7-14 h at intercostal blockade. At a single epidural injection effect duration when using concentration of 5 mg/ml makes from 2 to 5 h, and to 12 h – at a peripheral nerve block.
Use of solutions in concentration of 2,5 mg/ml renders smaller effect on motor nerves.

Pharmacokinetics. Bupivacaine has an indicator rka-8,2 a fractionation factor 346 (at 25 °C among N octanol / the phosphatic buffer рН 7,4).
Bupivacaine is completely absorbed in blood from an epidural space; absorption has two-phase character, the elimination half-life for two phases makes respectively 7 minutes and 6 hours. Slow elimination of bupivacaine is defined by existence of a slow phase of absorption of an epidural space that explains longer elimination half-life (T1/2) after epidural introduction in comparison with intravenous administration.
The general plasma clearance of bupivacaine makes 0,58 l/min, distribution volume in an equilibrium condition of 73 l, a final elimination half-life 2,7 hours, an intermediate indicator of hepatic extraction about 0,38 later in/in introductions. Bupivacaine, mainly, communicates with α1-кислыми plasma glycoproteins (linkng with proteins of plasma – 96%). The clearance of bupivacaine is almost completely caused by metabolism of drug in a liver and depends on activity of fermental systems of a liver more, than on perfusion of a liver. Metabolites have smaller pharmacological activity, than bupivacaine.
Plasma concentration of bupivacaine depends on a dosage of drug, a method of administration of drug, vascularization in the field of introduction.
At children aged from 1 year up to 7 years the pharmacokinetics of drug is similar to indicators at adults.
Gets through a placenta. Communication with proteins of plasma in an organism of a fruit is lower, than in mother's organism, concentration of untied fraction in an organism of a fruit and mother is identical.
Bupivacaine is exposed to metabolism in a liver, mainly, by an aromatic hydroxylation to 4-hydroxy-bupivacaine and N-dealkylation to 2,6 pipekoloksilidin (RRK). Both reactions happen to participation of an isoenzyme of CYP3A4 cytochrome. About 1% of bupivacaine is excreted with urine in an invariable look within a day after introduction, and about 5% in the form of RRK. Concentration of RRK and 4-hydroxy-bupivacaine in plasma in time and after the prolonged administration of bupivacaine low in relation to the entered drug dose.

Indications to use:

Different types of local anesthesia (anesthesia at an injury, surgical interventions, including Cesarean section, a labor pain relief, holding painful diagnostic procedures, for example, at an arthroscopy): a local infiltration anesthesia, conduction anesthesia (including intercostal blockade, blockade of big and small nerves, blockade of nerves in the head and a neck), caudal or lumbar epidural blockade, retrobulbar (regional) anesthesia.

Route of administration and doses:

Adults and children are more senior than 12 years
The table below is the management for a drug dosing at the often carried most out techniques. When calculating a necessary dose it is important to be based on clinical experience and assessment of the physical status of the patient.
Recommendations about dosing
For caudal blockade higher doses can be used (see the table). The doses specified in the table are considered necessary for successful blockade, and have to be considered as recommended for the average adult patient.
When performing of the prolonged blockade by means of the prolonged infusion or fractional administration of drug it is necessary to consider a possibility of increase in its concentration in a blood plasma to toxic or probability of emergence of local damage of nerve fibrils. The experience accumulated so far shows that introduction to the adult patient within 24 hours of 400 mg of drug is usually well transferred.
When using large volume of the solution containing Epinephrinum it is necessary to take a possibility of risk of development of system effects of Epinephrinum into account.

Blockade type           Dose of ml of mg                 of Nachalo Dlitel-       of the Indication
                                                   actions, ми    nost, hours    (comments)
Infiltration        ≤30 ≤150                           1-10 3-8            Surgical
                                                                                                  interventions
                                                                                                 postoperative 
                                                                                                 analgesia
Retrobulbar                                  2-4 10-20 5 4-8           Ophthalmosurgery
                                                                                                  (see the section "Special 
                                                                                                  instructions")
Peribulbarny      6-10 30-50                          10 4-8            Ophthalmosurgery 
                                                                                                 (see the section "Special 
                                                                                                  instructions")
Intercostal
(counting on a nerve)                               2-3 10-15 3-5 4-8           Surgical 
                                                                                                 interventions 
                                                                                                 and postoperative 
                                                                                                 analgesia, anesthesia 
                                                                                                 at an injury
Intrapleural
blockade                   20 100                            10-20 4-8          Postoperative 
                                                                                                 analgesia
Blockade humeral                                                                     Surgical
textures:                                                                                 interventions
axillary        30-40 150-175                  15-30 4-8
supraclavicular, 
interladder      20-30 100-150                  15-30 4-8
and subclavial
perivascular 
Blockade
sciatic                                                                               Surgical
nerve                     10-35 50-175                    15-30 4-8            interventions
Blockade                 10-35 50-175                    15-30 4-8             Surgical
femoral nerve,                                                                       operation
locking
nerve and
lateral
cutaneous nerve
hips (3 in 1)
Epidural       15-30 75-150                    15-30 2-3            Surgical
(on lumbar                                                                          interventions,
level)                                                                                      including Cesarean section,
                                                                                                  labor pain relief
                                                                                                 and postoperative
                                                                                                  anesthesia (dose
                                                                                                  considers trial
                                                                                                  test)
Epidural        5-10 25-50                10-15 2-3                    Intraoperative
(on chest                                                                               and postoperative
level)                                                                                      anesthesia.
                                                                                                  Therapy of pain syndromes 
                                                                                                 and anesthesia at 
                                                                                                 diagnostic procedures
                                                                                                  (the dose considers sample test)

The drug should be administered with care to avoid development of acute toxic reactions at accidental intravascular administration of drug. It is recommended to carry out carefully aspiration test to and in the course of administration of drug. If introduction of a high dose is required, for example, at epidural blockade, preliminary introduction of a test dose is recommended: 3 - 5 ml of bupivacaine with Epinephrinum. In case of accidental intravascular administration of drug there can be tranzitorny tachycardia which is easily revealed by the doctor. The main dose is entered slowly
For children 12 years are younger calculation of a dose has to be carried out taking into account body weight (on average to 2 mg/kg), at lumbosacral – 1,5-2 mg/kg of weight, at thoracolumbar – 1,5 - 2,5 mg/kg of weight. Addition of Epinephrinum increases blockade duration by 50 - 100%. with a speed of 25 - 50 mg/min. or fractionally bolyusno, constantly supporting verbal contact with the patient. At emergence of symptoms of intoxication, administration of drug has to be immediately stopped.

Features of use:

There are messages on a cardiac standstill or death in usage time of bupivacaine for epidural anesthesia or peripheral blockade. In certain cases resuscitation was complicated or impossible, despite undoubtedly good preparation and carrying out anesthesia.
Like other local anesthetics, bupivacaine can cause acute toxic reactions from the central nervous and cardiovascular systems if its use for local anesthesia results in high concentration of drug in blood. Most often it is shown in case of inadvertent intravascular introduction or at high vascularization
injection sites. Against the background of high concentration of bupivacaine in plasma cases of developing of ventricular arrhythmia, fibrillation of ventricles, a sudden cardiovascular collapse and death were recorded.
Regional anesthesia has to be carried out by experienced specialists in the equipped room corresponding in the way. The equipment and drugs necessary for carrying out cardiomonitoring and resuscitation actions have to be available to immediate use. When performing big blockade before administration of local anesthetic it is recommended to establish an intravenous catheter. The personnel have to undergo the corresponding training in technology of performance of anesthesia and have to be familiar with diagnosis and treatment of side effects of drug, system toxic reactions and other complications (see the section "Overdose").
Carrying out peripheral nervous blockade is connected with introduction of bigger volume of local anesthetic to area of high vascular vascularization, is often close to large vessels where the risk of inadvertent intravascular administration of local anesthetic or system absorption of a high dose of drug increases that in turn can lead to increase in plasma concentration.
When carrying out regional anesthesia it is necessary to be especially attentive to the following groups of patients:
• The patients receiving antiarrhytmic drugs of the III class (for example, Amiodaronum), have to be under careful observation, because of possible risk of development of complications from cordial vascular system.
• Patients of advanced age and the weakened patients.
• Patients with partial or total cordial block as local anesthetics can worsen conductivity of a myocardium.
• Patients with the progressing disease of a liver or with a heavy renal failure.
• Patients on late durations of gestation.
Certain types of blockade, irrespective of the applied local anesthetic, can be connected with serious adverse reactions, for example:
• The central blockade, especially against the background of a hypovolemia, can bring to
to oppression of activity of cardiovascular system.
• Big peripheral blockade can demand use of a large amount of local anesthetic in areas of high vascularization, often near big vessels where the risk of intravascular introduction and/or system absorption increases that can result in high concentration of drug in plasma.
• At a retrobulbar injection drug can accidentally get to a cranial subarachnoid space, causing a temporary blindness, an apnoea, spasms, a collapse and other side effects.
• At retrobulbar and peribulbarny administration of local anesthetics there is a small risk of emergence of permanent dysfunction of eye muscles. The injury and/or local toxic action on muscles and/or nerves are the main reasons. Weight of similar fabric reactions depends on degree of an injury, concentration of local anesthetic and duration of exposure of fabric local anesthetic. Therefore, as well as in case of use of other local anesthetics, it is necessary to use the smallest effective concentration and a dose of drug. Vasoconstrictors can strengthen fabric reactions and have to be used only according to indications.
• At injections in a neck or the head drug can accidentally get into an artery and in these cases even at use of low doses development of serious adverse reactions is possible.
• Paracervical blockade sometimes leads to emergence of bradycardia/tachycardia in a fruit therefore careful monitoring of a cordial rhythm at a fruit is obligatory.
When carrying out epidural anesthesia there can be hypotension and bradycardia. It is possible to reduce probability of these complications by preliminary introduction of crystalloid and colloidal solutions. At development of hypotension it is necessary to enter intravenously sympathomimetics at once; in need of their introduction it is necessary to repeat. At children the used doses have to correspond to age and weight.
Solution does not contain preservatives and has to be used immediately after opening of a bottle. The remains of solution have to be thrown out.

Side effects:

Side reactions on Маркаин are similar to the side reactions arising at intrathecal administration of other local anesthetics of long action. It is difficult to distinguish the side reactions caused by drug from physiological manifestations of blockade of nerves (for example, arterial hypotension, bradycardia, a temporary ischuria), the reactions caused directly (for example, a spinal hematoma) or indirectly (for example, meningitis, epidural abscess) introduction of a needle, or the reactions connected with leak of cerebrospinal fluid (for example, a post-puncture headache).
Very frequent (> 1/10)
From cardiovascular system: hypotension
From the digestive tract (DT): nausea
Frequent (> 1/100, <1/10)
From a nervous system: paresthesia, dizziness
From cardiovascular system: bradycardia, increase in the arterial pressure (AP)
From a GIT: vomiting
From urinogenital system: ischuria, urine incontience
Less frequent (> 1/1000, <1/100)
From a nervous system: signs and symptoms of toxicity from TsNS (spasms, paresthesia around a mouth, numbness of language, a hyperacusia, slight dizziness, visual disturbances, a loss of consciousness, a tremor, noise and a ring in ears, a dysarthtia)
Rare (<1/1000)
From cardiovascular system: cardiac standstill, arrhythmia
From a nervous system: inadvertent total spinal block, damage of peripheral nerves, paraplegia, paralysis, neuropathy, arachnoiditis
From respiratory system: respiratory depression
From organs of sight: diplopia
The general: allergic reactions, in the most hard cases – an acute anaphylaxis.

Interaction with other medicines:

Bupivacaine has to be used with care at the patients receiving other local anesthetics or drugs which are similar on structure to local anesthetics of amide type, such as antiarrhytmic drugs (for example, lidocaine, мексилетин), because of a possibility of development of the additive toxic effect. Combined use of bupivacaine with antiarrhytmic drugs of the III class (for example, Amiodaronum) separately was not studied, however it is recommended to be careful at co-administration of these drugs (see.
section "Special Instructions").
Inhibitors of a monoaminooxidase or tricyclic antidepressants increase risk of development of the expressed increase in arterial pressure.
The drugs containing oxytocin or ergotamine promote development of steady increase in arterial pressure with possible complications from cardiovascular and cerebrovascular system.
The combination to the general inhalation anesthesia a halothane increases risk of development of arrhythmia.
When processing the place of an injection of local anesthetic the disinfecting solutions containing heavy metals the risk of development of local reaction in the form of morbidity and hypostasis increases.
Drugs structurally similar to local anesthetics, for example, токаинид, increase risk of development of the additive toxic effect.
At combined use with drugs, the oppressing TsNS, local anesthetics strengthen oppression of TsNS.
Solubility of bupivacaine decreases at рН> 6,5, it has to be considered if alkaline solutions since precipitated calcium superphosphate can be formed are added.
Influence on ability to manage transport and work with mechanisms
Depending on a dose, local anesthetics can exert the minimum impact on thought processes and temporarily break locomotory function and coordination.

Contraindications:

Hypersensitivity to any of components of drug or to local anesthetics of amide type;
• diseases of the central nervous system (CNS) (as well as at epidural administration of other local anesthetics)
• the expressed arterial hypotension (cardiogenic or hypovolemic shock);
• children's age (up to 2 years);
Drug is not used when carrying out intravenous regional anesthesia (blockade on Bira) (accidental penetration of bupivacaine into a circulatory bed can cause development of acute system toxic reactions).
With care: Cardiovascular insufficiency (progressing), heart blocks, inflammatory diseases or infection of the place of an injection (is possible at an infiltration anesthesia), deficit of cholinesterase, a renal failure, advanced age (65 years), late duration of gestation (the III trimester), the general serious condition, decrease in a hepatic blood-groove (for example are more senior, at chronic heart failure, liver diseases), co-administration of antiarrhytmic means (including beta adrenoblockers), need of carrying out paracervical anesthesia, children's age (up to 12 years);
at peridural appointment (caudal and lumbar anesthesia) - the previous neurologic diseases, a septicaemia, a zatrudnennost of carrying out a puncture because of deformation of a backbone.
Bupivacaine has to be used with care at the patients receiving other local anesthetics or drugs structurally similar to local anesthetics of amide type, such as antiarrhytmic drugs (for example, lidocaine, мексилетин). Pregnancy and lactation
It is necessary to use drug only if the expected advantage for mother, exceeds possible risk for a fruit.
Bupivacaine was used at a large number of pregnant women and women of childbearing age, however, specific changes of reproductive function at women of childbearing age and increase in frequency of defects of development in a fruit were not noted so far.
Addition of Epinephrinum to a bipuvakain can reduce a blood stream in a uterus and its contractility, especially at accidental administration of solution of anesthetic in mother's vessels. The side effects caused by effect of local anesthetic in a fruit such as bradycardia, most often are found at paracervical blockade (anesthetic at the same time reaches a fruit in high concentration).
As well as other local anesthetics, bupivacaine can get into breast milk in the insignificant quantities which are not constituting danger to the child.

Overdose:

Acute system intoxication
At accidental intravascular introduction toxic reaction is shown within 1-3 minutes while at overdose
the maximum concentration of drug in a blood plasma can be reached within 20-30 minutes depending on the place of an injection, at the same time symptoms of intoxication are shown slowly. Toxic reactions are shown mainly from the central nervous and cardiovascular system.
From the central nervous system
Intoxication is shown gradually in the form of signs and symptoms of dysfunction of the central nervous system with the increasing severity. Initial displays of intoxication are: paresthesia around a mouth, dizziness, numbness of language, the perception of usual sounds and a sonitus patholologically increased. Dysfunction of sight and a tremor are the most serious signs and precede development of generalized spasms. These phenomena should not be regarded mistakenly as neurotic behavior. After them the loss of consciousness and development of big convulsive attacks which can last from several seconds to several minutes is possible. Owing to the increased muscular activity and disturbance of normal process of breath after the beginning of spasms the hypoxia and a hypercapnia quickly develop. In hard cases the apnoea can develop. Acidosis strengthens toxic effect of local anesthetics.
These phenomena pass due to redistribution of local anesthetic from the central nervous system and metabolism of drug. Stopping of the toxic phenomena can quickly come if only anesthetic was not entered in very large number.
From cardiovascular system
Toxic action on cardiovascular system is observed in hard cases. It is preceded, as a rule, by manifestations of toxic action on TsNS. At the patients who are in a condition of deep sedation or the general anesthesia, prodromal neurologic symptoms can be absent. Against the background of high concentration of bupivacaine in plasma cases of developing of hypotension, arrhythmia and cardiac standstill were recorded. In a number of exceptional cases the cardiac standstill occurred without the prodromal neurologic phenomena.
At children when performing blockade under the general anesthesia it is difficult to notice precursory symptoms of toxic effect of anesthetic.
Treatment of acute intoxication
At emergence of symptoms of the general intoxication maintenance of ventilation of the lungs, stopping of spasms and maintenance of blood circulation is necessary immediately. It is necessary to use oxygen and if necessary to adjust artificial ventilation (by means of a mask and a bag). If spasms do not stop independently within 15-20 seconds, it is necessary to administer the anticonvulsant drugs intravenously. Intravenous administration of 100-150 mg of thiopental of sodium quickly stops spasms, instead of it it is possible to enter intravenously 5-10 mg of diazepam though he acts more slowly. Succinylcholine quickly stops muscular spasms, however, at its use the intubation of a trachea and artificial ventilation of the lungs therefore this drug should be used only that who owns by these methods is required.
At explicit oppression of function of cardiovascular system (a lowering of arterial pressure – the ABP, and bradycardia) 5-10 mg of ephedrine enter intravenously, if necessary in 2-3 minutes repeat introduction. At a cardiac standstill immediately start cardiopulmonary resuscitation. Optimization of oxygenation and ventilation and support of circulation together with correction of acidosis as the hypoxia and acidosis will strengthen system toxic effects of local anesthetic are vital. As soon as possible it is necessary to enter Epinephrinum (0,1-0,2 mg intravenously or vnutriserdechno), if necessary introduction should be repeated.
At a cardiac standstill long resuscitation actions can be required.

Storage conditions:

Period of validity 3 years. Not to apply after the period of validity specified on packaging. At a temperature not above 25 °C, in places unavailable to children not to freeze.

Issue conditions:

According to the recipe

Packaging:

Solution for injections of 5 mg/ml in glass bottles on 20 ml.
On 20 ml in a bottle from borosilicate colourless glass with a rubber bung, an aluminum blooming ring and a plastic lid. On 5 bottles in a cardboard pack with the application instruction.