Маркаин® Spinal Hevi

General characteristics. Structure:

Active ingredient: bupivacaine a hydrochloride monohydrate for injections of 5,28 mg, the corresponding 5,0 mg of bupivacaine of a hydrochloride
Excipients: Dextrosums monohydrate of 80,0 mg, sodium hydroxide 2M for injections for finishing рН to 4,0-6,0, water for injections to 1 ml.
Description. Transparent colourless solution.

Pharmacological properties:

Bupivacaine – local anesthetic of amide type. At intrathecal introduction the effect occurs quickly, and its duration varies from average to long. Duration of effect depends on a dose.
Drug solution hyperbaric and in a subarachnoid space influences its distribution gravity. The small volume of distribution in intrathecal space results in smaller average concentration and reduction of duration of effect of drug in comparison with isobaric solution. The solutions which are not containing a dextrose give less predictable level of blockade.
Relative density at a temperature of 20 °C makes 1,026 (that corresponds 1,021 at a temperature 37ºС). рН solution makes 4,0-6,0.
Pharmacodynamics. Bupivacaine reversibly oppresses carrying out impulses on nerve fibril due to blocking of passing of ions of sodium through a cellular membrane.

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 from a subarachnoid space; absorption has two-phase character, the elimination half-life for two phases makes respectively, 50 and 408 minutes. Slow elimination of bupivacaine is defined by existence of a slow phase of absorption that explains longer elimination half-life (T1/2) after subarachnoidal introduction in comparison with intravenous administration. Concentration of bupivacaine in a blood plasma after intrathecal blockade is lower in comparison with other types of regional anesthesia as for intrathecal anesthesia smaller doses of drug are required. In general, increase in the maximum concentration
drug in a blood plasma makes about 0,4 mkg/ml on each entered 100 mg of drug. It means that the dose of 20 mg creates concentration in a blood plasma about 0,1 mkg/ml.
After 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.
Bupivacaine gets through a placental barrier with bystry achievement of balance on untied fraction. Extent of linkng with proteins of plasma in a blood-groove of a fruit is lower, than at mother that results in lower concentration of drug in fruit plasma in comparison with the general concentration of drug in a blood plasma of mother.
Bupivacaine gets into breast milk in the quantities which are not constituting danger to the child.
Bupivacaine is exposed to metabolism in a liver, mainly, by an aromatic hydroxylation to 4-hydroxy-bupivacaine and N-dealkylation to RRH. Both reactions happen to participation of enzymes of P4503A4 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 RRH. Concentration of RRH 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:

Intrathecal anesthesia (subarachnoidal, spinal) at surgical and obstetric interventions: surgeries on lower parts of an abdominal cavity (including Cesarean section), on the lower extremities (including a hip joint) and at urological operations lasting 1,5-3 hours (see the section "Route of Administration and Doses").

Route of administration and doses:

Intratekalno
Adults
The provided recommendations are approximate for the average adult.
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. It is necessary to use the smallest required dose for adequate anesthesia. Duration of anesthesia depends on a dose while it is difficult to predict distribution of drug on segments, especially at use of isobaric (simple) solution.
The recommended doses for drug Markain Spinal Hevi

Anesthesia level               Dose            Beginning of action,     action Duration,
                                                mg ml      min.                            hours
Indications:                                                               1,5-3 7,5-15 5-8 2-3
urological
operations.
Indications:                                                    operations 2-4 10-20 5-8 1,5-3
on lower
extremities, in that
number a hip, in
lower parts
abdominal cavity
(including Caesarian
section)

The recommended area of introduction – below L3.
At elderly patients and patients on late durations of gestation it is recommended to use the reduced drug dose.
Children (weighing up to 40 kg)
Markain Spinal Hevi can be applied at children. The difference between children and adults consists that newborns and babies have a volume of cerebrospinal fluid rather big therefore they need higher dose per body weight kg, than the adult, for achievement of the same level of blockade as from adults.
The recommended doses Markaina Spinal Hevi at children

Body weight, kg            Dose, mg/kg
<                                 5 0,4-0,5
                              5-15 0,3-0,4
                            15-40 0,25-0,3

Features of use:

Intrathecal anesthesia has to be carried out only under control of the experienced specialist in appropriately equipped operating room.
Medicines and the medical equipment for resuscitation actions have to be prepared for use.
Prior to the beginning of intrathecal anesthesia venous access, for example, in the form of a venous catheter has to be provided.
The personnel which are carrying out anesthesia have to be appropriately prepared and trained in diagnosis and treatment of possible side effects, system toxic reactions or other possible complications (see the section "Overdose").
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. Especially it can be shown in case of inadvertent intravascular introduction. 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. However the doses which are usually used for intrathecal anesthesia do not result in high system concentration of drug.
Rare, but in too time serious side reaction which can develop at spinal anesthesia is the high or total spinal block leading to oppression of activity of cardiovascular and respiratory systems. Frustration from cardiovascular system are caused by extensive sympathetic blockade which can lead to hypotension, bradycardia and even a cardiac standstill. Blockade of an innervation of respiratory muscles, including diaphragms, causes breath disturbance.
At patients with a hypovolemia during intrathecal anesthesia the expressed arterial hypotension irrespective of the used local anesthetic can develop. Arterial hypotension which usually arises at adults after intrathecal blockade, is seldom noted at children aged to 8 years.
Damage of nerve terminations is a rare complication of intrathecal anesthesia and can lead to paresthesia, anesthesia, muscular weakness and a paraplegia. Occasionally these disturbances have constant character.
Markain Spinal Hevi does not contain preservatives, the ampoule is intended for disposable. The remains of solution have to be thrown out.
As Markain Spinal Hevi is a part of drug a dextrose, when autoclaving caramelization in this connection, repeated sterilization is not recommended is possible.

Side effects:

Side reactions on Markain Spinal Hevi 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: arterial hypotension, bradycardia
From the digestive tract (DT): nausea
Frequent (> 1/100, <1/10)
From a nervous system: post-puncture headache
From a GIT: vomiting
From urinogenital system: ischuria, urine incontience
Less frequent (> 1/1000, <1/100)
From a nervous system: paresthesia, paresis, dizesteziya
From a musculoskeletal system: muscular weakness, pain in lumbar area
Rare (<1/1000)
From cardiovascular system: cardiac standstill
From a nervous system: total spinal block, paraplegia, paralysis, neuropathy, arachnoiditis
From respiratory system: respiratory depression
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 a class III (for example, Amiodaronum) separately was not studied, however it is recommended to be careful at co-administration of these drugs (see also section "Special Instructions").
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.
At combined use with drugs, the oppressing TsNS, local anesthetics strengthen oppression of TsNS.
Inhibitors of a monoaminooxidase or tricyclic antidepressants together with bupivacaine increase risk of development of the expressed increase in arterial pressure.
The combination of a bupivakin to the general inhalation anesthesia a halothane increases risk of development of arrhythmia.
Incompatibility
It is not recommended to mix solutions for intrathecal anesthesia with other drugs.
Influence on ability to drive the car and to work with technical devices
In addition to direct anesthetic effect local anesthetics can have the insignificant oppressing effect on cognitive function and coordination and to cause temporary disturbances of motive function even in the absence of system toxicity.

Contraindications:

Hypersensitivity to any of components of drug or to other local anesthetics of amide type.
It is necessary to take into account the general contraindications to carrying out intrathecal anesthesia:
• acute diseases of the central nervous system (CNS), such, as, meningitis, poliomyelitis, intracraneal hemorrhage, and also TsNS new growths;
• narrowing of the spinal channel and a disease of a backbone in an aggravation phase (a spondylitis, a tumor) or a recent injury (change) of a backbone;
• septicaemia;
• pernicious anemia with the subacute combined degeneration of a spinal cord;
• pustulous damage of skin in the place of an estimated puncture or adjoining on the place of a puncture;
• cardiogenic or hypovolemic shock;
• disturbance of coagulability of blood or the accompanying anticoagulating
therapy.
With care: to the weakened elderly patients or patients with serious associated diseases, such as an atrioventricular block of II and III degrees, the heavy liver or renal failure, however regional anesthesia is more preferable to these groups of patients. The patients accepting antiarrhytmic class drug III (for example, Amiodaronum), need careful observation and monitoring of an ECG because of a possibility of development of the undesirable phenomena from cardiovascular system (see the section "Interaction with Other Drugs").
There is an increased risk of high or total spinal block at elderly patients and at patients on late durations of gestation. Therefore at such patients it is recommended to apply the reduced drug doses (see the section "Route of Administration and Doses").
It is necessary to be careful when carrying out intrathecal anesthesia at patients with neurologic diseases, such as multiple sclerosis, a hemiplegia, a paraplegia and neuromuscular frustration though it is not proved that intrathecal anesthesia leads to an aggravation of symptoms at these diseases. Before carrying out intrathecal anesthesia it is necessary to be convinced of such cases that the potential advantage for the patient exceeds possible risk.
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), because of a possibility of development of the additive toxic effect.
Pregnancy and lactation
Pregnancy
Bupivacaine was applied at a large number of pregnant women and women of childbearing age. Influence of drug on reproductive function or increase in frequency of malformations was not noted (see the section "Pharmacokinetics"). At patients on late durations of gestation it is recommended to use the reduced drug doses (see the section "Route of Administration and Doses").
Lactation
Bupivacaine gets into breast milk in the quantities which are not constituting danger to the child.

Overdose:

Acute system toxicity
Markaina Spinal Hevi according to recommendations does not result use in such concentration of drug in plasma at which there can be system toxic manifestations. However when using Markaina Spinal Hevi with other local anesthetics can develop acute system toxicity due to summing of toxic effects in combinations.
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.
Especially it can be shown in case of inadvertent intravascular introduction. 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. However the doses which are usually used for intrathecal anesthesia do not result in high system concentration of drug.
From the central nervous system
At bupivacaine use 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 more 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, disturbances of normal process of breath after the beginning of spasms quickly appear a hypoxia and a hypercapnia. 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
the toxic phenomena can quickly come if only anesthetic was not entered in very large number.
Treatment of acute system toxicity
At emergence of the first signs of acute system toxicity or the total spinal block it is necessary to stop immediately administration of drug and to carry out symptomatic therapy cardiovascular and neurologic (spasms, oppression of TsNS) disturbances.
In case of a cardiac standstill it is necessary to resort to cardiopulmonary resuscitation immediately. It is vital to support ventilation of the lungs, blood circulation and adequate oxygenation, and also to carry out correction of acidosis.
At oppression of activity of cardiovascular system (arterial hypotension, bradycardia) intravenous administration of 5-10 mg of ephedrine which if necessary can be repeated in 2-3 min. is necessary. Children should enter an ephedrine dose according to their age and weight.
At emergence of spasms it is necessary to carry out the therapy directed to maintenance of activity of cardiovascular system, ensuring adequate oxygenation and stopping of spasms. If necessary it is necessary to provide supply of oxygen and artificial ventilation of the lungs (by means of Ambu's bag or an intubation of a trachea). If within 15-20 seconds of a spasm do not stop independently, it is necessary to use anticonvulsant means: thiopental of sodium of 1-3 mg/kg in/in provides bystry stopping of spasms; it is possible to use 0,1 mg/kg of diazepam in/in (action develops more slowly in comparison with effect of thiopental). Long spasms can interfere with ventilation and oxygenation. In such cases for bystry stopping of spasms it is possible to resort to an intubation of a trachea and introduction of a muscle relaxant (for example, сукцинилхолин 1 mg/kg).

Storage conditions:

To store at a temperature of 2-25 °C. Not to freeze. To store in the places unavailable to children. Period of storage 3 years. Not to apply after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Solution for injections of 5 mg/ml. On 4 ml of drug in ampoules from transparent colourless glass. 5 ampoules placed in a blister strip packaging PVC/paper in a cardboard pack with the application instruction.
On an ampoule above a notch (the place of a break) paint put a color point.