Markain - instructions for use, doses, side effects, contraindications

Composition:Composition (1ml):
Active ingredient: bupivacaine hydrochloride monohydrate 5.28 mg, corresponding to 5.0 mg bupivacaine hydrochloride;
Excipients: sodium chloride 8.0 mg, sodium hydroxide 2 mol / l or hydrochloric acid 2 mol / l to pH 4, water for injection up to 1.0 ml.

Description:clear, colorless solution.

Pharmacotherapeutic group:local anesthetic

ATX: & nbsp

N.01.B.B.01 Bupivacaine

Pharmacodynamics:The local anesthetic is a long-acting amide type, 4 times stronger than lidocaine. Reversibly blocks the impulse through the nerve fiber due to the effect on the sodium channels. Has hypotensive effect, slows heart rate. Postoperative analgesia is maintained for 7-14 hours with intercostal blockade. With a single epidural injection, the duration of the effect using a concentration of 5 mg / ml is from 2 to 5 hours, and, up to 12 hours - with peripheral nerve block.
The use of solutions at a concentration of 2.5 mg / ml has less effect on the motor nerves.

Pharmacokinetics:

Bupivacaine has a pKa-8,2 index of separation of 346 (at 25 ° C in n-octanol / phosphate buffer pH 7.4).
Bupivacaine completely absorbed into the blood from the epidural space; the absorption is biphasic, the half-life for the two phases is 7 minutes and 6 hours, respectively. The slow elimination of bupivacaine is determined by the presence of a slow phase of absorption of the epidural space, which explains the longer half-life (T_1/2) after epidural administration compared with intravenous administration.
The total plasma clearance of bupivacaine is 0.58 L / min, the volume of distribution in the equilibrium state is 73 L, the final half-life is 2.7 hours, the intermediate hepatic extraction is about 0.38 after IV. Bupivacaine, mainly binds to α1-acid plasma glycoproteins (binding to plasma proteins - 96%). Bupivacaine clearance is almost entirely due to the metabolism of the drug in the liver and is more dependent on the activity of the liver's enzyme systems than on liver perfusion. Metabolites have less pharmacological activity than bupivacaine.
The plasma concentration of bupivacaine depends on the dosage of the drug, the method of administration of the drug, the vascularization in the area of administration.
In children aged 1 to 7 years, the pharmacokinetics of the drug are similar to those in adults.
Penetrates through the placenta. The connection with plasma proteins in the fetus is lower than in the mother's body, the concentration of unbound fraction in the fetus and mother is the same.
Bupivacaine is metabolized in the liver, mainly by aromatic hydroxylation to 4-hydroxy-bupivacaine and N-dealkylation to 2,6-pi pecoxyl id on (RRB).Both reactions occur with the participation of cytochrome CYP3A4 isoenzyme. About 1% of bupivacaine is excreted in the urine unchanged during the day after administration, and approximately 5% in the form of PPC. The concentration of PPC and 4-hydroxy-bupivacaine in plasma during and after prolonged bupivacaine administration is low relative to the administered dose of the drug.

Indications:Different types of local anesthesia (anesthesia with trauma, surgical interventions, including cesarean section, anesthesia of labor, painful diagnostic procedures, for example, in arthroscopy): local infiltration anesthesia, conductive anesthesia (including intercostal blockade, blockage of large and small nerves, blockade nerves in the head and neck), caudal or lumbar epidural block, retrobulbar (regional) anesthesia.

Contraindications:Hypersensitivity to any of the components of the drug or to local anesthetics of the amide type;
- diseases of the central nervous system (CNS) (as well as with epidural administration of other local anesthetics)
- severe arterial hypotension (cardiogenic or hypovolemic shock);
- Children's age (up to 2 years);
The drug is not used for intravenous regional anesthesia (Bira blockade) (accidental penetration of bupivacaine into the bloodstream can cause the development of acute systemic toxic reactions).

Carefully:Cardiovascular insufficiency (possibly progression), heart block, inflammatory diseases or infection of the injection site (with infiltration anesthesia), cholinesterase deficiency, renal insufficiency, elderly age (over 65), late pregnancy (III trimester), general severe condition, decrease in hepatic blood flow (for example, in chronic heart failure, liver diseases), simultaneous administration of antiarrhythmic drugs (including beta-adrene for locators), the need to conduct ratservikalnoy anesthesia, children's age (12 years); '
with epidural appointment (caudal and lumbar anesthesia) -previous neurological diseases, septicemia, difficulty in performing puncture due to spinal deformity.
Bupivacaine should be used with caution in patients,receiving other local anesthetics or preparations structurally similar to local anesthetics of the amide type, such as antiarrhythmics (eg, lidocaine, mexiletine).

Pregnancy and lactation:Use the drug only if the expected benefit for the mother exceeds the possible risk to the fetus.
Bupivacaine was used in a large number of pregnant women and women of childbearing age, however, until now, there have been no specific changes in the reproductive function in women of childbearing age and an increase in the frequency of developmental defects in the fetus.
The addition of epinephrine to bipuvacaine may reduce blood flow in the uterus and its contractility, especially when the anesthetic solution is accidentally injected into the mother's vessels. Side effects caused by the action of local anesthetic in the fetus, such as bradycardia, are most often detected with paracervical blockade (the anesthetic at the same time reaches the fetus in high concentrations).
As well as other local anesthetics, bupivacaine can penetrate into breast milk in small quantities that do not pose a danger to the child.

Dosing and Administration:Adults and children over 12 years of age
The following table is a guide for dosing the drug with the most frequently performed procedures. When calculating the required dose, it is important to base on clinical experience and assess the patient's physical status.
Dose recommendations The dosages indicated in the table are considered necessary for successful blockade, and should be considered as recommended for the average adult patient.
For caudal blockade, higher doses may be used (see table).
When performing prolonged blockages with the help of prolonged infusion or fractional administration of the drug, one should consider the possibility of increasing its concentration in the blood plasma to toxic or the probability of local injury of nerve fibers. The experience accumulated to date shows that administration to an adult patient within 24 hours of 400 mg of the drug is usually well tolerated.
When using a large volume of a solution containing epinephrine, the risk of developing systemic effects of epinephrine should be considered.

Type of blockade	The dose of ml mg	Start actions, mines	The term tion, clock	Indications (comments)
Infiltration	<30 <150	1-10	3-8	Surgical interventions and postoperative analgesia
Retrobulbarnaya	2-4 10-20	5	4-8	Ophthalmic surgery (see section "Special instructions")
Peribulbar	6-10 30-50	10	4-8	Ophthalmic surgery (see section "Special instructions")
Intercostal (per nerve)	2-3 10-15	3-5	4-8	Surgical interventions and postoperative analgesia, anesthesia in trauma
Intrapelural blockade	20 100	10-20	4-8	Postoperative analgesia
Shoulder blockade plexus: axillary supraclavicular, interlace and subclavian perivascular	30-40 150-175 20-30 100-150	15-30 15-30	4-8 4-8	Surgical interventions
Blockade sciatic nerve	10-35 50-175	15-30	4-8	Surgical interventions
Blockade the femoral nerve, the nerve block and the lateral cutaneous nerve of the thigh (3 in 1)	10-35 50-175	15-30	4-8	Surgical operations
Epidural lumbar level)	15-30 75-150	15-30	2-3	Surgical interventions, including cesarean section, delivery anesthesia and postoperative analgesia (dose allows for a trial test)
Epidural (at the thoracic level)	5-10 25-50	10-15	2-3	Surgical interventions (dose allows for a trial test)
Caudal anesthesia	20-30 100-150	15-30	2-3	Intraoperative and postoperative analgesia.Therapy of pain syndromes and anesthesia in diagnostic procedures (the dose takes into account the test test)

The drug should be administered with caution to avoid the development of acute toxic reactions with accidental intravascular administration of the drug. It is recommended that the aspiration sample be thoroughly performed before and during the administration of the preparation. If a large dose is required, for example, with epidural blockade, a pre-introduction of the test dose is recommended: 3-5 ml of bupivacaine with epinephrine. In the case of accidental intravascular injection of the drug, transient tachycardia, easily detected by a physician, may occur. The main dose is administered slowly at a rate of 25-50 mg / min or fractional bolus, constantly maintaining verbal contact with the patient. When signs of intoxication appear, the drug should be discontinued immediately.
For children younger than 12 years, the calculation of the dose should be based on body weight (on average, up to 2 mg / kg), for lumbosacral - 1.5-2 mg / kg, for thoracolumbular -1.5-2.5 mg / kg body weight . The addition of epinephrine increases the duration of the blockade by 50-100%.

Side effects:Side effects on Marcain® are similar to adverse reactions that occur with the intrathecal administration of other local long-acting anesthetics. Adverse reactions caused by the drug itself are difficult to distinguish from the physiological manifestations of nerve blockade (eg, arterial hypotension, bradycardia, temporary urinary retention), reactions caused directly (eg, spinal hematoma) or indirectly (eg, meningitis, epidural abscess) by insertion of a needle, or reactions associated with leakage of spinal fluid (eg, post-puncture headache).

Very frequent (> 1/10)	From the cardiovascular system: hypotension From the gastrointestinal tract (GIT): nausea
Frequent (> 1/100, <1/10)	From the nervous system: paresthesia, dizziness From the cardiovascular system: bradycardia, increased blood pressure (BP) From the digestive tract: vomiting On the part of the genitourinary system: urinary retention, incontinence
Less frequent (> 1/1000, <1/100)	From the side of the nervous system: signs and symptoms of toxicity from the side of the CNS (cramps, paresthesia around the mouth, numbness of the tongue, hyperacusis, lightheadedness, visual disturbances, loss of consciousness, tremor, noise and ringing in the ears, dysarthria)
Rare (<1/1000)	From the cardiovascular system: cardiac arrest, arrhythmia From the nervous system: unintended total spinal block, peripheral nerve damage, paraplegia, paralysis, neuropathy, arachnoiditis From the respiratory system: respiratory depression On the part of the organs of vision: diplopia General: allergic reactions, in the most severe cases - anaphylactic shock.

Overdose:Acute systemic intoxication
Toxic reactions are manifested mainly from the central nervous and cardiovascular systems. These reactions are caused by a high concentration of local anesthetic in the blood, which can result from accidental intravascular injection, overdose or exceptionally high absorption from the high vascularization area (see section "Special instructions").
Reactions from the central nervous system are similar for all local anesthetics of the amide type, while manifestations from the cardiovascular system are different for different drugs.
A random intravascular injection of a local anesthetic can cause an immediate toxic reaction (within a few seconds-minutes).While overdose signs of systemic toxicity develop later, 15-60 minutes after the injection, due to a slow increase in the concentration of the drug in the blood plasma.
From the central nervous system
Intoxication manifests itself gradually in the form of signs and symptoms of impaired function of the central nervous system with an increasing degree of severity. The initial manifestations of intoxication are:
paresthesia around the mouth, dizziness, numbness of the tongue, pathologically increased perception of ordinary sounds and tinnitus. Disturbance of vision and tremor are the most serious signs and precede the development of generalized seizures. These phenomena should not be mistakenly regarded as neurotic behavior. Following them, loss of consciousness and the development of large seizures can occur, which can last from a few seconds to several minutes. Due to increased muscular activity and disruption of the normal breathing process, hypoxia and hypercapnia quickly appear after the onset of seizures. In severe cases, apnea may develop. Acidosis increases the toxic effect of local anesthetics.These phenomena are due to the redistribution of local anesthetic from the central nervous system and the metabolism of the drug. Coping toxic effects can occur quickly, unless anesthetic has been introduced in a very large amount.
From the side of the cardiovascular system
Cardiovascular toxicity leads to the most severe consequences and usually precedes the appearance of toxic reactions from the central nervous system, which can be masked by general anesthesia or deep sedation with drugs such as benzodiazepines or barbiturates.
Against the background of a high concentration of local anesthetics in the plasma, development of arterial hypotension, bradycardia, arrhythmia and, in some cases, cardiac arrest was noted.
Toxic reactions from the cardiovascular system are often associated with impaired myocardial conductivity, which in turn can lead to a decrease in the minute volume of the heart, lower blood pressure, AV blockade, bradycardia and in some cases to ventricular arrhythmias, including tachycardia and ventricular fibrillation, and stopping heart.These toxic effects often precede the manifestation of symptoms of acute toxicity from the central nervous system, for example, in the form of convulsions, but in rare cases, cardiac arrest can occur without the appearance of previous signs from the central nervous system.
With a random rapid intravenous bolus injection in the coronary vessels, a high plasma concentration of bupivacaine can be observed, which affects blood circulation and leads to the development of independent cardiotoxic effects or preceded the development of toxic effects from the central nervous system. In this connection, myocardial depression can manifest itself as the first symptoms of intoxication. Special attention should be paid to the early signs of development of intoxication in children, since in this group of patients the most pronounced blockade is most often after the onset of anesthesia. Treatment of acute intoxication When symptoms of general intoxication appear, the drug should be discontinued immediately. Therapy should be aimed at maintaining ventilation, cramping seizures and maintaining blood circulation. It should be used oxygen and if necessary, establish artificial ventilation (using a mask and a bag).
If convulsions do not stop on their own within 15-20 seconds, then anticonvulsants should be injected intravenously. Intravenous injection of 100-150 mg of thiopental sodium quickly cures convulsions, instead of it can be administered intravenously 5-10 mg of diazepam, although it acts more slowly. Suxamethonium quickly suppresses muscle cramps, however, it requires intubation of the trachea and artificial ventilation of the lungs, so this drug should be used only by those who own these methods.
With obvious inhibition of the cardiovascular system (blood pressure reduction - AD, and bradycardia) intravenously administered 5-10 mg ephedrine, if necessary, after 2-3 minutes, the administration is repeated. At a cardiac arrest immediately proceed to cardiopulmonary resuscitation. It is vital to optimize oxygenation and ventilation and support circulation along with correction of acidosis, since hypoxia and acidosis will intensify the systemic toxic effects of the local anesthetic. It should be introduced as soon as possible epinephrine (adrenaline) (0.1-0.2 mg intravenously or intracardiac), if necessary, repeat the introduction. Also, consideration should be given to the need for appropriate therapy with intravenous solutions and the use of fat emulsions.
When cardiac arrest may require prolonged resuscitation. When choosing a dosing regimen in children, one should take into account the age and body weight.

Interaction:Bupivacaine should be used with caution in patients receiving other local anesthetics or drugs that are similar in structure to local anesthetic agents of the amide type, such as antiarrhythmics (eg, lidocaine, mexiletine), because of the possibility of developing an additive toxic effect. Joint use of bupivacaine with antiarrhythmic drugs Ill class (for example, amiodarone) has not been studied separately, but caution should be exercised while prescribing these drugs (see section "Special instructions").
Monoamine oxidase inhibitors or tricyclic antidepressants increase the risk of a marked increase in blood pressure.
Preparations containing oxytocin or ergotamine, promote the development of a steady increase in blood pressure with possible complications from the cardiovascular and cerebrovascular system.
The combination with total inhalation anesthesia halothane increases the risk of arrhythmia.
When treating the site of injection of a local anesthetic with disinfectant solutions containing heavy metals, the risk of developing a local reaction in the form of tenderness and swelling increases.
Preparations structurally similar to local anesthetics, for example, toxainide, increase the risk of developing an additive toxic effect.
When combined with drugs that depress the central nervous system, local anesthetics increase CNS depression.
The solubility of bupivacaine decreases at pH> 6.5, this should be taken into account if alkaline solutions are added, since a precipitate may form.

Special instructions:Regional anesthesia should be performed by experienced specialists in an appropriately equipped room. The equipment and preparations necessary for cardiac monitoring and resuscitation should be available for immediate use.When performing large blockades before the introduction of a local anesthetic, it is recommended to install an intravenous catheter. The staff should undergo appropriate training in the technique of anesthesia and should be familiar with the diagnosis and treatment of the side effects of the drug, systemic toxic reactions and other complications (see "Overdose"),
There are reports of cardiac arrest or death during the use of bupivacaine for epidural anesthesia or peripheral blockade. In some cases, resuscitation was difficult or impossible, despite the undoubtedly good preparation and anesthesia.
The peripheral nerve blockade is associated with the introduction of a larger volume of local anesthetic into the area of high vascularization, often close to large vessels, where the risk of unintentional intravascular injection of local anesthetic or systemic absorption of a large dose of the drug increases, which in turn can lead to an increase in plasma concentration.
Like other local anesthetics, bupivacaine can cause acute toxic reactions from the central nervous and cardiovascular systems,if its use for local anesthesia leads to a high concentration of the drug in the blood. Most often this is manifested in the case of unintentional intravascular injection or with high vascularization of the site of administration. Against the background of a high concentration of bupivacaine in the plasma, cases of ventricular arrhythmia, ventricular fibrillation, sudden cardiovascular collapse and death were documented.
Certain types of blockades, regardless of the local anesthetic used, can be associated with serious adverse reactions, for example:
- Central blockades, especially against hypovolemia, can lead to depression of the cardiovascular system.
- Large peripheral blockages may require the use of a large amount of local anesthetic in areas of high vascularization, often near large vessels, where the risk of intravascular administration and / or systemic absorption increases, which can lead to a high concentration of the drug in the plasma.
- With retrobulbar injection, the drug can accidentally enter the cranial subarachnoid space, causing temporary blindness, apnea, convulsions, collapse and other side effects.
- With retrobulbar and peribulbar injection of local anesthetics, there is a small risk of permanent damage to the function of the eye muscles. The main causes are trauma and / or local toxic effects on muscles and / or nerves. The severity of these tissue reactions depends on the degree of injury, the concentration of the local anesthetic and the duration of exposure of the tissue with a local anesthetic. Therefore, as with other local anesthetics, the lowest effective concentration and dose of the drug should be used. Vasoconstrictors can enhance tissue reactions and should be used only on indications.
- When injected into the neck or head, the drug may accidentally enter the artery, and in these cases, even with low doses, serious adverse reactions may develop.
- Paracervical blockade sometimes leads to the appearance of
bradycardia / tachycardia in the fetus, so careful monitoring of the heart rhythm of the fetus is mandatory.
- There have been reports of cases of chondrolisis in postoperative prolonged intra-articular infusion of local anesthetics. In most of the cases described, infusion into the shoulder joint was performed.Causal relationship with the use of anesthetics is not established. Marcain® should not be used for prolonged intra-articular infusion.
When conducting regional anesthesia, you should be especially attentive to the following groups of patients:
- Patients receiving antiarrhythmic drugs of III class (for example, amiodarone), should be carefully monitored, because of the possible risk of complications from the cardiovascular system.
- Older patients and weakened patients.
- Patients with partial or complete cardiac blockade, since local anesthetics can impair myocardial conductivity.
- Patients with progressive liver disease or with severe renal dysfunction.
- Patients in late pregnancy.
When conducting epidural anesthesia, there may be a drop in blood pressure and a bradycardia. The probability of these complications can be reduced by the preliminary administration of crystalloid and colloidal solutions. With a decrease in blood pressure, immediately introduce sympathomimetics intravenously; If necessary, their introduction should be repeated.In children, the doses used must correspond to the age and body weight. The drug contains sodium, so in the case of a salt-free diet with a limited intake, the sodium content should be taken into account.
The solution does not contain preservatives and should be administered immediately after opening the vial. Remains of the solution must be disposed of.

Effect on the ability to drive transp. cf. and fur:Depending on the dose, local anesthetics can have minimal effect on mental processes and temporarily disrupt locomotor function and coordination.

Form release / dosage:Solution for injection 5 mg / ml in glass bottles of 20 ml.

Packaging:For 20 ml in a bottle of borosilicate colorless glass with a rubber stopper, an aluminum crimping ring and a plastic lid. For 5 bottles in a cardboard box with instructions for use.

Storage conditions:At temperatures not above 25 ° C, in places inaccessible to children, do not freeze.

Shelf life:3 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N014085 / 01

Date of registration:13.04.2009

The owner of the registration certificate:AstraZeneca UK LtdAstraZeneca UK Ltd United Kingdom

Manufacturer: & nbsp

RECIPHARM MONTS France

Information update date: & nbsp2015-12-02

Illustrated instructions

Instructions

Markain (Marcaine® )