Markain Adrenaline - instructions for use, dose, side effects, contraindications

Active substanceBupivacaine + EpinephrineBupivacaine + Epinephrine

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solution for injections

Dosage form: & nbspinjection

Composition:

1 ml of the solution contains:

Active substances: bupivacaine hydrochloride monohydrate 5.28 mg, corresponding to 5 mg bupivacaine hydrochloride, epinephrine hydrotartrate (adrenaline hydrotartrate) 9.1 μg, corresponding to 5 μg epinephrine (epinephrine);

Excipients: sodium chloride 8.0 mg, sodium disulfite (sodium metabisulphite) 0.5 mg, sodium hydroxide or hydrochloric acid (up to pH 3.3-5.0), water for injection up to 1 ml.

Description:Transparent colorless liquid.

Pharmacotherapeutic group:Local anesthetic + alpha and beta-adrenomimetic

ATX: & nbsp

S.01.H.A Local Anesthetics

Pharmacodynamics:

Markainin® Adrenaline is a combination drug consisting of a local anesthetic-bupivacaine and alpha-and beta-adrenomimetic-epinephrine.

Bupivacaine is a long-acting anesthetic, an 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.

With a single epidural injection of 5 mg / ml of the drug, the effect lasts from 2 to 5 hours and up to 12 hours with peripheral blockade.

The use of solutions at a concentration of 2.5 mg / ml has less effect on the motor nerves.

The addition of an epinephrine vasoconstrictor leads to a decrease in the rate of absorption of the anesthetic and, as a consequence, to the enhancement and prolongation of the action of bupivacaine.

Pharmacokinetics:

The pKa of bupivacaine is 8.2, the partition coefficient is 346 (at 25 ° C in n-octanol / phosphate buffer pH 7.4).

Bupivacaine is completely absorbed into the blood from the epidural space; absorption is biphasic, the half-life for the two phases is, respectively, 7 minutes and 6 hours. The slow elimination of bupivacaine is determined by the presence of a slow absorption phase from the epidural space, which explains the longer half-life (T_1/2 ) after epidural administration compared with intravenous administration.

The addition of epinephrine to a solution of bupivacaine may reduce the maximum plasma concentration, although the time until the maximum plasma concentration is usually changed little.

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 the α 1-acid plasma glycoprotein (binding to plasma proteins - 96%). Bupivacaine clearance is almost entirely due to the metabolism of bupivacaine 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.

In children aged 1 to 7 years, the pharmacokinetics of bupivacaine are similar to those in adults.

Penetrates through the placenta. The relationship of bupivacaine 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-hydroxybupivacaine and N-dealkylation to pipecoloxylidine (PPC). Both reactions occur with the participation of the CYP3A4 isoenzyme. About 1% of bupivacaine is excreted by the kidneys unchanged during the day after administration, and approximately 5% in the form of PPK.The concentration of AUC and 4-hydroxybupivacaine in plasma during and after prolonged administration of bupivacaine is low relative to the administered dose of the drug.

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

Contraindications:

- Hypersensitivity to any of the components of the drug or to local anesthetics of the amide type;

- Hypersensitivity to sodium disulfite (sodium metabisulphite), which is a part of solutions containing epinephrine;

- Children's age (up to 2 years);

- Diseases of the central nervous system, septicemia, pustular lesions of the skin at the injection site (as in the epidural administration of other local anesthetics).

Marcainin® Epinephrine is not used in epidural anesthesia in patients with severe arterial hypotension, such as cardiogenic or hypovolemic shock.

Markainin® Adrenaline is not used for intravenous regional anesthesia (Biru blockade) (accidental penetration of bupivacaine into the bloodstream can cause the development of acute systemic toxic reactions).

Carefully:

Cardiovascular failure (possibly progression), atrioventricular (AV) blockade of II and III degree, inflammatory diseases, cholinesterase deficiency, renal failure, elderly age (over 65), late pregnancy (III trimester), general severe condition, decreased hepatic blood flow (eg, chronic heart failure, liver disease), simultaneous use of antiarrhythmic drugs (including beta-blockers), the need for paracervical anesthesia, children's (up to 12 years).

With epidural administration (caudal and lumbar anesthesia) - previous neurological diseases, deformity or other changes in the spine. 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 antiarrhythmic drugs (for example, lidocaine, mexiletine).

Solutions containing epinephrine, should be used with caution in patients with severe or untreated hypertension, poorly controlled thyrotoxicosis, coronary heart disease, AV blockade, cerebrovascular disorders, complicated diabetes mellitus, or other conditions that may worsen under the influence of epinephrine. Caution should be exercised in cases of peripheral administration of the drug in areas with reduced blood circulation (such as fingers and toes).

Pregnancy and lactation:

Marcainin® Adrenaline should be used only if the expected benefit to 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 bupivacaine can 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,most often found 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 amounts that do not pose a risk to the newborn.

There is no evidence of epinephrine in breast milk, the probability of exposure to a newborn is extremely low.

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.

Dosing recommendations

Bupivacaine doses indicated in the table are considered necessary for successful blockade, and should be considered as recommended doses for the average adult patient. Typically, a dose of local anesthetic containing epinephrine, is equal to the dose of anesthetic without epinephrine.

There are large individual differences in the beginning and duration of the action, so it is impossible to establish the exact dose.When using other methods of regional anesthesia, reference should be made to the data of the reference books.

When a large volume of 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 the actions, h	Indications (comments)
Infiltration anesthesia	≤30 ≤150	1-10	3-8	Surgical interventions and postoperative analgesia
Retrobulbar blockade	2-4 10-20	≈5	4-8	Ophthalmic Surgery
Peribulbar blockade	6-10 30-50	≈10	4-8	Ophthalmic Surgery
Intercostal blockade (per nerve)	2-3 10-15	3-5	4-8	Surgical interventions and postoperative analgesia, anesthesia in trauma
Intrapleural blockade	20 100	10-20	4-8	Postoperative analgesia
Shoulder blockade plexus: axillary supraclavicular, interlace and subclavian perivascular	10-35 50-175 20-30 100-150	15-30 15-30	4-8 4-8	Surgical interventions
Blockade of the sciatic nerve	10-20 50-100	15-30	4-8	Surgical interventions
Blockade of the femoral nerve, the nerve block and the atheal cutaneous nerve of the thigh (3 in 1)	20-30 100-150	15-30	4-8	Surgical interventions
Lumbar epidural anesthesia	15-30 75-150	15-30	2-3	Surgical interventions, including cesarean section (dose allows for a trial test)
Thoracic epidural anesthesia	5-10 25-50	10-15	2-3	Surgical interventions (dose allows for a trial test)
Caudal epidural anesthesia in adults	20-30 100-150	15-30	2-3	Intraoperative and postoperative analgesia (dose allows for a trial test)

Note: When large volumes of solutions containing epinephrine, there is a risk of developing systemic effects of epinephrine.

≈ - approximately

≤ - not more than

The maximum recommended dose: <30 ml (150 mg bupivacaine). The maximum recommended dose is determined from the calculation of 2 mg / kg of body weight and is 150 mg of bupivacaine for adults for 4 hours. 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.

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. With epidural blockade, it is recommended that the test dose be pre-introduced: 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 under 12 years of age, the dose should be calculated taking into account the body weight (on average, up to 2 mg / kg), for lumbosacral - 1.5-2 μ / kg, for thoracolumbular - 1.5-2.5 mg / kg . Adding epinephrine increases the duration of the blockade by 50-100%. Recommendations for use. The solution does not contain preservatives and should be administered immediately after opening the vial. Remains of solution should be discarded.

Because of the instability of epinephrine, solutions containing it should not be sterilized. Avoid prolonged contact between local anesthetic solutions containing epinephrine (low pH) and metal surfaces (for example, needles or metal parts of the syringe), because of the possibility of developing irritation (swelling, edema) on dissolved metal ions (especially copper) in the area of administration, and possibly accelerating the decay of epinephrine.

The solubility of bupivacaine decreases at pH> 6.5, which should be taken into account when alkaline solutions are added, since a precipitate may form.

When mixing epinephrine-containing solutions with alkaline solutions, rapid destruction of epinephrine can occur.

Side effects:

Adverse reactions to Markain® Adrenaline similar to adverse reactions occurring after intrathecal administration of other local anesthetics for long periods. Side reactions caused by the medication, it is difficult to distinguish from the physiological manifestations nerve blocks (e.g., lowering blood pressure, bradycardia, temporary urinary retention) reactions caused directly (e.g., spinal hematoma) or indirectly (e.g., meningitis, epidural abscess) introducing needle , or reactions associated with leakage of spinal fluid (eg, post-puncture headache).

Very often (> 1/10)	From the cardiovascular system: arterial hypotension From the gastrointestinal tract (GIT): nausea
Often (> 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
Infrequently (> 1/1000, <1/100)	From the side of the nervous system: signs and symptoms of toxicity from the central nervous system and cardiovascular system (convulsions, paresthesia around the mouth, numbness of the tongue, hyperacusis, visual disturbances, tremor, lightheadedness, loss of consciousness, noise and ringing in the ears, dysarthria)
Rarely (<1/1000)	From the cardiovascular system: cardiac arrest, arrhythmia From the nervous system: unintentional total spinal block, damage peripheral nerves, paraplegia, paralysis, neuropathy, arachnoiditis From the respiratory system: respiratory depression From the side of the organ 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. In case of accidental intravascular injection, a toxic reaction occurs within 1-3 minutes, while in case of an overdose, the maximum plasma concentrations of the drug can be reached within 20-30 minutes, depending on the injection site, and the signs of intoxication develop slowly.

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. 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 breathing disorders, 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 a redistribution of the local anesthetic from the central nervous system and the metabolism of bupivacaine. 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 cardiac output, lower blood pressure, AV blockade, bradycardia, and in some cases to ventricular arrhythmias, including tachycardia and ventricular fibrillation, and cardiac arrest. 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.In the case of a rapid intravenous bolus injection, a high plasma concentration of bupivacaine can be observed in the coronary vessels that affects blood circulation and leads to the development of independent cardiotoxic effects or preceded by 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.

In case of an overdose, the possible systemic effects of epinephrine should also be considered.

Treatment of acute intoxication

When there are signs of general intoxication, it is necessary to stop the drug immediately. Therapy should be aimed at maintaining ventilation, cramping seizures and maintaining blood circulation. It should be applied 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. Suxametonium quickly suppresses muscle cramps, however, it requires tracheal intubation and artificial ventilation, so this drug should be used only by those who own these methods.

With obvious oppression of the cardiovascular system (lowering blood pressure and bradycardia) intravenously administered 5-10 mg of 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 class III antiarrhythmic drugs (eg, amiodarone) has not been studied separately, but caution should be exercised when using these drugs at the same time (see section "Special instructions").

It is necessary to avoid joint use of epinephrine-containing solutions or to use them with caution in patients taking tricyclic antidepressants because of the possible risk of a pronounced prolonged increase in blood pressure.

Preparations containing oxytocin or ergotamine, contribute to the development of a steady increase in blood pressure with possible complications from the cardiovascular system.

The combination with total inhalation anesthesia halothane and enflurane increases the risk of developing severe arrhythmia.

When treating the site of injection of a local anesthetic with disinfectant solutions containing heavy metals, the risk of developing a local reaction like soreness and edema 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.

Non-cardioselective beta-blockers, such as propranolol, strengthen the pressor effect of epinephrine, which can lead to severe arterial hypertension and bradycardia.

Neuroleptics, such as derivatives of phenothiazine and butyrophenone, can reduce the vasopressor effect of epinephrine.

When using bupivacaine with narcotic analgesics during epidural anesthesia, an additive effect develops, but respiratory depression is increased.

Special instructions:

Regional anesthesia should be performed by experienced specialists in an appropriately equipped room. The equipment and preparations necessary for cardiomonitoring and resuscitation should be ready for immediate use. When blockades are performed using large doses of the drug, an intravenous catheter is recommended before the introduction of a local anesthetic.

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 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 the background of 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 highvascularization, often near large vessels, where the risk of intravascular injection 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 and other supplements 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 bradycardia / tachycardia in the fetus, so careful monitoring of the heart rhythm in 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® Adrenaline 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 Class III antiarrhythmic drugs (for example, amiodarone), should be under close supervision, 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 worsen 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. Solutions containing epinephrine, should be used with caution in patients with severe or untreated hypertension, poorly controlled thyrotoxicosis, coronary heart disease, AV blockade, cerebrovascular disorders, complicated diabetes mellitus, or other conditions that may worsen under the influence of epinephrine. Caution should be exercised in cases of peripheral administration of the drug in areas with reduced blood circulation (such as fingers and toes).

The drug Marcain® Adrenaline contains sodium disulfite. Sulfite can cause allergic reactions (including symptoms of anaphylaxis and bronchospasm up to life-threatening) in susceptible people.

The prevalence of hypersensitivity to sulfites in the general population is unknown and, apparently, is low. Increased sensitivity to sulfites is more common in patients with bronchial asthma compared with those without bronchial asthma.

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 little effect on mental processes and temporarily disrupt locomotor function and coordination. Care should be taken when managing transport and engaging in other potentially hazardous activities requiring increased concentration and speed of psychomotor reactions, as the drug may cause dizziness and other side effects that may affect these abilities.

Form release / dosage:Solution for injection 5 mg / ml + 5 μg / ml.

Packaging:For 20 ml in bottles of borosilicate colorless glass with a rubber stopper, an aluminum crimping ring and a plastic lid.For 5 vials with instructions for use in a cardboard pack with the control of the first autopsy.

Storage conditions:Store in a dark place at a temperature of no higher than 15 ° C. Do not freeze. Keep out of the reach of children.

Shelf life:2 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N016240 / 01

Date of registration:04.03.2010 / 22.03.2017

Expiration Date:Unlimited

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

Manufacturer: & nbsp

RECIPHARM MONTS France

Representation: & nbspAstraZeneca Pharmaceuticals Ltd.AstraZeneca Pharmaceuticals Ltd.

Information update date: & nbsp26.03.2018

Illustrated instructions

Instructions

Markainin® Adrenaline (Marcaine® Adrenaline)