Universal reference book for medicines
Product name: MARKINE ADRENALINE (MARCAINE ADRENALINE)

Active substance: bupivacaine, epinephrine

Type: Local anesthetic with vasoconstrictor component

Manufacturer: ASTRAZENECA UK (UK) manufactured by ASTRAZENECA MONTS (France)
Composition, form of production and packaging
Solution for injection
1 ml 1 fl.

bupivacaine hydrochloride 5 mg 100 mg

epinephrine (in the form of a hydrotartrate) 5 μg 100 μg

20 ml - bottles (5) - packs cardboard.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2010.

PHARMACHOLOGIC EFFECT

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, 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 blockade.

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

Adding a vasoconstrictor of epinephrine leads to a decrease in the rate of absorption of anesthetic and, as a consequence, to an increase and prolongation of the action of the drug.

PHARMACOKINETICS

Bupivacaine has a pKa-8.2
separation coefficient 346 (at 25 ° C in n-octanol / phosphate buffer pH 7.4).
Bupivacaine is completely absorbed into the blood from the subarachnoid 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 T 1/2after epidural administration compared with intravenous administration.
The total plasma clearance of bupivacaine is 0.58 liters per minute, the volume of distribution in the equilibrium state is 73 liters, the final T 1/2 is 2.7 hours, the intermediate hepatic extraction is about 0.38 after intravenous administration.
Bupivacaine is mainly associated with? 1-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.
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 pipecoloxylidin (PPC). Both reactions occur with the participation of cytochrome P4503A4 enzymes. 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 the 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 in trauma, surgical interventions, including cesarean section, analgesia of labor, painful diagnostic procedures, for example, in arthroscopy);

- local infiltration anesthesia, conductive anesthesia (including intercostal blockade, blockage of large and small nerves, blockage of nerves in the head and neck area), caudal or lumbar epidural blockade, retrobulbar (regional) anesthesia.

DOSING MODE

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

The doses indicated in the table are considered necessary for successful blockade, and should be considered as recommended doses for the average adult patient.
As a rule, the 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 using a large volume of a solution containing epinephrine, one should take into account the possibility of developing systemic effects of epinephrine.

Type of blockade Dose Commencement of action min Duration h Indications Comments

ml mg

Infiltration? 30-150 1-3 4-8 Surgical interventions and postoperative analgesia

Retrobulbarnaya 2-4 10-20 5 4-8 Ophthalmic Surgery

Peribulbar 6-10 30-50 10 4-8 - // -

Intercostal (per nerve) 2-3 10-15 3-5 4-8 Surgical interventions and postoperative analgesia, anesthesia with trauma

Interpleural blockade 20 100 10-20 4-8 Postoperative analgesia

Blockade of the brachial plexus: Axillary supraclavicular, intercostal and subclavian perivascular 30-40 20-30 150-200 100-150 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, obstructive nerve and lateral cutaneous nerve of the thigh (3 in 1) 20-30 100-150 15-30 4-8 Surgical operations

Lumbar epidural 15-30 75-150 15-30 2-3 Surgical interventions, including cesarean section The dose allows for a trial test

Thoracic epidural 5-10 25-50 10-15 2-3 Surgical interventions Dose takes into account the test test

Caudal epidural anesthesia in adults 20-30 100-150 15-30 2-3 Intraoperative and postoperative analgesia The dose allows for a trial test

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

The maximum recommended dose: 30 ml (150 mg bupivacaine hydrochloride).
The maximum recommended dose is determined from the calculation of 2 mg / kg of body weight and is 150 mg of bupivacaine hydrochloride for adults over a 4-hour period. The maximum allowed daily dose is 400 mg (80 ml Marcaine epinephrine).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 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 thoracolumbic -1.5-2.5 mg / kg body weight.
Adding epinephrine increases the duration of the blockade by 50-100%.
Recommendations for use.
The solution does not contain preservatives and should be used immediately after opening the container. The solution is intended for single use only. 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 (eg needles or metal parts of the syringe), because of the possibility of developing allergic reactions in the area of ​​administration, and possibly accelerating the decay of epinephrine.

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.
SIDE EFFECT

Adverse reactions to Markain are similar to the side reactions that occur when intrathecal injection 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 side of the cardiovascular system: arterial hypotension From the digestive tract: nausea

Frequent (> 1/100, <1/10) From the side of the nervous system: paresthesia, dizziness From the cardiovascular system: bradycardia, arterial hypertension From the digestive tract: vomiting From 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 central nervous system and cardiovascular system (convulsions, paresthesia, numbness of the tongue, visual disturbances, tremor, chills, loss of consciousness, noise and ringing in the ears, dysarthria, headache)

Rare (<1/1000) From the side of the cardiovascular system: cardiac arrest, arrhythmias From the nervous system: unintentional total spinal block, paraplegia, paralysis, neuropathy, arachnoiditis Respiratory system: respiratory depression Viewpoint: diplopia General: allergic reactions, in the most severe cases - anaphylactic shock.

CONTRAINDICATIONS

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

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

- hypersensitivity to any of the components of the drug (eg methyl parahydroxybenzoate) or to local anesthetics of the amide type;

- hypersensitivity to sodium metabisulphite, which is part of solutions containing epinephrine.

The drug is not used in epidural anesthesia in patients with severe arterial hypotension, such as cardiogenic or hypovolemic shock.

The drug is not used for intravenous regional anesthesia (Viru blockade) (accidental penetration of bupivacaine into the bloodstream can cause the development of acute systemic toxic reactions);

With caution: cardiovascular insufficiency (possibly progression), AV blockade II and III degree, inflammatory diseases, cholinesterase deficiency, renal failure, elderly age (over 65 years), late pregnancy (III trimester), general severe condition, decrease (eg, chronic heart failure, liver disease), simultaneous administration of antiarrhythmic drugs (including beta-blockers), the need for paracervical anesthesia, children's age
(up to 12 years);
at epidural appointment (caudal and lumbar anesthesia) - previous neurological diseases, deformity or other changes of the spine.
Bupivacaine should be used with caution in patients receiving other local anesthetics or preparations structurally similar to local anesthetic agents of the amide type, such as antiarrhythmics (eg, 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, diabetic complications, 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

With caution: late pregnancy (III trimester).

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 no specific changes in the reproductive function, for example, increased the frequency of developmental defects.

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, are most often detected with paracervical blockade (the anesthetic at the same time reaches the fetus in high concentrations).
As with 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.

APPLICATION FOR FUNCTIONS OF THE LIVER

With caution: kidney failure.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

With caution: decreased hepatic blood flow (eg, in chronic heart failure, liver disease).

APPLICATION FOR CHILDREN

Contraindicated in children up to 2 years.
With caution: 2 to 12 years.
APPLICATION IN ELDERLY PATIENTS

With caution: the elderly (over 65 years).

SPECIAL INSTRUCTIONS

There are reports of cardiac arrest or death while using bupivacaine for epidural anesthesia or peripheral blockade.
In some cases, resuscitation was difficult or impossible, despite the undoubtedly good preparation and anesthesia.
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.
Regional and local anesthesia, with the exception of small procedures, should be carried out by experienced specialists in an appropriately equipped room, with availability of ready-to-use equipment and preparations necessary for cardiac monitoring and resuscitation.

When performing large blockades before the introduction of a local anesthetic, it is recommended to install an intravenous catheter.
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").
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.

When conducting regional anesthesia, you should be especially attentive to the following groups of patients:

- Patients receiving Class III antiarrhythmics (eg, amiodarone) should be closely 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.

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 inhibition 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.
Developed complications should be timely diagnosed and stopped.
- 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 additives may enhance tissue reactions and should be used only when indicated.
- For injection in the neck or scalp preparation can accidentally fall into the artery and in these cases, even when using low doses may develop serious adverse reactions.
Paracervical blockade sometimes gives rise to bradycardia / tachycardia in the fetus, therefore careful monitoring fetal heart rate is required.
Marcaine epinephrine solution comprises sodium metabisulfite. Sulfite can cause allergic-type reactions (including anaphylactic symptoms and asthmatic episodes up to life-threatening) in susceptible individuals. The incidence of hypersensitivity to sulfite in the general population is unknown and, apparently, is low. Increased sensitivity to sulfite is more common in asthmatics compared with those not suffering from asthmatic symptoms.
The solution contains no preservatives and should be used immediately after the container opening. Remains of the solution should be discarded.
OVERDOSE

Acute systemic toxicity
Accidental intravascular administration of a toxic reaction occurs within 1-3 minutes, while an overdose, the maximum plasma concentration of the drug can be achieved in 20-30 minutes, depending on the injection site, and the signs of intoxication occur slowly . Toxic reactions occur mainly on the central nervous and cardiovascular system.
Against the background of high plasma concentrations of bupivacaine in cases of ventricular arrhythmia were reported, ventricular fibrillation, sudden cardiovascular collapse and death.
From the side of the central nervous system

Intoxication gradually manifested as signs and symptoms of the disorder of the central nervous system with increasing severity. Initial manifestations of toxicity are: paresthesia around the mouth, dizziness, numbness language pathologically increased perception of ordinary sounds and tinnitus. Impaired function of vision and tremors are more serious symptoms and precede the onset of generalized convulsions. These events should not be mistakenly viewed as neurotic behavior. Following them, possible loss of consciousness and the development of large seizures that can last from several seconds to several minutes. Due to increased muscle activity and disruption of the normal respiratory process after onset seizures appear quickly hypoxia and hypercapnia. In severe cases apnea may occur.Acidosis increases the toxic effects of local anesthetics.
These phenomena are due to redistribution of the local anesthetic agent from the central nervous system and metabolism of the drug. Relief of toxic effects can occur quickly if the anesthetic was not introduced in a very large number.
Cardio-vascular system.
Toxic reactions manifested by cardiovascular system, lead to more serious consequences and usually precede the manifestation of toxic reactions in the central nervous system that can be masked with general anesthesia or deep sedation using drugs such as benzodiazepines or barbiturates.
Against the background of high local concentrations of: anesthetics plasma noted the development of arterial hypotension, bradycardia, arrhythmias, and in some cases, cardiac arrest.
Toxic reactions on the part of the cardiovascular system are often associated with the suppression of cardiac conduction and infarction, which in turn can lead to a decrease in cardiac output, hypotension, the AV block, bradycardia, and in some cases, to ventricular arrhythmias, including ventricular tachycardia and atrial fibrillation and cardiac arrest. These toxic manifestations often precede the manifestation of symptoms of acute toxicity of the central nervous system, for example in the form of convulsion, however, in rare cases, cardiac arrest may occur without showing signs preceding the central nervous system. In the case of rapid intravenous bolus injection, plasma high 'concentration of bupivacaine can be observed in the coronary vessels,influence on the vascular circulation and leads to the development of self-ically kardiotoksi effects or toxic effects of the earlier development of the central nervous system. In this connection, myocardial depression can appear as the first symptoms of intoxication. It should pay particular attention to the early signs of intoxication in children, since this group of patients most often after the onset of anesthesia is achieved more pronounced blockade.because this group of patients most often after the onset of anesthesia is achieved more pronounced blockade.because this group of patients most often after the onset of anesthesia is achieved more pronounced blockade.
Treatment of acute toxicity
If signs of intoxication should immediately discontinue administration of the drug. Therapy should be aimed at maintaining ventilation, treatment of seizures and maintain circulation. Use oxygen and establish artificial ventilation when required (using the mask and bag). If convulsions do not stop spontaneously within 15-20 seconds, enter anticonvulsant drugs intravenously. Intravenous administration of 100-150 mg of thiopental rapidly relieves cramps, instead you can enter 5-10 mg diazepam intravenously, although it acts more slowly. Suxamethonium quickly relieves muscle cramps, however, at its use is required intubation and mechanical ventilation, so the drug should be used only for those who own methods of data.
By explicitly inhibition function of the cardiovascular system (reduced blood pressure and bradycardia) intravenously 5-10 mg ephedrine, if necessary after 2-3 minutes is repeated administration. During cardiac arrest, immediately start to cardiopulmonary resuscitation. It is vital to optimize oxygenation and ventilation and circulation support, together with the correction of acidosis, since hypoxia and acidosis will enhance systemic toxic effects of local anesthetic. As quickly as possible enter epinephrine (0.1-0.2 mg intravenously or intracardiac) administration should be repeated if necessary.
In cardiac arrest may require prolonged resuscitation.
DRUG INTERACTION

Bupivacaine should be used with caution in patients receiving other medications or local anesthetics which are similar in structure to local anesthetics of amide type, such as antiarrhythmic drugs (e.g., lidocaine, mexiletine), because of the potential toxic effect of the additive. The combined use of bupivacaine with antiarrhythmic drugs of class III (e.g., amiodarone) alone has not been studied, but caution is recommended with concomitant administration of these drugs (see. "Special instructions" section).
Monoamine oxidase inhibitors or tricyclic antidepressants increase the risk of pronounced increase in blood pressure.
Preparations containing oxytocin or ergotamine, promote the development of a sustainable increase in blood pressure with possible complications of the cardiovascular and cerebrovascular system.
The combination of a general inhalation anesthesia with halothane increases the risk of arrhythmia.
When applied to the site of injection of local anesthetic disinfectant solutions containing heavy metals, increases the risk of local reaction as pain and swelling.
Drugs structurally similar to local anesthetics, such as tocainide, increase the risk of additive toxic effects.
In a joint application with drugs depressing the central nervous system, local anesthetics increase CNS depression.
A non-cardioselective beta-blockers, such as propranolol enhance the pressor effect of epinephrine, which can lead to severe hypertension and bradycardia.
Antipsychotics such as phenothiazine and butyrophenone derivatives may decrease the pressor effect of epinephrine.
When bupivacaine narcotic analgesics during epidural develops additive effect, but enhanced respiratory depression.
Anticoagulants (ardeparin, dalteparin, danaparoid, enoxaparin, heparin, warfarin) increase the risk of bleeding.
TERMS OF RELEASE FROM PHARMACY

On prescription.

TERMS AND CONDITIONS OF STORAGE

List B. The temperature is not above 15 ° C, protected from light, do not freeze. Keep out of the reach of children.
Shelf life - 2 years.
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