BUPIVACAINA 2.5 mg/ml Инъекционный раствор

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1. BUPIVACAINE ANGELINI 5 mg/ml, injectable hyperbaric solution

BUPIVACAINE ANGELINI 5 mg/ml, injectable hyperbaric solution

BUPIVACAINE HYDROCHLORIDE

PHARMACOTHERAPEUTIC CATEGORY
Local anesthetics of the amide type.

THERAPEUTIC INDICATIONS
Bupivacaine Angelini can be used in every type of peripheral anesthesia:

• local infiltration, truncular, loco-regional
• sympathetic block
• epidural, sacral
• spinal subarachnoid. Bupivacaine Angelini is therefore indicated in all surgical interventions of general surgery, orthopedics, ophthalmology, otorhinolaryngology, dentistry, obstetrics and gynecology, dermatology, either used alone or in association with narcosis.

BUPIVACAINE ANGELINI 5mg/ml hyperbaric injectable solution

• Spinal anesthesia in adults and children of all ages.

CONTRAINDICATIONS
Hypersensitivity to the active ingredient, to any of the excipients or to other substances
closely related from a chemical point of view; in particular to local anesthetics of the
same group (amide type).
The use of Bupivacaine should be avoided in patients for whom a state of
pregnancy is ascertained or presumed (see “ Pregnancy”).
Cases of cardiac arrest following the use of bupivacaine for epidural anesthesia in laboring women have been reported; in most cases, this occurred following the use of the 0.75% solution. Therefore, the use of Bupivacaine at 0.75% should be avoided in epidural anesthesia
in obstetrics. This concentration should be reserved for those surgical procedures where a high degree of muscle relaxation and a prolonged effect are necessary.
The product is also contraindicated in paracervical block and in intravenous regional anesthesia (Bier Block).
General contraindications must be taken into consideration in case of intrathecal anesthesia:

• acute active diseases of the central nervous system, such as meningitis, tumors, poliomyelitis and intracranial hemorrhages
• spinal stenosis and active disease of the spine (e.g. spondylitis, tuberculosis, tumor) or recent trauma (e.g. fractures)
• septicemia
• pernicious anemia combined with subacute spinal cord degeneration
• pyogenic skin infection at the injection site or in the surrounding area
• cardiogenic or hypovolemic shock
• coagulation disorders or ongoing anticoagulant treatments.

PRECAUTIONS FOR USE
The safety and efficacy of some injections of Bupivacaine Angelini for anesthetizing parts of the
body during surgical procedures have not been established in children under 12 years of age and in
children under 1 year of age.
The total dosage must be corrected in relation to the general conditions, age and relevant
anamnestic data of the patient.
Cases of cardiac arrest or death have been reported following the use of bupivacaine for epidural anesthesia or peripheral nerve block. In some cases, resuscitation proved difficult or
impossible despite the preparation and conduct of the personnel appearing adequate. In most cases, this occurred following the use of the 7.5
mg/ml solution.
Intrathecal anesthesia must be performed only by a doctor or under the supervision of clinicians
with the necessary competence and experience.
Bupivacaine, like all local anesthetics, when used for anesthetic procedures
locals that determine high blood concentrations of the drug, can cause acute toxic effects
on the central nervous system and the cardiovascular system, especially in the event of
accidental intravascular administration or injection into highly vascularized areas. Following
high systemic concentrations of bupivacaine, ventricular arrhythmias, ventricular fibrillation, sudden cardiovascular collapse and death have been reported. However, at the doses normally
used for intrathecal anesthesia, high systemic concentrations are not expected.
Regional anesthesia procedures must always be performed in adequately
equipped areas and by qualified personnel. Immediate availability of
equipment and drugs necessary for monitoring and emergency resuscitation is required.
In patients undergoing major block or receiving high doses of the drug, a venous catheter must be inserted before administration of the local anesthetic. The doctor
must have undergone complete and adequate training on the procedure to be used and
must be experienced in the diagnosis and treatment of adverse effects, systemic toxicity or other
complications (see “ Adverse effects” and “ Overdose”).
Blocking major peripheral nerves may involve administering a large volume of
local anesthetic in highly vascularized areas, often near large vessels where there is an
increased risk of intravascular injection and/or rapid systemic absorption, which can
lead to high plasma concentrations.
Although regional anesthesia frequently represents the anesthetic technique of choice,
some patients require special attention to reduce the risk of dangerous adverse effects:

• elderly or debilitated patients;
• patients with partial or complete cardiac block as local anesthetics can depress cardiac conduction;
• patients with advanced liver disease or severe renal impairment;
• hypovolemic patients may develop severe and sudden hypotension during intrathecal anesthesia, regardless of the local anesthetic used. Hypotension is normally observed after intrathecal block in adults;
• patients treated with class III antiarrhythmic drugs (e.g. amiodarone) should be closely monitored and the possibility of ECG monitoring should be considered as effects on the heart may be additive. This medicine should be administered with great caution and under strict medical supervision if:
• they have to undergo an anesthesia called stellate ganglion block.

The doctor will monitor you during treatment with this medicine as some
local anesthesia techniques may be associated with severe adverse reactions,
regardless of the local anesthetic used:

• Central nervous block: can cause cardiovascular depression especially in the presence of hypovolemia. Epidural anesthesia should therefore be used with caution in patients with reduced cardiovascular function.
• Stellate ganglion block: can cause adverse effects similar to those of central nervous block as well as cardiac toxicity with increased or decreased heart rate up to cardiac arrest.
• Retrobulbar injections: can, in very rare cases, reach the cerebral subarachnoid space causing temporary blindness, cardiovascular collapse, apnea, convulsions, etc. Such reactions must be diagnosed and treated immediately.
• Retro- and peribulbar injections of local anesthetics: involve a low risk of persistent muscle dysfunction at the ocular level. Primary causes include trauma and/or local toxic effects on muscles and/or nerves. The severity of such reactions to the tissues is related to the extent of the trauma, the concentration of local anesthetic and the duration of tissue exposure to the local anesthetic. As with all local anesthetics, it is therefore necessary to use the lowest doses and concentrations that can allow to obtain the desired effect. Vasoconstrictors can worsen reactions to the tissues and should be used only if indicated.
• Paracervical block can sometimes cause fetal bradycardia/tachycardia. Careful monitoring of fetal heart rate is therefore necessary.

A rare but serious adverse reaction following spinal anesthesia is total or high spinal block and
consequent cardiovascular and respiratory depression. Cardiovascular depression is
caused by extensive sympathetic block with resulting profound hypotension and bradycardia or
even cardiac arrest. Respiratory depression can be caused by blocking the
innervation of the respiratory muscles, including the diaphragm. The risk of total or high spinal block is
higher in elderly patients. In these patients the dose should therefore be reduced.
The onset of neurological damage is a rare consequence of intrathecal anesthesia and can
involve paresthesia, anesthesia, motor weakness and paralysis. Occasionally such damage is
permanent.
Caution is recommended in patients with neurological disorders such as multiple sclerosis, hemiplegia,
paraplegia and neuromuscular disorders, even if it is believed that intrathecal anesthesia does not negatively affect
such disorders. Before starting treatment, it is necessary to consider whether the benefits outweigh the possible risks to the patient.
Epidural anesthesia can cause hypotension and bradycardia. The risk can be reduced with the
pre-filling of the circulation with crystalloid or colloid solutions. Hypotension must be
treated immediately with the administration, possibly repeated, of a
sympathomimetic intravenously. In children, the dosage must be adjusted to age and
weight.
Cases of reduced or absent efficacy have been reported with the use of Bupivacaine Angelini, especially in the case of spinal anesthesia.
As with other local anesthetics, literature and post-marketing surveillance reports report
lack of efficacy following spinal anesthesia in a variable percentage. The most common reasons for such inefficacy may be technical problems, inadequate doses or inappropriate positioning of the patient. In the presence of correct dosage and injection technique, the reason for an inadequate block may be attributable to maldistribution of the active ingredient, variability
in the anatomy of the subarachnoid space, or resistance to the effects of the local anesthetic.
When bupivacaine is administered intra-articularly, caution is recommended
if a recent major intra-articular trauma is suspected or if surgery has
produced extensive exposure of the joint as this may accelerate absorption and
determine higher plasma concentrations.
If infiltrations are carried out for local anesthesia in areas devoid of collateral circulation possibilities (fingers, root of the penis, etc.) it is a precautionary rule to use the anesthetic without
vasoconstrictor to avoid ischemic necrosis. If moderate ischemia is desired, use Bupivacaine Angelini 0.50% injectable solution with adrenaline. The product must be
used with absolute caution in subjects undergoing treatment with MAOI drugs or tricyclic antidepressants. Before use, the doctor must ascertain the state of the circulatory conditions of the
subjects to be treated. It is advisable to use an adequate dose-test possibly in association
with adrenaline, in order to promptly avoid an accidental intravenous or
intrathecal injection. The anesthetic solution must be injected with caution in small doses after about 10
seconds from a preliminary aspiration. Especially when highly vascularized areas are to be infiltrated, it is advisable to let about 2 minutes pass before proceeding with the actual loco-
regional block.
The patient must be kept under accurate control immediately suspending the
administration at the first sign of alarm (for example changes in sensorium).

It is necessary to have immediate availability of equipment, drugs and qualified personnel
for emergency treatment, as serious reactions, sometimes with a fatal outcome, have been reported following the use of
local anesthetics, even in the absence of individual hypersensitivity in the history.
INTERACTIONS
Inform your doctor or pharmacist if you have recently taken any other medicine,
including those without a prescription.
Bupivacaine should be used with caution in patients treated with other local anesthetics or
substances structurally related to amide-type local anesthetics, such as certain
antiarrhythmics such as lidocaine, mexiletine and tocainide as systemic toxic effects are
additive. Caution is advised in patients treated with class III antiarrhythmics (e.g. amiodarone)
despite the absence of specific interaction studies with this class of drugs (see
“ Precautions for use”).
The product must be used with absolute caution in subjects undergoing treatment with MAOI drugs or tricyclic antidepressants.

SPECIAL WARNINGS

Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
Pregnancy
Do not use the drug in known or presumed pregnancy (see “ Contraindications”).
Breastfeeding
Like other local anesthetics, bupivacaine may be excreted in breast milk but in such small
quantity that there is generally no risk to the newborn.

EFFECTS ON THE ABILITY TO DRIVE VEHICLES AND OPERATE MACHINERY
Local anesthetics, in addition to the direct anesthetic effect, can have a very mild effect on
mental function and coordination, even in the absence of evident central nervous system toxicity and can temporarily negatively affect locomotion and degree of
vigilance.

DOSE, MODE AND TIME OF ADMINISTRATION
Use in children and adolescents
Depending on the type of anesthesia required, BUPIVACAINE ANGELINI is slowly infused into the
vertebral canal (part of the spinal cord) or other parts of the body by an experienced anesthesiologist in
pediatric anesthetic techniques. Dosages depend on the patient's age and weight and will be
determined by the anesthesiologist.

BUPIVACAINE ANGELINI 5mg/ml hyperbaric injectable solution
Neonates, infants and children up to 40 kg.
Bupivacaine Angelini 5 mg/ml hyperbaric injectable solution can be used in children.
One of the differences between small children and adults is a relatively high volume of cerebrospinal fluid
in neonates and infants, which requires a relatively higher dose/kg to achieve the same level of block
compared to adults.
Pediatric regional anesthesia procedures must be performed by qualified physicians with
technical experience and familiarity with this type of patient.
The doses reported in the table should be taken as guidelines for use in pediatrics, although
variations may occur on an individual basis. Reference texts should be consulted for factors that may affect
specific block techniques and for individual patient needs. The lowest dose necessary to achieve adequate
anesthesia should be used.

Recommended dosages in neonates, infants and children
Adults
Bupivacaine is usually used in minimum dosages, varying according to the indications, from 2-3 mg to
100-150 mg as indicated for guidance in the table:

• (a): the dosage is intended for each intercostal space.
• (b): start with 10 ml then 3-5-8 ml every 4-6 hours, depending on the segments to be anesthetized and the patient's age. Caution: vials, not containing preservatives, should be used for a single administration. Any remnants should be discarded. The maximum dosage for an adult and for a single administration should not exceed 150 mg, corresponding to 30 ml of the 0.50% solution; more generally, the safety dose, for both adults and children, which is advisable not to exceed, is 2 mg/Kg for a single administration. In prolonged analgesic therapy, doses usually ranging from 0.25 to 1 mg/Kg of body weight are used; administration can be repeated 2-3 times in 24 hours. NB When performing prolonged blocks for successive bolus administration, the risk of reaching toxic plasma concentrations or inducing local neuronal damage must be considered.

The dose to be administered must be calculated based on the doctor's experience and
knowledge of the patient's clinical condition. The lowest doses that can
allow adequate anesthesia should be used. Individual variations may occur
regarding the onset and duration of action. Reference texts should be consulted for factors that may affect
specific block techniques and for individual patient needs. The degree of anesthesia spread can be difficult to predict but is
influenced by the volume of drug administered, especially regarding isobaric solutions.
To prevent accidental intravascular injection, aspiration should be performed before and
during the administration of the main dose, which should be injected slowly or in increasing doses. During the procedure, carefully monitor the patient's vital functions and
maintain verbal contact. If epidural anesthesia is required, it is recommended to
precede a test dose of 3-5 ml of bupivacaine with adrenaline. An intravascular injection

accidental can be recognized by a temporary increase in heart rate;
an accidental intrathecal injection is recognized by signs of spinal block. At the first sign of
toxicity, immediately stop administration (see “ Undesirable Effects -

Acute systemic toxicityand Treatment of acute systemic toxicity”).
Any overdose of anesthetic should be avoided and never administer two maximum doses
of it without at least 24 hours having elapsed. It is still necessary to use the lowest doses and concentrations that can allow to
achieve the desired effect.

OVERDOSE
Accidental intravascular injection of local anesthetics can cause immediate systemic toxic reactions
(ranging from a few seconds to a few minutes). In case of overdose, systemic toxicity manifests later (15-60 minutes after injection) and this is due to a slowed
increase in blood concentrations of local anesthetic (see “ Undesirable Effects -

Acute systemic toxicityand Treatment of acute systemic toxicity”).
Hyperbaric Bupivacaine Angelini, under the recommended conditions of use, is unlikely to
promote blood levels high enough to cause systemic toxicity. However, if other
local anesthetics are administered concurrently, the toxic effects are additive and can
cause systemic toxicity (see “ Undesirable Effects - Acute systemic toxicityand Treatment

of acute systemic toxicity”).
When the first signs of overdose appear, stop administering the preparation and,
place the patient in a horizontal position, ensure the patency of the airways. If
breathing difficulties occur, intervene with assisted ventilation (in emergencies, the Ambu balloon can also be used). The use of bulbous stimulants is not recommended as they
increase oxygen consumption. The appearance of convulsive manifestations can be
controlled with diazepam intravenously (10-20 mg); barbiturates are instead discouraged as they can
exacerbate bulbar depression.
To support circulation, corticosteroids can be used intravenously; diluted solutions of alpha-beta-stimulants with vasoconstrictor action (mefentermine, metaraminol
and others) or atropine sulfate can be added. The correction of any acidosis that has occurred can
be corrected with the use of appropriate sodium bicarbonate solutions intravenously.

In case of ingestion/accidental intake of an excessive dose of Bupivacaine Angelini
immediately notify the doctor or go to the nearest hospital.
If you have any doubts about the use of Bupivacaine Angelini, consult your doctor or pharmacist.
UNDESIRABLE EFFECTS
Additional undesirable effects in children and adolescents
Adverse reactions in children are similar to those in adults.

General
Like all medicines, Bupivacaine Angelini can cause side effects, although not everyone
experience them.
The profile of adverse reactions of Bupivacaine Angelini is similar to that of other
long-acting local anesthetics. Drug adverse reactions are difficult to
distinguish from the physiological effects resulting from nerve conduction block (such as decreased
blood pressure, bradycardia, temporary urinary retention) and events caused
directly by the injection (e.g. nerve fiber trauma, spinal hematoma) or
indirectly (e.g. epidural abscess and meningitis) or events associated with cerebrospinal fluid leakage (e.g. post-dural headache). The onset of neurological damage is a
rare but well-known consequence of regional anesthesia and in particular, epidural and
spinal anesthesia.

Table of adverse reactions

Other adverse effects reported include phenomena of central nervous system stimulation
(excitation, disorientation, mydriasis, increased metabolism and body temperature,
trismus, sweating, tachypnea, bronchodilation, vasodilation) and allergic reactions with
local manifestations (urticaria, pruritus) or systemic (bronchospasm, laryngeal edema).

If any of the side effects worsen, or if you notice any side effect
Acute systemic toxicity
Systemic toxic reactions primarily affect the central nervous system and the cardiovascular system. These reactions are caused by high blood concentrations of the local anesthetic
following accidental intravascular injection, overdose or exceptionally rapid absorption
from highly vascularized areas (see “ Precautions for use”). Reactions
to the central nervous system are similar to those of other amidic-type local anesthetics while reactions at the cardiac level depend, both quantitatively and
qualitatively, to a greater extent on the drug.
Hyperbaric Bupivacaine Angelini, under the recommended conditions of use, is unlikely to
promote blood levels high enough to cause systemic toxicity. However, if other
local anesthetics are administered concurrently, the toxic effects are additive and can
cause systemic toxicity.
Toxicity to the central nervous systemmanifests gradually, with symptoms and signs
of increasing severity. The first symptoms are, as a rule, paresthesia in the circumoral region,
insensitivity of the tongue, empty head sensation, hyperacusis, tinnitus and visual disturbances. Dysarthria,
muscle spasm or tremor are more serious manifestations and precede the onset of
generalized seizures. These signs should not be confused with erotic behaviors.
Unconsciousness and seizures may follow, which can last from a few seconds to several
minutes. After the convulsions, due to increased muscle activity, interference with
breathing and possible airway obstruction, hypoxia and hypercapnia occur rapidly. In severe cases, apnea can occur. Acidosis, hyperkalemia, hypocalcemia
and hypoxia increase and amplify the toxic effects of local anesthetics.
Return of the patient to initial clinical conditions is consequent to redistribution
of the local anesthetic from the central nervous system and subsequent metabolism and excretion. Recovery can be rapid if large amounts of drug have not been administered.
In severe cases, effects on the cardiovascular systemcan occur, generally
preceded by signs of central nervous system toxicity. In deeply sedated patients or
undergoing general anesthesia, effects on the cardiovascular system may
occur without prodromic effects of the central nervous system. As a result of high
systemic concentrations of local anesthetics, hypotension, bradycardia, can occur
arrhythmias and even cardiac arrest but in rare cases cardiac arrest has occurred without prodromic effects
of the central nervous system.
In children, it may be difficult to detect the onset of early signs of local anesthetic systemic toxicity when the block is administered during general anesthesia.

Treatment of acute systemic toxicity
Administration of the local anesthetic must be discontinued immediately if signs of acute systemic toxicity or total spinal block appear.
Symptoms of central nervous system toxicity (convulsions, central nervous system depression) must be treated immediately with adequate support of airway patency and breathing, and with the administration of anticonvulsants, such as diazepam at a dose of 10-20 mg intravenously; barbiturates, on the other hand, are not recommended as they may exacerbate bulbar depression. Circulation may be supported with the administration of corticosteroids at appropriate doses intravenously; diluted solutions of alpha-beta-stimulants with vasoconstrictor action (mefentermine, metaraminol and others) or of atropine sulfate may be added.
If circulatory arrest occurs, cardiopulmonary resuscitation must be performed immediately. It is vitally important to ensure optimal oxygenation, support ventilation and circulation, and treat acidosis.
If cardiovascular depression (hypotension, bradycardia) occurs, appropriate treatment with intravenous fluids, vasopressors and/or inotropic agents should be considered. In children, the dosage must be adjusted to age and weight.
If cardiac arrest occurs, it may be necessary to prolong resuscitation maneuvers to achieve a favorable outcome.

EXPIRY DATE AND STORAGE
Expiry date: see the expiry date indicated on the packaging.

The expiry date refers to the product in intact packaging, correctly stored.
Caution: Do not use the product after the expiry date printed on the packaging.

Medicines should not be disposed of via drains or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.
Keep the medicine out of the reach and sight of children.
COMPOSITION
Bupivacaina Angelini 5 mg/ml (0.5%) hyperbaric injectable solution
1 ml of hyperbaric solution contains: Active ingredient :Bupivacaine 5 mg (as hydrochloride)
Excipients: glucose monohydrate, sodium hydroxide, water for injections

PHARMACEUTICAL FORM AND CONTENT
Bupivacaina Angelini 5 mg/ml (0.5%) hyperbaric injectable solution
Injectable solution: pack of 10 glass vials type I of 4 ml.

Marketing Authorisation Holder
AZIENDE CHIMICHE RIUNITE ANGELINI FRANCESCO - A.C.R.A.F. S.p.A.
Viale Amelia, 70 - 00181 ROMA

MANUFACTURER
A.C.R.A.F. S.p.A., Via Vecchia del Pinocchio 22 - 60131 ANCONA