Bupivacaine Hydrochloride

Bupivacaine Hydrochloride

5mg/ml Solution for Spinal Injection

Drug Category: Local Anesthetic

Brand Name: Sensorcaine 0.5% Heavy

Clinical Particulars

Therapeutic Indications:

Spinal anesthesia for surgery, e.g. urological surgery and surgery on the lower limbs lasting 2-3 hours, abdominal surgery lasting 45-60 minutes.

Dosage and method of administrations:

Bupivacaine hydrochloride Spinal Heavy should only be used by clinicians with experience of regional anesthesia or under their supervision. The lowest possible dose for adequate anesthesia should be used.

The doses given below are guides for adults and the dosage should be adjusted to the individual patients.

The dose should be reduced in elderly patients and patients in late stages of pregnancy.

Indication	Dose mL	Dose mg	Time to onset of effect in minutes (approx.)	Duration of effect in hours (approx.)
Urological surgery Surgery on lower limbs, including hip surgery Abdominal surgery (including cesarean section)	1.5-3 ml 2-4 ml 2-4 ml	7.5-15 mg 10-20 mg 10-20 mg	5-8 min 5-8 min 5-8 min	2-3 hours 2-3 hours 45-60 min

The recommended injection site is the L₃-L₄ intervertebral space. There is currently no experience of doses higher than 20 mg. A spinal injection is given only after the subarachnoid space has been clearly identified by means of lumbar puncture (clear cerebrospinal fluid runs out via the spinal needle or is seen on aspiration). In the event of unsuccessful anesthesia, a new attempt to administer the drug should only be made by injecting at a different level and with a smaller volume. One cause of lack of effect may be poor intrathecal distribution of the drug, and this can be helped by altering the patient's position.

Contraindications:

Hypersensitivity to local anesthetics of the amide type or to other components of the product. Diseases of the central nervous system (e.g. meningitis, poliomelitis, intracranial hemorrhage). Local pyogenic infection at or adjacent to the injection site. Spinal stenosis and active disease (e.g. spondylitis, tumor) or trauma (e.g. fracture of the spine). Septicemia, pernicious anemia with subacute degeneration of the spinal cord. Spinal anesthesia should not be given to patients in shock. Nor should spinal anesthesia be given to patients with coagulation disorders or to patients receiving ongoing anticoagulation treatment.

Special warning and precaution for use:

One should be aware that spinal anesthesia can sometimes lead to major blocks, with paralysis of intercostal muscles and the diaphragm, especially in pregnant women.

Caution should be exercised in patients with degree II or III-AV block since local anesthetics can lower the conduction capacity of the myocardium. Elderly patients and patients with severe hepatic disease, severely impaired renal function or in generally reduced general condition also require special attention.

Patients treated with class III anti-arrhythmic drugs (e.g. amiodarone) should be closely observed and ECG monitoring should be considered, since the cardiac effects of bupivacaine and class III anti-arrhythmic drugs can be addictive.

Like all local anesthetic drugs, bupivacaine can cause acute central nervous and cardiovascular toxic effects in cases of use leading to high concentrations in the blood. This applies particularly after inadvertent intravascular administration.

Ventricular arrhythmia, ventricular fibrillation, sudden cardiovascular collapse and death have been reported in association with high systemic concentrations of bupivacaine. However, with doses normally used for spinal anesthesia high systemic concentrations are uncommon.

An uncommon, but dangerous, side effect in spinal anesthesia is extensive or total spinal blockade, which results in cardiovascular depression and respiratory depression. The cardiovascular depression is caused by extensive sympathetic blockade, which can result in hypotension and bradycardia, or even cardiac arrest. Respiratory depression can be caused by blockade of the innervation of the respiratory muscles, including the diaphragm. There is an increased risk of extensive or total spinal blockade in elderly patients and patients in late stages of pregnancy. The dose should therefore be reduced for these patients.

Spinal anesthesia can lead to a fall in blood pressure and bradycardia. The risk can be reduced by means of intravenous administration of crystalloid or colloid solution. A fall in blood pressure should be treated immediately, for example with ephedrine 5-10mg intravenously, repeated as required.

In rare cases spinal anesthesia can cause neurological damage, resulting in paresthesia, anesthesia, motor weakness and paralysis. Neurological disorders, such as multiple sclerosis, hemiplegia, paraplegia and neuromuscular disturbances are not thought to be adversely affected by spinal anesthesia, but caution should be exercised.

Interactions with other medical products and other forms of interactions:

Bupivacaine should be use with caution with other local anesthesia or drugs that are structurally similar to local anesthetics, i.e. class IB anti-arrhythmic drugs, as the toxic effects are additive.

No specific interaction studies with local anesthesia and class III anti-arrhythmic drugs (e.g. amiodarone) have been carried out, but caution is recommended (see Special warning and special precautions for use).

Pregnancy and Lactation:

Pregnancy

No known risks for the fetus from use during pregnancy. However, note that the dose should be reduced for patients in late stages of pregnancy (see Special warning and special precautions for use).

Lactation

Bupivacaine passes into breast milk, but the risk of this affecting the child appears unlikely with therapeutic doses.

Effects on ability to drive and use machines:

Depending on the dose and method of administration, bupivacaine can have a transient effect on movement and coordination.

Undesirable effects:

Undesirable effects caused by the product itself can be difficult to distinguish form the physiological effects of the nerve block (e.g. fall in blood pressure, bradycardia, temporary urinary retention), events caused directly by the needle puncture (e.g. spinal hematoma) or caused indirectly by the needle puncture (e.g. meningitis, epidural abscess) or events associated with leakage of cerebrospinal fluid ( e.g. post lumbar puncture headache).

Very common (>1/10)	General: Nausea Circ.: Hypotension, bradycardia
Common (>1/100)	CNS: Post lumbar puncture headache GI: Vomiting Genitourinary: Urinary retention, urinary incontinence
Uncommon (1/100-1/1000)	CNS: Paresthesia, paresia, dysesthesia Musculoskel.: Muscle weakness, back pain
Rare (<1/1000)	Circ.: Cardiac arrest General: Allergic reactions, anaphylactic shock CNS: Accidental total spinal blockade, paraplegia, paralysis, neurophathy, arachnoiditis Airways: Respiratory depression

Overdose:

Bupivacaine can cause acute toxic effects of a central nervous and cardiovascular nature if it is given in high doses, especially if it is administered intravascularly. However, the dose used in spinal anesthesia is low (≤ 20% of the dose used for epidural anesthesia) and thus the risk of overdosage is unlikely. In cases of concomitantly administration with other local anesthetics, however, systemic toxic effects may occur, ass the toxic effects are additive.

Treatment of complications

In cases of total spinal blockade adequate ventilation must be ensured (patent airways, oxygen, intubation and controlled ventialtion if necessary). If there is a fall in blood pressure a vasopressor (preferably with an inotropic effect) should be given, e.g. ephedrine 5-10mg intravenously.

If signs of acute systemic toxicity occur the administration of local anesthesia must be stopped immediately. Treatment must be given to maintain good ventilation, oxygenation and circulation. Oxygen must always be given, and assisted ventilation if necessary. If convulsions do not cease spontaneously within 15-20 seconds, theopentone sodium 1-3 mg/kg should be given intravenously to facilitate ventilation or diazepam 0.1 mg/kg intravenously ( acts rather more slowly). Prolonged seizures jeopardize the patient's respiration and oxygenation. Injection of muscle relaxants (e.g. suxamethonium 1mg/kg) creates more favourable conditions for ventilation and oxygenation of the patient, but requires experience of tracheal intubation and controlled ventilation. In cases of a fall in blood pressure/bradycardia, a vasopressor should be given (e.g. ephedrine 5-10 mg intravenously, which may be repeated after 2-3 minutes). In the event of circulatory arrest, cardiopulmonary resuscitation should be instituted immediately. It is important to maintain good oxygenation, respiration and circulation, and to treat acidosis.

Children must be given doses in proportion to their age and body weight for treatment of systemic toxicity.

Pharmacological Properties

Pharmacodynamic Properties

Bupivacaine hydrochloride spinal heavy contains bupivacaine, which is a long-acting local anesthetic of the amide type. Bupivacaine reversibly blocks impulse conduction in the nerves by inhibiting the transport of sodium ions through the nerve membrane. Similar effects can also be seen on excitatory membranes in the brain and myocardium.

Bupivacaine hydrochloride spinal heavy is intended for hyperbaric spinal anesthesia. The relative density of the solution for injection is 1.026 at 20^oC (equivalent to 1.021 at 37^oC) and the initial distribution into the subarachnoid space is markedly influenced by gravity.

For administration into the spine, a small dose is given, which gives a relatively low concentration and short duration of effects. Bupivacaine hydrochloride spinal (without glucose) produces a less predictable block, but with a longer duration of effects than bupivacaine hydrochloride spinal heavy (with glucose).

Pharmacokinetic Properties:

Bupivacaine is very liposoluble with an oil/water distribution coefficient of 27.5.

Bupivacaine displays complete and bi-phasic absorption from the subarachnoid space, with half-lives for the two phases of approx. 50 and approx. 400 minutes, with large variations. The slow absorption phase is the rate-determining factor in the elimination of bupivacaine, which explains why the apparent half-life is longer than after intravenous administration.

Absorption form the subarachnoid space is relatively slow, which, in combination with the low dose required a spinal anesthesia, gives relatively low plasma concentration (approx. 0.4 mg/mL per 100 mg injected).

After intravenous administration, total plasma clearances is approx. 0.58 L/min, the volume of distribution in steady state is approx. 73 L, the elimination half-life is 2.7 hours, and the hepatic extraction ration is approx. 0.40. Bupivacaine is metabolized almost completely in the liver, predominantly through aromatic hydroxylation to 4-hydorxybupivacaine and N-dealkylation to PPX, both of which are mediated by cytochrome P450 3A4. Clearance is thus depended on hepatic perfusion and the activity of the metabolizing enzyme.

Bupivacaine crosses the placenta and the concentration of free bupivacaine is the same in the the mother and the fetus. However, the total plasma concentration is lower in the fetus, which has a lower degree of protein binding.

Pharmaceutical Particulars

Incompatibilities:

Additions to spinal solutions are not recommended.

Shelf-Life:

Please refer to the expiration date.

The solution must be used as soon as possible after the container has been opened.

Storage:

Store at a temperature not exceeding above 25^oC. Do not freeze.