LISAMETHYLE

Injection contains bupivacaine hydrochloride, an amide local anesthetic, as the active pharmaceutical ingredient.

The route of administration for Bupivacaine Hydrochloride Injection (without epinephrine) is by injection, for infiltration, perineural, caudal, epidural, or retrobulbar use.

Multiple-dose vials contain methylparaben.

Bupivacaine hydrochloride is 2-piperidinecarboxamide, 1-butyl.

• N -(2,6-dimethylphenyl)-, monohydrochloride, monohydrate.

It is a white crystalline powder that is freely soluble in 95 percent ethanol, soluble in water, and slightly soluble in chloroform or acetone.

It has the following structural formula

Bupivacaine Hydrochloride Injection, USP is a clear and colorless sterile isotonic solution.

Each mL of single-dose vial contains 2.5 mg, 5 mg, or 7.5 mg of bupivacaine hydrochloride (equivalent to 2.22 mg, 4.44 mg, or 6.66 mg of bupivacaine, respectively), sodium chloride for isotonicity, sodium hydroxide or hydrochloric acid to adjust the pH between and 6.5, in water for injection.

For the multiple-dose vials, each mL also contains 1 mg methylparaben as preservative. image description.

Injection is indicated in adults for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures.

Specific concentrations and presentations of Bupivacaine Hydrochloride Injection are recommended for each type of block indicated to produce local or regional anesthesia or analgesia.

Injection contains bupivacaine, an amide local anesthetic.

For each type of block indicated to produce local or regional anesthesia or analgesia, specific concentrations and presentations are recommended.

Limitations of Use Not all blocks are indicated for use with Bupivacaine Hydrochloride Injection given clinically significant risks associated with use.

Thromboembolic accident Lactation History of psychiatric illness Recent history of intestinal anastomosis Cancer Septic shock Cirhrosis Ulcerous colitis Diabetes Diverticulitis Child between 30 months and 15 years Epilepsy Stress Glaucoma Glaucoma, family history (de) Pregnancy Herpes eye Hypertension Hypothyroidism Bacterial infection Intramuscular injection Congestive heart failure Hepatic impairment Renal impairment Surreal impairment Exanthemous disease Psychiatric illness Severe myasthenia Cortisonic myopathy Infants under 30 months of age Newborn exposed in utero to the medicine Osteoporosis Brain malaria Dialysis patient High dose treated patient Phoechromocytoma Poliomyelitis Premature Presence of varicella or measles in patient's environment Psychosis Systemic scleroderma Multiple sclerosis Sports Elderly Subject at risk of heart Subject at risk of thromboembolic accident Subject at risk of seizure Subject at risk of psychiatric illness Subject at risk for tumour lysis syndrome Subject at risk of tuberculosis Subject with a positive reaction to tuberculin Subject from an anguillasis endemic area Cushing's syndrome Allergic field Extended treatment Renal transplantation Cranial trauma Neuromuscular disorder Tuberculosis, history Evolutionary tuberculosis Gastroduodenal ulcer, history (d) Evolving gastroduodenal ulcer Non-live or inactivated vaccines.

Bupivacaine blocks the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential.

In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers.

Clinically, the order of loss of nerve function is as follows: pain, temperature, touch, proprioception, and skeletal muscle tone.

Epinephrine is a vasoconstrictor added to bupivacaine to slow absorption into the general circulation and thus prolong maintenance of an active tissue concentration. 12.2 Pharmacodynamics Systemic absorption of bupivacaine produces effects on the cardiovascular system and CNS.

At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal.

However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities.

In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure.

These cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine.

Following systemic absorption, bupivacaine can produce CNS stimulation, CNS depression, or both.

Apparent central stimulation is manifested as restlessness, tremors, and shivering, progressing to convulsions, followed by CNS depression and coma progressing ultimately to respiratory arrest.

However, bupivacaine has a primary depressant effect on the medulla and on higher centers.

The depressed stage may occur without a prior excited state.

The duration of local anesthesia after administration of Bupivacaine Hydrochloride Injection is longer than that observed after administration of other commonly used short-acting local anesthetics.

There appears to be period of analgesia that persists after the resolution of the block and return of sensation.

The onset of action following dental injections is usually to 10 minutes and may last up to 7 hours.

The duration of anesthetic effect is prolonged by the addition of epinephrine 1:200,000. 12.3 Pharmacokinetics Systemic plasma levels of bupivacaine following administration of Bupivacaine Hydrochloride Injection do not correlate with local efficacy.

The rate of systemic absorption of bupivacaine is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution.

A dilute concentration of epinephrine (1:200,000) usually reduces the rate of absorption and peak plasma concentration of bupivacaine, permitting the use of moderately larger total doses and sometimes prolonging the duration of action.

After injection of Bupivacaine Hydrochloride

Injection for caudal, epidural, or peripheral nerve block, peak levels of bupivacaine in the blood are reached in to 45 minutes, followed by a decline to insignificant levels during the next three to six hours.

Bupivacaine appears to cross the placenta by passive diffusion.

The rate and degree of diffusion is governed by the degree of plasma protein binding, the degree of ionization, and the degree of lipid solubility.

Fetal/maternal ratios of bupivacaine appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer.

Bupivacaine with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4).

The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug.

Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation.

Depending upon the route of administration, bupivacaine is distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.

Pharmacokinetic studies on the plasma profile of bupivacaine after direct intravenous injection (Bupivacaine Hydrochloride Injection is not approved for intravenous use) suggest a three-compartment open model.

The first compartment is represented by the rapid intravascular distribution of the drug.

The second compartment represents the equilibration of the drug throughout the highly perfused organs such as the brain, myocardium, lungs, kidneys, and liver.

The third compartment represents an equilibration of the drug with poorly perfused tissues, such as muscle and fat.

The half-life of bupivacaine in adults is 2.7 hours.

Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid.

Pipecoloxylidine is the major metabolite of bupivacaine.

The elimination of drug from tissue distribution depends largely upon the availability of binding sites in the circulation to carry it to the liver where it is metabolized.

The kidney is the main excretory organ for most local anesthetics and their metabolites.

Urinary excretion is affected by urinary perfusion and factors affecting urinary pH.

Only 6% of bupivacaine is excreted unchanged in the urine.

Elderly patients exhibited higher peak plasma concentrations than younger patients following administration of Bupivacaine Hydrochloride Injection.

The total plasma clearance was decreased in these patients.

Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic disease.

Patients with hepatic disease, especially those with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics.

Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of renal disease, factors affecting urinary pH, and renal blood flow.

Mechanism of action

Physiological glucocorticoids ( cortisone and hydrocortisone) are essential metabolic hormones.

Synthetic corticosteroids, including dexamethasone, are used primarily for their anti-inflammatory effect.

At high doses, they decrease the immune response.

Their metabolic and sodium retention effect is less than that of hydrocortisone.

• Alkaline phosphates (increase)
• Leucocytosis Hyperuricaemia ASAT (increase)
• Lipidaemia (amendment)
• Hypokalaemia Hypercalcuria ALT (increase)
• Skin atrophy (Common)
• Acne (Common)
• Rash
• Skin Erythema Vergeture Skin striation Skin depigmentation Urticaria Hyperhidrosis
• Pruritus Pétechie Recovery delay (Common)
• Fatigue Peripheral edema Hypopituitarism
• Cushingoid syndrome Hirsutism Inhibition of hypothalamo-pituito-adrenal axis Menstrual irregularity
• Echymosis Hematoma Hepatitis Abnormal skin test Oedema of Quincke Hypersensitivity
• Anaphylactoid reaction Anaphylactic reaction Esophagus candidiasis Infection (Common)
• Opportunistic infection Peritonitis Injection site reaction Waterproof detention (Common)
• Negative nitrogen balance Insulin resistance Hypokalemic alkalosis Glucose tolerance
• Weight (increase)
• Metabolic acidosis Appetite increased Epidural lipomatosis Subcapsular cataract (Common)
• Papillary edema Glaucoma Chorioretinopathy Cataract Intraocular hypertension Blurty vision
• Eye infection (aggravation)
• Exophthalmia Cornea thinning Feeling dizzy Dysgueusia
• Insomnia (Common)
• Confusion-oniric state (Rare)
• Manic access (Rare)
• Cognitive disorder
• Mood disorder Irritability Drug addiction Suicidal ideation Behavioural disorder
• Schizophrenia (aggravation)
• Hallucination Depression Euphoria Mental confusion Emotional disorder
• Mania Psychosis Delicious Personality disorder Anxiety Hypertension (Common)
• Hypertrophic cardiomyopathy
• Arrhythmia Congestive puff Hypotension Myocardial closure Lung embolism Telangiectasia
• Malaise Thromboembolic accident Congestive heart failure Gastroduodenal ulcer (Common)
• Digestive perforation Abdominal distension Acute Pancreatitis Dyspepsia Vomiting
• Cystic pneumatosis of the intestine Hoquet Nausea Digestive haemorrhage Abdominal pain
• Diarrhoea Esophagus Ulcer Esophagitis Muscle weakness (Common)
• Growth retardation (Common)
• Cortisonic myopathy Osteonecrosis Osteoporosis Myopathy Pathological fracture Muscle atrophy
• Muscle pain Strand cut Aseptic osteonecrosis of femoral heads Joint pain Convulsions (Rare)
• Headache Amnesia Intracranial hypertension Weaning syndrome Renal scleroderma crisis.

Clinical Presentation Acute emergencies from use of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection are generally related to high plasma levels encountered during therapeutic use or to unintended intrathecal injection.

If not treated immediately, convulsions with simultaneous hypoxia, hypercarbia, and acidosis plus myocardial depression from the direct effects of bupivacaine may result in cardiac arrhythmias, bradycardia, asystole, ventricular fibrillation, or cardiac arrest.

Respiratory abnormalities, including apnea, may occur.

Hypoventilation or apnea due to unintentional intrathecal injection of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted.

If cardiac arrest should occur, successful outcome may require prolonged resuscitative efforts.

The first step in the management of systemic toxic reactions, as well as hypoventilation or apnea due to unintentional intrathecal injection of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask.

Endotracheal intubation, using drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask if difficulty is encountered in the maintenance of a patent airway, or if prolonged ventilatory support (assisted or controlled) is indicated.

If necessary, use drugs to manage the convulsions.

A bolus intravenous dose of a benzodiazepine will counteract CNS stimulation related to Bupivacaine Hydrochloride Injection.

Immediately after the institution of ventilatory measures, evaluate the adequacy of the circulation.

Supportive treatment of circulatory depression may require Advance Cardiac Life Support measures.

Serious Neurologic Adverse Reactions with Epidural Administration Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids.

Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke.

These serious neurologic events have been reported with and without use of fluoroscopy.

The safety and effectiveness of epidural administration of corticosteroids have not been established, and corticosteroids are not approved for this use.

This product is not suitable for multi-dose use.

Following administration of the desired dose, any remaining suspension should be discarded.

Injection of methylprednisolone acetate may result in dermal and/or subdermal changes forming depressions in the skin at the injection site.

In order to minimize the incidence of dermal and subdermal atrophy, care must be exercised not to exceed recommended doses in injections.

Multiple small injections into the area of the lesion should be made whenever possible.

The technique of intra-articular and intramuscular injection should include precautions against injection or leakage into the dermis.

Injection into the deltoid muscle should be avoided because of a high incidence of subcutaneous atrophy.

It is critical that, during administration of methylprednisolone acetate injectable suspension, appropriate technique be used and care taken to ensure proper placement of drug.

Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy See ADVERSE REACTIONS.

Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during, and after the stressful situation.

Results from one multicenter, randomized, placebo-controlled study with methylprednisolone hemisuccinate, an IV corticosteroid, showed an increase in early (at 2 weeks) and late (at 6 months) mortality in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment.

High doses of systemic corticosteroids, including methylprednisolone acetate, should not be used for the treatment of traumatic brain injury.

Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium.

These effects are less likely to occur with synthetic derivatives when used in large doses.

Dietary salt restriction and potassium supplementation may be necessary.

All corticosteroids increase calcium excretion.

Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients.

Hypothalamic-pituitary adrenal (HPA) axis suppression.

Cushing’s syndrome, and Hyperglycemia: Monitor patients for these conditions with chronic use.

Corticosteroids can produce reversible

HPA axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment.

Drug induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage.

This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted.

Infections General Persons who are on corticosteroids are more susceptible to infections than are healthy individuals.

There may be decreased resistance and inability to localize infection when corticosteroids are used.

Infections with any pathogen (viral, bacterial, fungal, protozoan, or helminthic) in any location of the body, may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents.

These infections may be mild, but can be severe and at times fatal.

With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases.

Do not use intra-articularly, intrabursally, or for intratendinous administration for local effect in the presence of an acute infection.

Corticosteroids may mask some signs of infection and new infections may appear during their use.

Infections Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug interactions.

There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions, Amphotericin B injection and potassium-depleting agents.

Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, and Toxoplasma.

It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea.

Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation.

In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Corticosteroids should not be used in cerebral malaria.

There is currently no evidence of benefit from steroids in this condition.

The use of corticosteroids in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen.

If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary, as reactivation of the disease may occur.

During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids.

Killed or inactivated vaccines may be administered.

However, the response to such vaccines cannot be predicted.

Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy (e.g., for Addison’s disease).

Infections Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids.

In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure.

The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known.

If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated.

If exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated.

If chicken pox develops, treatment with antiviral agents should be considered.

Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses.

The use of systemic corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes.

Corticosteroids should be used cautiously in patients with ocular herpes simplex because of corneal perforation.

Corticosteroids should not be used in active ocular herpes simplex.

Injection/Bupivacaine Hydrochloride and Epinephrine Injection is contraindicated in: obstetrical paracervical block anesthesia.

Its use in this technique has resulted in fetal bradycardia and death. intravenous regional anesthesia (Bier Block) . patients with a known hypersensitivity to bupivacaine or to any local anesthetic agent of the amide-type or to other components of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection.

Obstetrical paracervical block anesthesia.

Its use in this technique has resulted in fetal bradycardia and death.

Intravenous regional anesthesia (Bier Block).

Known hypersensitivity to bupivacaine or to any local anesthetic agent of the amide-type or to other components of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection.

Not for intrathecal use.

Avoid use of solutions containing antimicrobial preservatives (i.e., multiple-dose vials) for epidural or caudal anesthesia.

Three mL of Bupivacaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (0.5% bupivacaine with 1:200,000 epinephrine) is recommended for use as a test dose prior to caudal and lumbar epidural blocks when clinical conditions permit.

See full prescribing information for

Recommended concentrations and dosages of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection according to type of block.

Additional dosage and administration information pertaining to use in epidural anesthesia, test dose for caudal and lumbar epidural blocks, use in dentistry, and use in ophthalmic surgery. 2.1 Important Dosage and Administration Information Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection is not for intrathecal use.

Avoid use of Bupivacaine Hydrochloride

Injection/Bupivacaine Hydrochloride and Epinephrine Injection solutions containing antimicrobial preservatives (i.e., multiple-dose vials) for epidural or caudal anesthesia.

Discard unused portions of solution not containing preservatives, i.e., those supplied in single-dose vials, following initial use.

Visually inspect this product for particulate matter and discoloration prior to administration whenever solution and container permit.

Injection/Bupivacaine Hydrochloride and Epinephrine Injection are clear, colorless solutions.

Do not administer solutions which are discolored or contain particulate matter.

Mixing or the prior or intercurrent use of any other local anesthetic with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection is not recommended because of insufficient data on the clinical use of such mixtures.

Administration Precautions Bupivacaine Hydrochloride Injection

Injection/Bupivacaine Hydrochloride and Epinephrine Injection are to be administered in carefully adjusted dosages by or under the supervision of experienced clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed.

Injection/Bupivacaine Hydrochloride and Epinephrine Injection only if the following are immediately available: oxygen, cardiopulmonary resuscitative equipment and drugs, and the personnel resources needed for proper management of toxic reactions and related emergencies.

The toxic effects of local anesthetics are additive.

Monitor for neurologic and cardiovascular effects related to local anesthetic systemic toxicity when additional local anesthetics are administered with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection.

Aspirate for blood or cerebrospinal fluid (where applicable) prior to injecting Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection, both the initial dose and all subsequent doses, to avoid intravascular or intrathecal injection.

However, a negative aspiration for blood or cerebrospinal fluid does not ensure against an intravascular or intrathecal injection.

Avoid rapid injection of a large volume of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection and use fractional (incremental) doses when feasible.

During major regional nerve blocks, such as those of the brachial plexus or lower extremity, the patient should have an indwelling intravenous catheter to assure adequate intravenous access.

The lowest dosage of Bupivacaine Hydrochloride

Injection/Bupivacaine Hydrochloride and Epinephrine Injection that results in effective anesthesia should be used to avoid high plasma levels and serious adverse reactions.

Perform careful and constant monitoring of cardiovascular and respiratory (adequacy of oxygenation and ventilation) vital signs and the patient's level of consciousness after each local anesthetic injection.

Injection in carefully restricted quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply such as digits, nose, external ear, or penis. 2.2 Recommended Concentrations and Dosages of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection The dosage of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient.

Administer the smallest dosage and concentration required to produce the desired result.

The types of block and recommended Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection concentrations are shown in Table 1.

Table 1.

Types of Block and Recommended Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection Concentrations Type of Block Bupivacaine Hydrochloride Bupivacaine Hydrochloride and Epinephrine 0.25% (2.5 mg/mL) 0.5% (5 mg/mL) 0.75% (7.5 mg/mL) Bupivacaine Hydrochloride Injection 0.75% (7.5 mg/mL) is not recommended for nonobstetrical surgical procedures in pregnant patients. 0.25% (2.5 mg/mL) 0.5% (5 mg/mL) ✓= indicated use.

Local infiltration ✓ ✓ Peripheral nerve block ✓ ✓ ✓ ✓ Retrobulbar block ✓ Sympathetic block ✓ Caudal block Avoid use of multiple-dose vials of Bupivacaine Hydrochloride Injection and Bupivacaine Hydrochloride and Epinephrine Injection for caudal or epidural anesthesia. ✓ ✓ ✓ ✓ Lumbar epidural block ✓ ✓ ✓ (not for obstetrical anesthesia) ✓ ✓ Epidural test dose ✓ Dental block ✓ At recommended dosages, Bupivacaine Hydrochloride/Bupivacaine Hydrochloride and Epinephrine produces complete sensory block, but the effect on motor function differs among the three concentrations.

Table 2 provides information on the expected effect on motor function for the three concentrations.

Table 2.

Injection/Bupivacaine Hydrochloride and Epinephrine Injection Concentration vs. Motor Function Bupivacaine Hydrochloride Injection Concentration Motor Function 0.25% (2.5 mg/mL) These products include Bupivacaine Hydrochloride Injection and Bupivacaine Hydrochloride and Epinephrine Injection [the epinephrine concentration (1:200,000) is not included in the table.

When used for caudal, epidural, or peripheral nerve block, produces incomplete motor block.

Should be used for operations in which muscle relaxation is not important, or when another means of providing muscle relaxation is used concurrently.

Onset of action may be slower than with the 0.5% (5 mg/mL) or 0.75% (7.5 mg/mL) solutions. 0.5% (5 mg/mL) Provides motor blockade for caudal, epidural, or nerve block, but muscle relaxation may be inadequate for operations in which complete muscle relaxation is essential. 0.75% (7.5 mg/mL) These are only Bupivacaine Hydrochloride Injection products [there is no 0.75% (7.5 mg/mL) concentration for Bupivacaine Hydrochloride and Epinephrine Injection.

Produces complete motor block.

Most useful for epidural block in abdominal operations requiring complete muscle relaxation, and for retrobulbar anesthesia.

Not for obstetrical anesthesia.

The duration of anesthesia with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection is such that for most indications, a single-dose is sufficient.

The maximum dosage limit within the recommended dosage range must be individualized in each case after evaluating the size and physical status of the patient, as well as the anticipated rate of systemic absorption from a particular injection site.

The dosages in

Table are recommended as a guide for use in the average adult.

These doses may be repeated once every three hours.

Do not exceed a total daily dosage of 400 mg in 24 hours.

The duration of anesthetic effect may be prolonged by the addition of epinephrine.

Table 3.

Recommended Concentrations and Doses of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection in Adults Type of Block Concentration of Bupivacaine Hydrochloride Injection Each Dose Motor Block With continuous (intermittent) techniques, repeat doses increase the degree of motor block.

The first repeat dose of 0.5% (5 mg/mL) may produce complete motor block.

Intercostal nerve block with 0.25% (2.5 mg/mL) also may produce complete motor block for intra-thoracic and upper intra-abdominal surgery. mL mg of Bupivacaine Hydrochloride Injection Local infiltration 0.25% (2.5 mg/mL) Solutions with or without epinephrine (i.e., applies to Bupivacaine Hydrochloride Injection and Bupivacaine Hydrochloride and Epinephrine Injection).

Injection products include epinephrine (1:200,000).

Up to 70 (without epinephrine) Up to 175 (without epinephrine) ― Up to 90 (with epinephrine) Up to 225 (with epinephrine) Peripheral nerve block 0.5% (5 mg/mL) 5–35 (without epinephrine) 25–175 (without epinephrine) moderate to complete 5–45 (with epinephrine) 25–225 (with epinephrine) 0.25% (2.5 mg/mL) 5–70 (without epinephrine) 12.5–175 (without epinephrine) moderate to complete 5–90 (with epinephrine) 12.5–225 (with epinephrine) Retrobulbar block 0.75% (7.5 mg/mL) 2–4 15–30 complete Sympathetic block 0.25% (2.5 mg/mL) 20–50 50–125 ― Caudal block 0.5% (5 mg/mL) 15–30 75–150 moderate to complete 0.25% (2.5 mg/mL) 15–30 37.5–75 moderate Lumbar epidural block 0.75% (7.5 mg/mL) For single-dose use; not for intermittent epidural technique.

Not for obstetrical anesthesia. 10–20 75–150 complete 0.5% (5 mg/mL) 10–20 50–100 moderate to complete 0.25% (2.5 mg/mL) 10–20 25–50 partial to moderate Epidural test dose 0.5% (5 mg/mL) with epinephrine 2–3 10–15 (10–15 micrograms epinephrine) ― Dental 0.5% (5 mg/mL) with epinephrine 1.8–3.6 per site 9–18 per site ― 2.3 Use in Epidural Anesthesia During the administration of epidural anesthesia, it is recommended that a test dose of Bupivacaine Hydrochloride and Epinephrine Injection without antimicrobial preservative (0.5% bupivacaine with 1:200,000 epinephrine) be administered initially and the effects monitored before the full dose is given.

When using a "continuous" catheter technique, test doses should be given prior to both the initial and all supplemental doses, because a catheter in the epidural space can migrate into a blood vessel or through the dura.

During epidural administration, administer Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection, 0.5% (5 mg/mL) and Bupivacaine Hydrochloride Injection 0.75% (7.5 mg/mL) solutions in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection.

Administer injections slowly, with frequent aspirations before and during the injection to avoid intravascular injection.

Perform syringe aspirations before and during each supplemental injection in continu.

Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F).

Injection, USP ─ Solutions of bupivacaine hydrochloride that do not contain epinephrine may be autoclaved.

Autoclave at 15-pound pressure, 121 °C (250 °F) for 15 minutes.

This product is clear and colorless.

Do not use the solution if it is discolored or if it contains a precipitate.

NDC 0409-1159-01 Tray of 25 single-dose teartop vials 0.25% 25 mg/10 mL (2.5 mg/mL) NDC 0409-1159-02 Tray of 25 single-dose teartop vials 0.25% 75 mg/30 mL (2.5 mg/mL) NDC 0409-1160-01 Tray of 25 multiple-dose fliptop vials 0.25% 125 mg/50 mL (2.5 mg/mL) NDC 0409-1163-01 Tray of 25 multiple-dose fliptop vials 0.5% 250 mg/50 mL (5 mg/mL) NDC 0409-1162-01 Tray of 25 single-dose teartop vials 0.5% 50 mg/10 mL (5 mg/mL) NDC 0409-1162-02 Tray of 25 single-dose teartop vials 0.5% 150 mg/30 mL (5 mg/mL) NDC 0409-1165-01 Tray of 25 single-dose teartop vials 0.75% 75 mg/10 mL (7.5 mg/mL) NDC 0409-1165-02 Tray of 25 single-dose teartop vials 0.75% 225 mg/30 mL (7.5 mg/mL) For single-dose vials: Discard unused portion.

Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F).

Injection/Bupivacaine Hydrochloride and Epinephrine Injection is contraindicated for obstetrical paracervical block anesthesia.

Its use in this technique has resulted in fetal bradycardia and death.

There are no available data on use of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection in pregnant women to inform a drug-associated risk of adverse developmental outcomes.

In animal studies, embryo-fetal lethality was noted when bupivacaine was administered subcutaneously to pregnant rabbits during organogenesis at clinically relevant doses.

Decreased pup survival was observed in a rat pre.

• and post-natal developmental study (dosing from implantation through weaning) at a dose level comparable to the daily maximum recommended human dose (MRHD) on a body surface area (BSA) basis.

Based on animal data, advise pregnant women of the potential risks to a fetus.

Local anesthetics rapidly cross the placenta, and when used for epidural, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity.

The incidence and degree of toxicity depend upon the procedure performed, the type, and amount of drug used, and the technique of drug administration.

Adverse reactions in the parturient, fetus, and neonate involve alterations of the CNS, peripheral vascular tone, and cardiac function.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Clinical Considerations Maternal Adverse Reactions

Maternal hypotension has resulted from regional anesthesia.

Local anesthetics produce vasodilation by blocking sympathetic nerves.

The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus.

Therefore, during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels be accomplished.

Elevating the patient's legs will also help prevent decreases in blood pressure.

The fetal heart rate also should be monitored continuously and electronic fetal monitoring is highly advisable.

Epidural, caudal, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts.

Epidural anesthesia has been reported to prolong the second stage of labor by removing the parturient's reflex urge to bear down or by interfering with motor function.

The use of obstetrical anesthesia may increase the need for forceps assistance.

The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life.

This has not been reported with bupivacaine.

It is extremely important to avoid aortocaval compression by the gravid uterus during administration of regional block to parturients.

To do this, the patient must be maintained in the left lateral decubitus position or a blanket roll or sandbag may be placed beneath the right hip and gravid uterus displaced to the left.

Bupivacaine hydrochloride produced developmental toxicity when administered subcutaneously to pregnant rats and rabbits at clinically relevant doses.

Bupivacaine hydrochloride was administered subcutaneously to rats at doses of 4.4, 13.3, & 40 mg/kg and to rabbits at doses of 1.3, 5.8, & 22.2 mg/kg during the period of organogenesis (implantation to closure of the hard palate).

The high doses are comparable to the daily MRHD of 400 mg/day on a mg/m 2 BSA basis.

No embryo-fetal effects were observed in rats at the high dose which caused increased maternal lethality.

An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity with the fetal No Observed Adverse Effect Level representing approximately 0.3 times the MRHD on a BSA basis.

In a rat pre-and post-natal developmental study (dosing from implantation through weaning) conducted at subcutaneous doses of 4.4, 13.3, & 40 mg/kg, decreased pup survival was observed at the high dose.

The high dose is comparable to the daily MRHD of 400 mg/day on a BSA basis.

Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects.

Because of the potential for serious adverse reactions in nursing infants from corticosteroids, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Injection/Bupivacaine Hydrochloride and Epinephrine Injection is approved for use in adults.

Injection/Bupivacaine Hydrochloride and Epinephrine Injection in pediatric patients younger than 12 years is not recommended.

Continuous infusions of bupivacaine in pediatric patients have been reported to result in high systemic levels of bupivacaine and seizures; high plasma levels may also be associated with cardiovascular abnormalities.

Patients 65 years and over, particularly those with hypertension, may be at increased risk for developing hypotension while undergoing anesthesia with Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection.

In clinical studies of bupivacaine, elderly patients reached the maximal spread of analgesia and maximal motor blockade more rapidly than younger adult patients.

Differences in various pharmacokinetic parameters have been observed between elderly and younger adult patients.

This product is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Elderly patients may require lower doses of Bupivacaine Hydrochloride Injection/Bupivacaine Hydrochloride and Epinephrine Injection.