DRUGS & SUPPLEMENTS

Bupivacaine

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Bupivacaine uses


Indications and Usage (1) (12/2015)
Dosage and Administration (2) (12/2015)
Dosage and Administration, Injection Instructions (2.1) (12/2015)
Dosage and Administration, Compatibility Considerations (2.2) (12/2015)
Warnings and Precautions,

Warnings and Precautions Specific to Bupivacaine (5.2)

(12/2015)

Bupivacaine is indicated for administration into the surgical site to produce postsurgical analgesia.

Bupivacaine has not been studied for use in patients younger than 18 years of age.

Bupivacaine is a liposome injection of Bupivacaine, an amide local anesthetic, indicated for single-dose infiltration into the surgical site to produce postsurgical analgesia (1).

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2. DOSAGE AND ADMINISTRATION

Bupivacaine is intended for single-dose administration only.

The recommended dose of Bupivacaine is based on the following factors:

  • Size of the surgical site
  • Volume required to cover the area
  • Individual patient factors that may impact the safety of an amide local anesthetic
  • Maximum dose of 266 mg

As general guidance in selecting the proper dosing for the planned surgical site, two examples of dosing are provided. One example of the recommended dose comes from a study in patients undergoing bunionectomy. A total of 8 mL (106 mg) was administered as 7 mL of Bupivacaine infiltrated into the tissues surrounding the osteotomy, and 1 mL infiltrated into the subcutaneous tissue.

Another example comes from a study of patients undergoing hemorrhoidectomy. A total of 20 mL (266 mg) of Bupivacaine was diluted with 10 mL of saline, for a total of 30 mL, divided into six 5 mL aliquots, injected by visualizing the anal sphincter as a clock face and slowly infiltrating one aliquot to each of the even numbers to produce a field block.

Bupivacaine is intended for single-dose administration only.

The recommended dose of Bupivacaine is based on the following factors:

  • Size of the surgical site
  • Volume required to cover the area
  • Individual patient factors that may impact the safety of an amide local anesthetic
  • Maximum dose of 266 mg (20 mL)

Inject Bupivacaine slowly into soft tissue via infiltration (2.1).

2.1 Injection Instructions

Bupivacaine should be injected slowly into soft tissues of the surgical site with frequent aspiration to check for blood and minimize the risk of intravascular injection.

  • Bupivacaine is intended for single-dose administration only.
  • Different formulations of Bupivacaine are not bioequivalent even if the milligram strength is the same. Therefore, it is not possible to convert dosing from any other formulations of Bupivacaine to Bupivacaine.
  • Bupivacaine should be administered with a 25 gauge or larger bore needle.
  • The maximum dosage of Bupivacaine should not exceed 266 mg (20 mL, 1.3% of undiluted drug).
  • Bupivacaine can be administered undiluted or diluted to increase volume up to a final concentration of 0.89 mg/mL (i.e. 1:14 dilution by volume) with normal (0.9%) saline or lactated Ringer’s solution.
  • Vials of Bupivacaine should be inverted multiple times to re-suspend the particles immediately prior to withdrawal from the vial
  • Diluted suspensions of Bupivacaine should be used within 4 hours of preparation in a syringe.
  • Do not administer Bupivacaine if the product is discolored.
  • Do not administer Bupivacaine if it is suspected that the vial has been frozen or exposed to high temperature (greater than 40°C or 104°F) for an extended period.

2.2 Compatibility Considerations

Some physicochemical incompatibilities exist between Bupivacaine and certain other drugs. Direct contact of Bupivacaine with these drugs results in a rapid increase in free Bupivacaine, altering Bupivacaine characteristics and potentially affecting the safety and efficacy of Bupivacaine. Therefore, admixing Bupivacaine with other drugs prior to administration is not recommended [See Drug Interactions (7)].

  • Non-bupivacaine based local anesthetics, including lidocaine, may cause an immediate release of Bupivacaine from Bupivacaine if administered together locally. The administration of Bupivacaine may follow the administration of lidocaine after a delay of 20 minutes or more.
  • Bupivacaine HCl administered together with Bupivacaine may impact the pharmacokinetic and/or physicochemical properties of Bupivacaine, and this effect is concentration dependent. Therefore, Bupivacaine HCl and Bupivacaine may be administered simultaneously in the same syringe, and Bupivacaine HCl may be injected immediately before Bupivacaine as long as the ratio of the milligram dose of Bupivacaine HCl solution to Bupivacaine does not exceed 1:2.

    The toxic effects of these drugs are additive and their administration should be used with caution including monitoring for neurologic and cardiovascular effects related to toxicity [See Warnings and Precautions (5.1) and Overdosage (10)].

  • When a topical antiseptic such as povidone iodine (e.g., Betadine®) is applied, the site should be allowed to dry before Bupivacaine is administered into the surgical site. Bupivacaine should not be allowed to come into contact with antiseptics such as povidone iodine in solution.

Studies conducted with Bupivacaine demonstrated that the most common implantable materials (polypropylene, PTFE, silicone, stainless steel, and titanium) are not affected by the presence of Bupivacaine any more than they are by saline. None of the materials studied had an adverse effect on Bupivacaine.

When administered in recommended doses and concentrations, Bupivacaine HCl does not ordinarily produce irritation or tissue damage and does not cause methemoglobinemia.

2.3 Non-Interchangeability with Other Formulations of Bupivacaine

Different formulations of Bupivacaine are not bioequivalent even if the milligram dosage is the same. Therefore, it is not possible to convert dosing from any other formulations of Bupivacaine to Bupivacaine and vice versa.

Liposomal encapsulation or incorporation in a lipid complex can substantially affect a drug's functional properties relative to those of the unencapsulated or nonlipid-associated drug. In addition, different liposomal or lipid-complexed products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect functional properties of these drug products. Do not substitute.

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3. DOSAGE FORMS AND STRENGTHS

Bupivacaine (bupivacaine liposome injectable suspension)

  • 20 mL single use vial, 1.3% (13.3 mg/mL)
  • 10 mL single use vial, 1.3% (13.3 mg/mL)

Bupivacaine (bupivacaine liposome injectable suspension)

20 mL single use vial, 1.3% (13.3 mg/mL) (3)

10 mL single use vial, 1.3% (13.3 mg/mL) (3)

4. CONTRAINDICATIONS

Bupivacaine is contraindicated in obstetrical paracervical block anesthesia. While Bupivacaine has not been tested with this technique, the use of Bupivacaine HCl with this technique has resulted in fetal bradycardia and death.

Bupivacaine is contraindicated in obstetrical paracervical block anesthesia (4).

5. WARNINGS AND PRECAUTIONS

  • Monitoring of cardiovascular and neurological status, as well as vital signs should be performed during and after injection of Bupivacaine as with other local anesthetic products.
  • Because amide-type local anesthetics, such as Bupivacaine, are metabolized by the liver, Bupivacaine should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations (5.1).
  • Other formulations of Bupivacaine should not be administered within 96 hours following administration of Bupivacaine (5.2).

5.1 Warnings and Precautions for Bupivacaine Containing Products

The safety and effectiveness of Bupivacaine and other amide-containing products depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. As there is a potential risk of severe life-threatening adverse effects associated with the administration of Bupivacaine, any bupivacaine-containing product should be administered in a setting where trained personnel and equipment are available to promptly treat patients who show evidence of neurological or cardiac toxicity [See Overdosage (10)].

Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient's state of consciousness should be performed after injection of Bupivacaine and other amide-containing products. Restlessness, anxiety, incoherent speech, lightheadedness, numbness and tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, tremors, twitching, depression, or drowsiness may be early warning signs of central nervous system toxicity.

Bupivacaine and other amide-containing products should also be used with caution in patients with impaired cardiovascular function because they may be less able to compensate for functional changes associated with the prolongation of AV conduction produced by these drugs.

Injection of multiple doses of Bupivacaine and other amide-containing products may cause significant increases in plasma concentrations with each repeated dose due to slow accumulation of the drug or its metabolites, or to slow metabolic degradation. Tolerance to elevated blood concentrations varies with the status of the patient.

Because amide-type local anesthetics, such as Bupivacaine, are metabolized by the liver, these drugs should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations.

Central Nervous System Reactions

The incidences of adverse neurologic reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Many of these effects may be related to local anesthetic techniques, with or without a contribution from the drug. Neurologic effects following infiltration of soft tissue may include persistent anesthesia, paresthesias, weakness, and paralysis, all of which may have slow, incomplete, or no recovery.

Central nervous system reactions are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision, or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils. The incidence of convulsions associated with the use of local anesthetics varies with the procedure used and the total dose administered.

Cardiovascular System Reactions

Toxic blood concentrations depress cardiac conductivity 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 [See Warnings and Precautions (5.1) and Overdosage (10)].

Allergic Reactions

Allergic-type reactions are rare and may occur as a result of hypersensitivity to the local anesthetic or to other formulation ingredients. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly anaphylactoid-like symptoms (including severe hypotension). Cross-sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitively established.

Chondrolysis

Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been postmarketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humerol chondrolysis have been described in pediatric patients and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness, and loss of motion can be variable, but may begin as early as the second month after surgery. Currently, there is no effective treatment for chondrolysis; patients who have experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement.

5.2 Warnings and Precautions Specific for Bupivacaine

As there is a potential risk of severe life-threatening adverse effects associated with the administration of Bupivacaine, Bupivacaine should be administered in a setting where trained personnel and equipment are available to promptly treat patients who show evidence of neurological or cardiac toxicity [See Overdosage (10)].

Caution should be taken to avoid accidental intravascular injection of Bupivacaine. Convulsions and cardiac arrest have occurred following accidental intravascular injection of Bupivacaine and other amide-containing products.

Using Bupivacaine followed by other Bupivacaine formulations has not been studied in clinical trials. Formulations of Bupivacaine other than Bupivacaine should not be administered within 96 hours following administration of Bupivacaine [See Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Bupivacaine has not been evaluated for the following uses and, therefore, is not recommended for these types of analgesia or routes of administration.

  • epidural
  • intrathecal
  • regional nerve blocks
  • intravascular or intra-articular use

Bupivacaine has not been evaluated for use in the following patient population and, therefore, it is not recommended for administration to these groups.

  • patients younger than 18 years old
  • pregnant patients

The ability of Bupivacaine to achieve effective anesthesia has not been studied. Therefore, Bupivacaine is not indicated for pre-incisional or pre-procedural loco-regional anesthetic techniques that require deep and complete sensory block in the area of administration.

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6. ADVERSE REACTIONS

Adverse reactions reported with an incidence greater than or equal to 10% following Bupivacaine administration were nausea, constipation, and vomiting.

To report SUSPECTED ADVERSE REACTIONS, contact Pacira Pharmaceuticals, Inc. at 1-855-RX-EXPAREL (1-855-793-9727) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Bupivacaine Adverse Reactions

The most commonly encountered acute adverse experiences to Bupivacaine and all amide-type local anesthetics that demand immediate counter-measures are related to the central nervous and cardiovascular systems.

High plasma concentrations of Bupivacaine can occur from overdosage, unintended intravascular injection, or accumulation of Bupivacaine in plasma secondary to decreased hepatic metabolic degradation of the drug or diminished plasma protein binding capacity due to acidosis, pathologically lowered plasma protein production, or competition with other drugs for protein binding sites. Although rare, some individuals have a lower tolerance to and are supersensitive to Bupivacaine and other amide-type local anesthetics and may rapidly develop signs of toxicity at low doses [See Overdosage (10)].

6.2 Clinical Trial Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The safety of Bupivacaine was evaluated in 10 randomized, double-blind, local administration into the surgical site clinical studies involving 823 patients undergoing various surgical procedures. Patients were administered a dose ranging from 66 to 532 mg of Bupivacaine. In these studies, the most common adverse reactions (incidence greater than or equal to 10%) following Bupivacaine administration were nausea, constipation, and vomiting.

The common adverse reactions (incidence greater than or equal to 2% to less than 10%) following Bupivacaine administration were pyrexia, dizziness, edema peripheral, anemia, hypotension, pruritus, tachycardia, headache, insomnia, anemia postoperative, muscle spasms, hemorrhagic anemia, back pain, somnolence, and procedural pain.

The less common/rare adverse reactions (incidence less than 2%) following Bupivacaine administration were chills, erythema, bradycardia, anxiety, urinary retention, pain, edema, tremor, dizziness postural, paresthesia, syncope, incision site edema, procedural hypertension, procedural hypotension, procedural nausea, muscular weakness, neck pain, pruritus generalized, rash pruritic, hyperhidrosis, cold sweat, urticaria, bradycardia, palpitations, sinus bradycardia, supraventricular extrasystoles, ventricular extrasystoles, ventricular tachycardia, hypertension, pallor, anxiety, confusional state, depression, agitation, restlessness, hypoxia, laryngospasm, apnea, respiratory depression, respiratory failure, body temperature increased, blood pressure increased, blood pressure decreased, oxygen saturation decreased, urinary incontinence, vision blurred, tinnitus, drug hypersensitivity, and hypersensitivity.

Neurological and Cardiac Adverse Reactions

In the Bupivacaine surgical site infiltration studies, adverse reactions with an incidence greater than or equal to 1% in the Nervous System Disorders system organ class following Bupivacaine administration were dizziness (6.2%), headache (3.8%), somnolence (2.1%), hypoesthesia (1.5%), and lethargy (1.3%). The adverse reactions with an incidence greater than or equal to 1% in the Cardiac Disorders system organ class following Bupivacaine administration were tachycardia (3.9%) and bradycardia (1.6%).

Adverse Reactions Reported in Placebo-Controlled Trials

Adverse reactions with an incidence greater than or equal to 2% reported by patients in clinical studies comparing 8 mL Bupivacaine 1.3% (106 mg) to placebo and 20 mL Bupivacaine 1.3% (266 mg) to placebo are shown in Table 1.

a Study 1: Bunionectomy
b Study 2: Hemorrhoidectomy
At each level of summation (overall, system organ class, preferred term), patients are only counted once.

Preferred terms are included where at least 2% of patients reported the event in any treatment group.

TEAE = treatment-emergent adverse event.

STUDY 1a STUDY 2b
Bupivacaine Placebo Bupivacaine Placebo
System Organ Class

Preferred Term

8 mL/1.3% (106 mg)

(N=97)

n (%)

(N=96)

n (%)

20 mL/1.3% (266 mg)

(N=95)

n (%)

(N=94)

n (%)

Any TEAE 53 (54.6) 59 (61.5) 10 (10.5) 17 (18.1)
Gastrointestinal Disorders 41 (42.3) 38 (39.6) 7 (7.4) 13 (13.8)
Nausea 39 (40.2) 36 (37.5) 2 (2.1) 1 (1.1)
Vomiting 27 (27.8) 17 (17.7) 2 (2.1) 4 (4.3)
Constipation 2 (2.1) 1 (1.0) 2 (2.1) 2 (2.1)
Anal Hemorrhage 0 (0.0) 0 (0.0) 3 (3.2) 4 (4.3)
Painful Defecation 0 (0.0) 0 (0.0) 2 (2.1) 5 (5.3)
Rectal Discharge 0 (0.0) 0 (0.0) 1 (1.1) 3 (3.2)
Nervous System Disorders 20 (20.6) 30 (31.3) 0 (0.0) 0 (0.0)
Dizziness 11 (11.3) 25 (26.0) 0 (0.0) 0 (0.0)
Headache 5 (5.2) 8 (8.3) 0 (0.0) 0 (0.0)
Somnolence 5 (5.2) 1 (1.0) 0 (0.0) 0 (0.0)
Syncope 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0)
Skin And Subcutaneous Tissue Disorders 8 (8.2) 7 (7.3) 0 (0.0) 0 (0.0)
Pruritus Generalized 5 (5.2) 6 (6.3) 0 (0.0) 0 (0.0)
Pruritus 3 (3.1) 1 (1.0) 0 (0.0) 0 (0.0)
Investigations 5 (5.2) 3 (3.1) 4 (4.2) 3 (3.2)
Alanine Aminotransferase Increased 3 (3.1) 3 (3.1) 1 (1.1) 0 (0.0)
Aspartate Aminotransferase Increased 3 (3.1) 2 (2.1) 0 (0.0) 0 (0.0)
Blood Creatinine Increased 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0)
Body Temperature Increased 0 (0.0) 0 (0.0) 3 (3.2) 3 (3.2)
General Disorders And Administration Site Conditions 4 (4.1) 0 (0.0) 1 (1.1) 1 (1.1)
Feeling Hot 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0)
Pyrexia 2 (2.1) 0 (0.0) 1 (1.1) 1 (1.1)
Infections And Infestations 2 (2.1) 1 (1.0) 0 (0.0) 0 (0.0)
Fungal Infection 2 (2.1) 1 (1.0) 0 (0.0) 0 (0.0)
Injury, Poisoning And Procedural Complications 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0)
Post Procedural Swelling 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0)
Metabolism And Nutrition Disorders 2 (2.1) 2 (2.1) 0 (0.0) 0 (0.0)
Decreased Appetite 2 (2.1) 2 (2.1) 0 (0.0) 0 (0.0)
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7. DRUG INTERACTIONS

Bupivacaine can be administered in the ready to use suspension or diluted to a concentration of up to 0.89 mg/mL (i.e., 1:14 dilution by volume) with normal (0.9%) saline or lactated Ringer’s solution. Bupivacaine must not be diluted with water or other hypotonic agents as it will result in disruption of the liposomal particles.

Bupivacaine should not be admixed with local anesthetics other than Bupivacaine. Non-bupivacaine based local anesthetics, including lidocaine, may cause an immediate release of Bupivacaine from Bupivacaine if administered together locally. The administration of Bupivacaine may follow the administration of lidocaine after a delay of 20 minutes or more.

Bupivacaine HCl administered together with Bupivacaine may impact the pharmacokinetic and/or physicochemical properties of Bupivacaine, and this effect is concentration dependent. Therefore, Bupivacaine HCl and Bupivacaine may be administered simultaneously in the same syringe, and Bupivacaine HCl may be injected immediately before Bupivacaine as long as the ratio of the milligram dose of Bupivacaine HCl solution to Bupivacaine does not exceed 1:2.

The toxic effects of these drugs are additive and their administration should be used with caution including monitoring for neurologic and cardiovascular effects related to toxicity [See Dosage and Administration (2.2), Warnings and Precautions (5.1) and Overdosage (10)].

Other than Bupivacaine as noted above, Bupivacaine should not be admixed with other drugs prior to administration.

  • Bupivacaine should not be admixed with lidocaine or other non-bupivacaine-based local anesthetics.
  • Bupivacaine may be administered after at least 20 minutes or more have elapsed following local administration of lidocaine.
  • Bupivacaine HCl, when injected immediately before or admixed with Bupivacaine, may impact the pharmacokinetic and/or physicochemical properties of the drugs (7).

8. USE IN SPECIFIC POPULATIONS

  • Pregnancy: Based on animal data, may cause fetal harm.
  • Pediatric Use: Safety and effectiveness in pediatric patients below the age of 18 have not been established (8.4).

8.1 Pregnancy

Risk Summary

There are no studies conducted with Bupivacaine in pregnant women. In animal reproduction studies, embryo-fetal deaths were observed with subcutaneous administration of Bupivacaine to rabbits during organogenesis at a dose equivalent to 1.6 times the maximum recommended human dose (MRHD) of 266 mg. Subcutaneous administration of Bupivacaine to rats from implantation through weaning produced decreased pup survival at a dose equivalent to 1.5 times the MRHD [see Data]. Based on animal data, advise pregnant women of the potential risks to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Clinical Considerations

Labor or Delivery

Bupivacaine is contraindicated for obstetrical paracervical block anesthesia. While Bupivacaine has not been studied with this technique, the use of Bupivacaine for obstetrical paracervical block anesthesia has resulted in fetal bradycardia and death.

Bupivacaine can rapidly cross the placenta, and when used for epidural, caudal, or pudendal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity [See Clinical Pharmacology (12.3)]. 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 central nervous system, peripheral vascular tone, and cardiac function.

Data

Animal Data

Bupivacaine hydrochloride was administered subcutaneously to rats and rabbits during the period of organogenesis (implantation to closure of the hard plate). Rat doses were 4.4, 13.3, and 40 mg/kg/day (equivalent to 0.2, 0.5 and 1.5 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight) and rabbit doses were 1.3, 5.8, and 22.2 mg/kg/day (equivalent to 0.1, 0.4 and 1.6 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight). No embryo-fetal effects were observed in rats at the doses tested with the high dose causing increased maternal lethality. An increase in embryo-fetal deaths was observed in rabbits at the high dose in the absence of maternal toxicity.

Decreased pup survival was noted at 1.5 times the MRHD in a rat pre- and post-natal development study when pregnant animals were administered subcutaneous doses of 4.4, 13.3, and 40 mg/kg/day buprenorphine hydrochloride (equivalent to 0.2, 0.5 and 1.5 times the MRHD, respectively, based on the BSA comparisons and a 60 kg human weight) from implantation through weaning (during pregnancy and lactation).

8.2 Lactation

Risk Summary

Limited published literature reports that Bupivacaine and its’ metabolite, pipecolylxylidide, are present in human milk at low levels. There is no available information on effects of the drug in the breastfed infant or effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Bupivacaine and any potential adverse effects on the breastfed infant from Bupivacaine or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of patients in the Bupivacaine surgical site infiltration clinical studies, 171 patients were greater than or equal to 65 years of age and 47 patients were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients. Clinical experience with Bupivacaine has not identified differences in efficacy or safety between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

In clinical studies, differences in various pharmacokinetic parameters have been observed between elderly and younger patients. Bupivacaine is known to be substantially excreted by the kidney, and the risk of toxic reactions to Bupivacaine 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 of Bupivacaine.

8.6 Hepatic Impairment

Because amide-type local anesthetics, such as Bupivacaine, are metabolized by the liver, these drugs should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations.

8.7 Renal Impairment

Bupivacaine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Care should be taken in dose selection of Bupivacaine.

10. OVERDOSAGE

Acute emergencies from local anesthetics are generally related to high plasma concentrations encountered during therapeutic use of local anesthetics or to unintended intravascular injection of local anesthetic solution [See Warnings and Precautions (5) and Adverse Reactions (6)].

In the clinical study program, maximum plasma concentration (Cmax) values of approximately 34,000 ng/mL were reported and likely reflected inadvertent intravascular administration of Bupivacaine or systemic absorption of Bupivacaine at the surgical site. The plasma Bupivacaine measurements did not discern between free and liposomal-bound Bupivacaine making the clinical relevance of the reported values uncertain; however, no discernible adverse events or clinical sequelae were observed in these patients.

11. DESCRIPTION

Bupivacaine is a sterile, non-pyrogenic white to off-white preservative-free aqueous suspension of multivesicular liposomes containing Bupivacaine. Bupivacaine is present at a concentration of 13.3 mg/mL. After injection of Bupivacaine into soft tissue, Bupivacaine is released from the multivesicular liposomes over a period of time.

11.1 Active Ingredient

Bupivacaine is related chemically and pharmacologically to the amide-type local anesthetics. It is a homologue of mepivacaine and is related chemically to lidocaine. All three of these anesthetics contain an amide linkage between the aromatic nucleus and the amino, or piperidine group. They differ in this respect from the procaine-type local anesthetics, which have an ester linkage. Chemically, Bupivacaine is 1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide with a molecular weight of 288.4. Bupivacaine has the following structural formula:

11.2 Lipid Formulation

The median diameter of the liposome particles ranges from 24 to 31 µm. The liposomes are suspended in a 0.9% sodium chloride solution. Each vial contains Bupivacaine at a nominal concentration of 13.3 mg/mL. Inactive ingredients and their nominal concentrations are: cholesterol, 4.7 mg/mL; 1, 2-dipalmitoyl-sn-glycero-3 phospho-rac-(1-glycerol) (DPPG), 0.9 mg/mL; tricaprylin, 2.0 mg/mL; and 1, 2-dierucoylphosphatidylcholine (DEPC), 8.2 mg/mL. The pH of Bupivacaine is in the range of 5.8 to 7.4.

Liposomal encapsulation or incorporation in a lipid complex can substantially affect a drug's functional properties relative to those of the unencapsulated or nonlipid-associated drug. In addition, different liposomal or lipid-complexed products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect functional properties of these drug products. Do not substitute.

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Local anesthetics block 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, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone.

12.2 Pharmacodynamics

Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. 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 conductivity 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. Clinical reports and animal research suggest that these cardiovascular changes are more likely to occur after accidental intravascular injection of Bupivacaine.

Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation is manifested as restlessness, tremors, and shivering progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited state.

12.3 Pharmacokinetics

Local infiltration of Bupivacaine results in significant systemic plasma levels of Bupivacaine which can persist for 96 hours [See Warnings and Precautions (5.2)]. Systemic plasma levels of Bupivacaine following administration of Bupivacaine are not correlated with local efficacy.

Absorption

The rate of systemic absorption of Bupivacaine is dependent upon the total dose of drug administered, the route of administration, and the vascularity of the administration site.

Pharmacokinetic parameters of Bupivacaine after local administration were evaluated following surgical procedures. Descriptive statistics of pharmacokinetic parameters of representative Bupivacaine doses in each study are provided in Table 2.

Note: Arithmetic mean (standard deviation) except Tmax where it is median (range).
Surgical Site Administration
Bunionectomy

106 mg (8 mL)

Hemorrhoidectomy

266 mg (20 mL)

(N=26) (N=25)
Cmax (ng/mL) 166 (92.7) 867 (353)
Tmax (h) 2 (0.5-24) 0.5 (0.25-36)
AUC(0-t) (h×ng/mL) 5864 (2038) 16,867 (7868)
AUC(inf) (h×ng/mL) 7105 (2283) 18,289 (7569)
t½ (h) 34 (17) 24 (39)

Distribution

After Bupivacaine has been released from Bupivacaine and is absorbed systemically, Bupivacaine distribution is expected to be the same as for any Bupivacaine HCl solution formulation.

Local anesthetics including Bupivacaine are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain.

Local anesthetics including Bupivacaine appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. Fetal/maternal ratios of local anesthetics 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, non-ionized drugs such as Bupivacaine readily enter the fetal blood from the maternal circulation.

Metabolism

Amide-type local anesthetics, such as Bupivacaine, are metabolized primarily in the liver via conjugation with glucuronic acid. Pipecolylxylidine (PPX) is the major metabolite of Bupivacaine; approximately 5% of Bupivacaine is converted to PPX. Elimination of drug depends largely upon the availability of plasma protein binding sites in the circulation to carry it to the liver where it is metabolized.

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.

Excretion

After Bupivacaine has been released from Bupivacaine and is absorbed systemically, Bupivacaine excretion is expected to be the same as for other Bupivacaine formulations.

The kidney is the main excretory organ for most local anesthetics and their metabolites. Only 6% of Bupivacaine is excreted unchanged in the urine.

Urinary excretion is affected by urinary perfusion and factors affecting urinary pH. Acidifying the urine hastens the renal elimination of 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.

Specific Populations

Hepatic Impairment

The effects of decreased hepatic function on Bupivacaine pharmacokinetics following administration of Bupivacaine were studied in patients with moderate hepatic impairment. Consistent with the hepatic clearance of Bupivacaine, mean plasma concentrations were higher in patients with moderate hepatic impairment than in the healthy control volunteers with approximately 1.5- and 1.6-fold increases in the mean values for Cmax and the area under the curve (AUC), respectively.

Because amide-type local anesthetics, such as Bupivacaine, are metabolized by the liver, these drugs should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at a greater risk of developing toxic plasma concentrations [See Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

Renal Impairment

Bupivacaine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Care should be taken in dose selection of Bupivacaine [See Use in Specific Populations (8.7)].

Age

Various pharmacokinetic parameters of the local anesthetics such as Bupivacaine can be significantly altered by the age of the patient.

In clinical studies, differences in various pharmacokinetic parameters have been observed between elderly and younger patients.

Bupivacaine is known to be substantially excreted by the kidney, and the risk of toxic 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 of Bupivacaine [See Use in Specific Populations (8.5)].

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis. Long-term studies in animals to evaluate the carcinogenic potential of Bupivacaine have not been conducted.

Mutagenesis. The mutagenic potential of Bupivacaine has not been determined.

Impairment of Fertility. The effect of Bupivacaine on fertility has not been determined.

14. CLINICAL STUDIES

The efficacy of Bupivacaine was compared to placebo in two multicenter, randomized, double-blinded clinical trials. One trial evaluated the treatments in patients undergoing bunionectomy; the other trial evaluated the treatments in patients undergoing hemorrhoidectomy.

14.1 Study 1

A multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial evaluated the safety and efficacy of 106 mg Bupivacaine in 193 patients undergoing bunionectomy. The mean age was 43 years (range 18 to 72).

Study medication was administered directly into the site at the conclusion of the surgery, prior to closure. There was an infiltration of 7 mL of Bupivacaine into the tissues surrounding the osteotomy and 1 mL into the subcutaneous tissue.

Pain intensity was rated by the patients on a 0 to 10 numeric rating scale (NRS) out to 72 hours. Postoperatively, patients were allowed rescue medication (5 mg oxycodone/325 mg acetaminophen orally every 4 to 6 hours as needed) or, if that was insufficient within the first 24 hours, ketorolac (15 to 30 mg IV). The primary outcome measure was the area under the curve (AUC) of the NRS pain intensity scores (cumulative pain scores) collected over the first 24 hour period. There was a significant treatment effect for Bupivacaine compared to placebo. Bupivacaine demonstrated a significant reduction in pain intensity compared to placebo for up to 24 hours (p<0.001).

14.2 Study 2

A multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial evaluated the safety and efficacy of 266 mg (20 mL) Bupivacaine in 189 patients undergoing hemorrhoidectomy. The mean age was 48 years (range 18 to 86).

Study medication was administered directly into the site (greater than or equal to 3 cm) at the conclusion of the surgery. Dilution of 20 mL of Bupivacaine with 10 mL of saline, for a total of 30 mL, was divided into six 5 mL aliquots. A field block was performed by visualizing the anal sphincter as a clock face and slowly infiltrating one aliquot to each of the even numbers.

Pain intensity was rated by the patients on a 0 to 10 NRS at multiple time points up to 72 hours. Postoperatively, patients were allowed rescue medication (morphine sulfate 10 mg intramuscular every 4 hours as needed).

The primary outcome measure was the AUC of the NRS pain intensity scores (cumulative pain scores) collected over the first 72 hour period.

There was a significant treatment effect for Bupivacaine compared to placebo. See Figure 1 for the mean pain intensity over time for the Bupivacaine and placebo treatment groups for the 72-hour efficacy period.

Figure 1. Mean Pain Intensity versus Time plot for hemorrhoidectomy study (C-316)

This resulted in a decrease in opioid consumption, the clinical benefit of which was not demonstrated.

Twenty-eight percent of patients treated with Bupivacaine required no rescue medication at 72 hours compared to 10% treated with placebo. For those patients who did require rescue medication, the mean amount of morphine sulfate intramuscular injections used over 72 hours was 22 mg for patients treated with Bupivacaine and 29 mg for patients treated with placebo.

The median time to rescue analgesic use was for 15 hours for patients treated with Bupivacaine and one hour for patients treated with placebo.

16. HOW SUPPLIED/STORAGE AND HANDLING

Bupivacaine (bupivacaine liposome injectable suspension) is available in single-use vials for infiltration.

20 mL single use vial, 1.3% (13.3 mg/mL) (NDC 65250-266-20) packaged in cartons of 10 (NDC 65250-266-09) and cartons of 4 (NDC 65250-266-04)

10 mL single use vial, 1.3% (13.3 mg/mL) (NDC 65250-133-10) packaged in cartons of 10 (NDC-65250-133-09) and cartons of 4 (NDC 65250-133-04)

Storage

Bupivacaine vials should be stored refrigerated between 2°C to 8°C (36°F to 46°F). Bupivacaine may be held at a controlled room temperature of 20°C to 25°C (68°F to 77°F) for up to 30 days in sealed, intact (unopened) vials. Vials should not be re-refrigerated.

Bupivacaine should not be frozen or exposed to high temperatures (greater than 40°C or 104°F) for an extended period. Do not administer Bupivacaine if it is suspected of having been frozen or exposed to high temperatures. Do not use the vial if the stopper is bulging.

Handling

  • Vials of Bupivacaine should be inverted to re-suspend the particles immediately prior to withdrawal from the vial. Multiple inversions may be necessary to re-suspend the particles if the contents of the vial have settled.
  • Vials should be visually inspected before use.
  • Do not filter.
  • Do not heat before use.
  • Do not autoclave.
  • Following withdrawal from the vial, Bupivacaine may be stored at controlled room temperature of 20°C to 25°C (68°F to 77°F) for up to 4 hours prior to administration.
  • Discard any unused portion in an appropriate manner.

17. PATIENT COUNSELING INFORMATION

Patients should be informed in advance that bupivacaine-containing products can cause temporary loss of sensation or motor activity in the area infiltrated. Physicians should discuss adverse reactions in the Bupivacaine prescribing information with their patients.

Pacira Pharmaceuticals, Inc.

San Diego, CA 92121 USA

Patent Numbers:

6,132,766

5,766,627

5,891,467

8,182,835

Trademark of Pacira Pharmaceuticals, Inc.

PACIRA

PHARMACEUTICALS, INC.

For additional information call 1-855-RX-EXPAREL (1-855-793-9727)

Package Label - 10 mL Vial Label

Package Label - 10 mL 10-count Carton Label

Package Label - 10 mL 4-count Carton Label

Package Label - 20 mL Vial Label

Package Label - 20 mL 10-count Carton Label

Package Label - 20 mL 4-count Carton Label

Bupivacaine pharmaceutical active ingredients containing related brand and generic drugs:

infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Bupivacaine available forms, composition, doses:

infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.

Price
Bupivacaine 0.25% ampul0.1 USD
Bupivacaine 0.25% on-q pump0.62 USD
Bupivacaine 0.25% vial0.11 USD
Bupivacaine 0.5% on-q pump0.63 USD
Bupivacaine hcl 0.5% on-q pump0.63 USD
Bupivacaine hcl powder18.36 USD
Bupivacaine hcl-ns 0.0625%0.25 USD
Bupivacaine hcl-ns 0.1%0.17 USD
Bupivacaine hcl-ns 0.125% bag0.1 USD
Bupivacaine hcl-ns 0.2%0.15 USD
Bupivacaine hcl-ns 0.25%0.1 USD
Bupivacaine-ns 0.1% on-q pump0.25 USD
Injectable; Injection; Bupivacaine Hydrochloride 0.25%
Injectable; Injection; Bupivacaine Hydrochloride 0.5%
Injectable; Injection; Bupivacaine Hydrochloride 1.25 mg / ml
Injectable; Injection; Bupivacaine Hydrochloride 2.5 mg / ml
Injectable; Injection; Bupivacaine Hydrochloride 5 mg / ml
Injectable; Injection; Bupivacaine Hydrochloride 7.5 mg / ml
Marcaine 0.25% vial0.26 USD
Marcaine spinal ampul0.93 USD
Sensorcaine 0.25% vial0.2 USD
Sensorcaine-dextr 0.75% amp2.36 USD

Bupivacaine destination | category:

infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Bupivacaine Anatomical Therapeutic Chemical codes:

infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Bupivacaine pharmaceutical companies:

infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."EXPAREL (BUPIVACAINE) INJECTION, SUSPENSION, LIPOSOMAL [PACIRA PHARMACEUTICALS INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."A3080-27 SPINAL () C47916 [SMITHS MEDICAL ASD, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."BUPIVACAINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Bupivacaine?

Depending on the reaction of the Bupivacaine after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Bupivacaine not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Bupivacaine addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sDrugs.com conducted a study on Bupivacaine, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Bupivacaine consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

One visitor reported side effects

Did you get side effects while taking the Bupivacaine drug, or were there no side effects?
According to the survey conducted by website sDrugs.com users, the below-mentioned percentages indicate the number of people experiencing the side effects and the number of people not experiencing the side effects when taking Bupivacaine medicine. Every drug produces minimal side effects, and they are negligible most times, when compared to the desired effect [use] of the medicine. Side effects depend on the dose you are taking, any drug interactions that happen when you are on other medications, if the patient is sensitive, and other associated conditions. If you cannot tolerate the side effects, consult your doctor immediately, so he can either adjust the dose or change the medication.
Visitors%
It has side effects1
100.0%

Two visitors reported doses

What is the dose of Bupivacaine drug you are taking?
According to the survey conducted among sDrugs.com website users, the maximum number of people are using the following dose 1-5mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Visitors%
1-5mg1
50.0%
6-10mg1
50.0%

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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