Bupivacaine

Bupivacaine liposome injectable suspension is indicated to produce postsurgical:

• Local analgesia via infiltration in adults
• Regional analgesia via an interscalene brachial plexus nerve block in adults

The safety and effectiveness of bupivacaine liposome injectable suspension have not been established to produce postsurgical regional analgesia via other nerve blocks besides an interscalene brachial plexus nerve block.

• Bupivacaine liposome injectable suspension is for single administration only (
  
  2.1 Important Dose, Preparation, and Administration Instructions

  • Bupivacaine liposome injectable suspension is for single administration only.
  • Bupivacaine liposome injectable suspension is
    not
    substitutable with other bupivacaine products even if the strength is the same. Therefore, it is not possible to convert a dose from other bupivacaine products to a bupivacaine liposome injectable suspension dose and vice versa.
  • Do
    not
    dilute bupivacaine liposome injectable suspension with water or other hypotonic agents, as it will result in disruption of the liposomal particles.
  • Do
    not
    administer bupivacaine liposome injectable suspension 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.
  • Inspect bupivacaine liposome injectable suspension visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do
    not
    administer bupivacaine liposome injectable suspension if the product is discolored.
  • Do
    not
    heat or autoclave before use.
  • Do
    not
    filter during administration.
  ).
  
• Bupivacaine liposome injectable suspension is not substitutable with other bupivacaine products even if the strength is the same. Therefore, it is not possible to convert a dose from other bupivacaine products to a bupivacaine liposome injectable suspension dose and vice versa (
  
  2.1 Important Dose, Preparation, and Administration Instructions

  • Bupivacaine liposome injectable suspension is for single administration only.
  • Bupivacaine liposome injectable suspension is
    not
    substitutable with other bupivacaine products even if the strength is the same. Therefore, it is not possible to convert a dose from other bupivacaine products to a bupivacaine liposome injectable suspension dose and vice versa.
  • Do
    not
    dilute bupivacaine liposome injectable suspension with water or other hypotonic agents, as it will result in disruption of the liposomal particles.
  • Do
    not
    administer bupivacaine liposome injectable suspension 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.
  • Inspect bupivacaine liposome injectable suspension visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do
    not
    administer bupivacaine liposome injectable suspension if the product is discolored.
  • Do
    not
    heat or autoclave before use.
  • Do
    not
    filter during administration.
  ,
  
  2.5 Compatibility Considerations

  Some physicochemical incompatibilities exist between bupivacaine liposome injectable suspension and certain other drugs. Direct contact of bupivacaine liposome injectable suspension with these drugs results in a rapid increase in free (unencapsulated) bupivacaine, altering bupivacaine liposome injectable suspension characteristics and potentially affecting the safety and efficacy of bupivacaine liposome injectable suspension. Therefore, admixing bupivacaine liposome injectable suspension 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 liposome injectable suspension if administered together locally. The administration of bupivacaine liposome injectable suspension may follow the administration of lidocaine after a delay of 20 minutes or more.
  • Bupivacaine HCl administered together with bupivacaine liposome injectable suspension may impact the pharmacokinetic and/or physicochemical properties of bupivacaine liposome injectable suspension, and this effect is concentration dependent. Therefore, bupivacaine HCl and bupivacaine liposome injectable suspension may be administered simultaneously in the same syringe, and bupivacaine HCl may be injected immediately before bupivacaine liposome injectable suspension if the ratio of the milligram dose of bupivacaine HCl solution to bupivacaine liposome injectable suspension 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 local anesthetic systemic 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 liposome injectable suspension is administered into the site. Bupivacaine liposome injectable suspension should not be allowed to come into contact with antiseptics such as povidone iodine in solution.

  Studies conducted with bupivacaine liposome injectable suspension demonstrated that the most common implantable materials (polypropylene, PTFE, silicone, stainless steel, and titanium) are not affected by the presence of bupivacaine liposome injectable suspension any more than they are by saline. None of the materials studied had an adverse effect on bupivacaine liposome injectable suspension.
  ).
  
• Do
  
  not
  dilute bupivacaine liposome injectable suspension with water or other hypotonic solutions (
  
  2.1 Important Dose, Preparation, and Administration Instructions

  • Bupivacaine liposome injectable suspension is for single administration only.
  • Bupivacaine liposome injectable suspension is
    not
    substitutable with other bupivacaine products even if the strength is the same. Therefore, it is not possible to convert a dose from other bupivacaine products to a bupivacaine liposome injectable suspension dose and vice versa.
  • Do
    not
    dilute bupivacaine liposome injectable suspension with water or other hypotonic agents, as it will result in disruption of the liposomal particles.
  • Do
    not
    administer bupivacaine liposome injectable suspension 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.
  • Inspect bupivacaine liposome injectable suspension visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do
    not
    administer bupivacaine liposome injectable suspension if the product is discolored.
  • Do
    not
    heat or autoclave before use.
  • Do
    not
    filter during administration.
  ).
  
• The recommended dose of bupivacaine liposome injectable suspension for:

• Local infiltration in adults is up to a maximum dose of 266 mg. See Full Prescribing Information for guidance on dose selection (
  
  2.2 Recommended Dose for Local Analgesia via Infiltration

  Local Analgesia via Infiltration in Adults

  The recommended dose of bupivacaine liposome injectable suspension for local infiltration in adults is up to a maximum dose of 266 mg, and 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

  As general guidance in selecting the proper bupivacaine liposome injectable suspension dose for local infiltration in adults, two examples are provided [

  see Clinical Studies (

  14.2)]. In adult patients undergoing:

  • Bunionectomy, a total of 106 mg (8 mL) of bupivacaine liposome injectable suspension was administered, with 7 mL infiltrated into the tissues surrounding the osteotomy, and 1 mL infiltrated into the subcutaneous tissue.
  • Hemorrhoidectomy, a total of 266 mg (20 mL) of bupivacaine liposome injectable suspension 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.
  ).
  
• Interscalene brachial plexus nerve block in adults is 133 mg (
  
  2.3 Recommended Dose for Regional Analgesia

  • The maximum recommended dose of bupivacaine liposome injectable suspension via perineural use for interscalene brachial plexus nerve block is 133 mg. For all nerve blocks, administer additional analgesics, which may include other immediate-release local anesthetics, as appropriate.
  • Regional Analgesia via Interscalene Brachial Plexus Nerve Block in Adults
  • The recommended dose of bupivacaine liposome injectable suspension for interscalene brachial plexus nerve block in adults is 133 mg and is based upon one study of patients undergoing either total shoulder arthroplasty or rotator cuff repair [
    see Clinical Studies (
    14.3
    )
    ].
  ).
  

• For the nerve block, administer additional analgesics, which may include other immediate-release local anesthetics, as appropriate (
  
  2.3 Recommended Dose for Regional Analgesia

  • The maximum recommended dose of bupivacaine liposome injectable suspension via perineural use for interscalene brachial plexus nerve block is 133 mg. For all nerve blocks, administer additional analgesics, which may include other immediate-release local anesthetics, as appropriate.
  • Regional Analgesia via Interscalene Brachial Plexus Nerve Block in Adults
  • The recommended dose of bupivacaine liposome injectable suspension for interscalene brachial plexus nerve block in adults is 133 mg and is based upon one study of patients undergoing either total shoulder arthroplasty or rotator cuff repair [
    see Clinical Studies (
    14.3
    )
    ].
  ).
  
• See Full Prescribing Information for important preparation and administration instructions and compatibility considerations (
  
  2.4 Preparation and Administration Instructions

  • Invert vials of bupivacaine liposome injectable suspension multiple times to re-suspend the particles immediately prior to withdrawal from the vial.
  • Administer bupivacaine liposome injectable suspension (1) undiluted or (2) diluted to increase volume up to a final concentration of 0.89 mg/mL (i.e., 1:14 dilution by volume) with 0.9% preservative-free Sodium Chloride Injection or lactated Ringer’s solution. Use diluted bupivacaine liposome injectable suspension within 4 hours of preparation in a syringe.
  • Administer bupivacaine liposome injectable suspension with a 25 gauge or larger bore needle to maintain the structural integrity of the liposomal bupivacaine particles.
  • Administer bupivacaine liposome injectable suspension slowly via infiltration or perineural use with frequent aspiration to check for blood and minimize the risk of inadvertent intravascular injection.
  • Discard unused portion.
  ,
  
  2.5 Compatibility Considerations

  Some physicochemical incompatibilities exist between bupivacaine liposome injectable suspension and certain other drugs. Direct contact of bupivacaine liposome injectable suspension with these drugs results in a rapid increase in free (unencapsulated) bupivacaine, altering bupivacaine liposome injectable suspension characteristics and potentially affecting the safety and efficacy of bupivacaine liposome injectable suspension. Therefore, admixing bupivacaine liposome injectable suspension 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 liposome injectable suspension if administered together locally. The administration of bupivacaine liposome injectable suspension may follow the administration of lidocaine after a delay of 20 minutes or more.
  • Bupivacaine HCl administered together with bupivacaine liposome injectable suspension may impact the pharmacokinetic and/or physicochemical properties of bupivacaine liposome injectable suspension, and this effect is concentration dependent. Therefore, bupivacaine HCl and bupivacaine liposome injectable suspension may be administered simultaneously in the same syringe, and bupivacaine HCl may be injected immediately before bupivacaine liposome injectable suspension if the ratio of the milligram dose of bupivacaine HCl solution to bupivacaine liposome injectable suspension 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 local anesthetic systemic 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 liposome injectable suspension is administered into the site. Bupivacaine liposome injectable suspension should not be allowed to come into contact with antiseptics such as povidone iodine in solution.

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

Bupivacaine liposome injectable suspension is a white to off-white, milky aqueous suspension that is available in the following vial sizes:

• 1.3% (133 mg/10 mL) (13.3 mg/mL) single-dose vial
• 1.3% (266 mg/20 mL) (13.3 mg/mL) single-dose vial

• Pregnancy
  : May cause fetal harm (
  
  8.1 Pregnancy

  Risk Summary

  There are no studies conducted with bupivacaine liposome injectable suspension 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% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

  Clinical Considerations

  Labor or Delivery

  Bupivacaine is contraindicated for obstetrical paracervical block anesthesia. While bupivacaine liposome injectable suspension 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

  ]. 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 bupivacaine 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).
  ).