EXPAREL Infiltration in Subjects Undergoing Femoral Nerve Block With Bupivacaine HCl for Total Knee Arthroplasty

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and pharmacokinetics of EXPAREL in subjects who undergo femoral nerve block with bupivacaine HCl for unilateral total knee arthroplasty (TKA).

Detailed Description
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On Day 1, eligible subjects will receive a single 20 mL dose of bupivacaine hydrochloride (HCl) 0.5% with epinephrine 1:200,000 within 2 hours prior to the surgical procedure as an ultrasound-guided femoral nerve block (FNB). EXPAREL 266 mg expanded to 60 mL with preservative-free sterile normal saline will be infiltrated into the surgical site prior to wound closure. There will be no local coadministration of the two drugs. Blood samples for bupivacaine pharmacokinetic (PK) analysis will be obtained from subjects at baseline (prior to bupivacaine HCl administration for nerve block), 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours after the beginning of EXPAREL administration, and on Day 14.

Official Title
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Evaluation of the Pharmacokinetics and Safety of Local Administration of EXPAREL in Subjects Undergoing Femoral Nerve Block With Bupivacaine HCl for Unilateral Total Knee Arthroplasty

Conditions
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Pain

Intervention / Treatment
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* Drug: Bupivacaine FNB
* Drug: EXPAREL Infiltration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females ≥18 years of age. American Society of Anesthesiologists (ASA) physical status 1, 2, or 3. Scheduled to undergo femoral nerve block in conjunction with unilateral TKA. Female subjects must be surgically sterile, at least 2 years postmenopausal, or using a medically acceptable method of birth control. Females of childbearing potential must have a documented negative blood or urine pregnancy test result within 24 hours before surgery. Able to provide informed consent, adhere to the study schedule, and complete all study assessments. Exclusion Criteria: History of hypersensitivity or idiosyncratic reactions to amide-type local anesthetics or opioids. Contraindication to bupivacaine. Received bupivacaine or any other local anesthetic within 7 days of EXPAREL administration. Currently pregnant, nursing, or planning to become pregnant during the study or within 1 month after EXPAREL administration. Planned concurrent surgical procedure (e.g., bilateral TKA). Body weight <50 kg (110 pounds) or a body mass index ≥45 kg/m2. Received any investigational drug within 30 days prior to EXPAREL administration, and/or has planned administration of another investigational product or procedure during the subject's participation in this study. Previous participation in an EXPAREL study. Malignancy in the last 2 years, with the exception of non-metastatic basal cell or squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix. Current or historical evidence of any clinically significant disease or condition, especially cardiovascular or neurological conditions that, in the opinion of the Investigator, may increase the risk of surgery or complicate the subject's postsurgical course. Clinically significant medical or psychiatric disease that, in the opinion of the Investigator, would constitute a contraindication to participation in the study, or cause inability to comply with the study requirements. In addition, the subject will be ineligible to receive EXPAREL if he or she meets the following criteria during surgery: Any clinically significant event or condition uncovered during the surgery (e.g., excessive bleeding, acute sepsis) that might render the subject medically unstable or complicate the subject's postsurgical course.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bupivacaine FNB + EXPAREL Infiltration<br>Femoral nerve block with bupivacaine HCl 0.5% with epinephrine 1:200,000 within 2 hours of the surgical procedure. Infiltration of EXPAREL 266 mg just prior to wound closure. | Drug: Bupivacaine FNB<br>* A single administration of bupivacaine HCl 0.5% with epinephrine 1:200,000 in 20 mL volume will be administered within 2 hours prior to the surgical procedure as an ultrasound-guided FNB.<br>* Other names: Bupivacaine;Drug: EXPAREL Infiltration<br>* A single dose of EXPAREL 266 mg expanded to 60 mL with preservative-free sterile normal saline will be infiltrated into the surgical site just prior to wound closure.<br>* Other names: Liposomal bupivacaine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) | The maximum observed plasma concentration of a drug in the body after the drug has been administered. Blood samples for bupivacaine pharmacokinetic (PK) analysis were to be obtained from subjects at baseline (prior to bupivacaine HCl administration for nerve block), 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours, and 14 days after the beginning of EXPAREL administration | Baseline, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours, and 14 days post-dose | 
| Time to Peak Plasma Concentration (Tmax) | The time to reach the maximum observed plasma concentration (Cmax) Blood samples for bupivacaine PK analysis were to be obtained from subjects at baseline (prior to bupivacaine HCl administration for nerve block), 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours, and 14 days after the beginning of EXPAREL administration | Baseline, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours, and 14 days post-dose | 
| Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration After Drug Administration (AUC0-last) | Total drug exposure up to the last measurable concentration Blood samples for bupivacaine PK analysis were to be obtained from subjects at baseline (prior to bupivacaine HCl administration for nerve block), 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours, and 14 days after the beginning of EXPAREL administration | Baseline, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours, and 14 days post-dose | 
| Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity After Drug Administration (AUC0-∞) | Total drug exposure, extrapolated to infinity Blood samples for bupivacaine PK analysis were to be obtained from subjects at baseline (prior to bupivacaine HCl administration for nerve block), 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours, and 14 days after the beginning of EXPAREL administration | Baseline, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours, and 14 days post-dose | 
| The Apparent Terminal Elimination Rate Constant (λz) | Blood samples for bupivacaine PK analysis were to be obtained from subjects at baseline (prior to bupivacaine HCl administration for nerve block), 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours, and 14 days after the beginning of EXPAREL administration | Baseline, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours, and 14 days post-dose | 
| The Apparent Terminal Elimination Half-life (t1/2el) | Blood samples for bupivacaine PK analysis were to be obtained from subjects at baseline (prior to bupivacaine HCl administration for nerve block), 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours, and 14 days after the beginning of EXPAREL administration | Baseline, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours, and 14 days post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Total knee arthroplasty