Studies 6 and 7: Inadequate Demonstration of Efficacy and Safety in Femoral Nerve Block in Total Knee Arthroplasty

Bupivacaine liposome injectable suspension was administered via a femoral nerve block in two placebo-controlled studies in adults (Studies 6 and 7). The results of these studies did not support a femoral nerve block indication due to inadequate safety data (Study 6) and/or due to inadequate efficacy findings (Study 7). In addition, patient falls were reported only in the bupivacaine liposome injectable suspension treatment groups, and none was reported in placebo groups.

Study 6

Study 6, a multicenter, randomized, double-blind, parallel-group, placebo-controlled study (NCT01683071), was conducted in 196 adult patients undergoing primary unilateral total knee arthroplasty (TKA) under general or spinal anesthesia. The mean age was 65 years (range 42 to 88). Prior to the surgical procedure, 266 mg (20 mL) of bupivacaine liposome injectable suspension or placebo was administered as a femoral nerve block with ultrasound guidance. Postsurgically, patients were allowed opioid rescue medication administered initially by intravenous injection of hydromorphone and subsequently by a patient-controlled analgesia (PCA) pump containing morphine or hydromorphone only. Once patients were tolerating oral medication, oral immediate-release oxycodone was administered on an as-needed basis (but not more than 10 mg every 4 hours) or, if that was insufficient, a third rescue of 1.25 mg/mL of 0.125% bupivacaine HCl was administered at a rate of 8 mL per hour via the previously placed femoral nerve catheter.

In this study, there was a statistically significant treatment effect for bupivacaine liposome injectable suspension compared to placebo in cumulative pain scores through 72 hours as measured by the AUC of the NRS pain (at rest) intensity scores.

There was a statistically significant, although small decrease in opioid consumption for the bupivacaine liposome injectable suspension treatment group compared to the placebo group, the clinical benefit of which has not been established. All patients in both the bupivacaine liposome injectable suspension and placebo treatment groups required opioid rescue medication during the first 72 hours. The mean amount of opioid rescue used over 72 hours was 76 mg for patients treated with bupivacaine liposome injectable suspension and 103 mg for patients treated with placebo.

The study was inadequate to fully characterize the safety of bupivacaine liposome injectable suspension when used for femoral nerve block due to patient falls, which occurred only in the bupivacaine liposome injectable suspension-treated patients and not in the placebo-treated patients.

Study 7

Study 7, a multicenter, randomized, double-blind, parallel-group, placebo-controlled study (NCT02713178), was conducted in 230 adult patients undergoing primary unilateral total knee arthroplasty (TKA) under general or spinal anesthesia. The mean age was 65 years (range 39 to 89). Prior to the surgical procedure, either 266 mg (20 mL) of bupivacaine liposome injectable suspension or 133 mg (10 mL) of bupivacaine liposome injectable suspension plus 10 mL of normal saline or placebo was administered as a femoral nerve block with ultrasound guidance. In addition to study drug, 8 mL of 0.5% bupivacaine HCl diluted with 8 mL of normal saline was administered by the surgeon as a periarticular infiltration to the posterior capsule (8 mL each behind the medial and lateral condyles) before placement of the prosthesis. Postsurgically, patients were allowed opioid rescue medication consisting of oral immediate-release oxycodone (initiated at 5 to 10 mg every 4 hours or as needed). If a patient could not tolerate oral medication, IV morphine (2.5 to 5 mg) or hydromorphone (0.5 to 1 mg) was permitted every 4 hours or as needed. Patient-controlled analgesia was not permitted. No other analgesic agents, including NSAIDs, were permitted through 108 hours.

However, to reflect the current standard of care of postsurgical multimodal therapy, all patients received cyclobenzaprine (a single dose of 10 mg orally or as needed) and acetaminophen/paracetamol (up to 1,000 mg orally or IV every 8 hours for a maximum total daily dose of 3000 mg) postsurgically.

In this study there were no statistically significant treatment effects for the bupivacaine liposome injectable suspension group compared to the placebo group in cumulative pain intensity scores or total opioid consumption. All patients in the bupivacaine liposome injectable suspension and placebo treatment groups required opioid rescue medication over 72 hours. The median Tmax of bupivacaine observed in this study was 72 hours with a range of 2.5 to 108 hours. Similar to Study 6, patient falls only occurred in the bupivacaine liposome injectable suspension-treated patients and not the placebo-treated patients.

Study 8: Lack of Efficacy in Intercostal Nerve Block for Posterolateral Thoracotomy

A multicenter, randomized, double-blind, placebo-controlled study was conducted in 191 adult patients undergoing posterolateral thoracotomy under general anesthesia (NCT01802411) (Study 8). The mean age was 58 years (range 18 to 82).

After the surgical procedure was completed but prior to the surgical site closure, 266 mg (20 mL) of bupivacaine liposome injectable suspension was administered by the surgeon as an intercostal nerve block divided into three equal doses in three syringes of approximately 88 mg in 6.6 mL volume per nerve, and administered to each of three nerve segments (index nerve, nerve above, and nerve below). Postsurgically, patients were allowed opioid rescue medication administered initially by intravenous fentanyl 100 mcg, which was to be administered once via bolus only. For the US sites, the second rescue medication was to be PCA-administered morphine or hydromorphone. For the European sites, the second rescue medication was to be intramuscular administered morphine up to 10 mg every 4 hours. At all sites, once a patient was tolerating oral medication, oral immediate-release oxycodone was administered (but not more than 10 mg every 4 hours). Patients who did not achieve adequate pain relief with this regimen were to be withdrawn from the study and followed for safety only.

In this study there were no statistically significant treatment effects for bupivacaine liposome injectable suspension 266 mg compared to placebo in cumulative pain intensity scores or total opioid consumption. Four percent of patients treated with bupivacaine liposome injectable suspension required no rescue medication at 72 hours compared to 1% treated with placebo. For those patients who did require rescue medication, the mean amount of opioid rescue used over 72 hours was 71 mg for patients treated with bupivacaine liposome injectable suspension and 71 mg for patients treated with placebo. The median T max of bupivacaine observed in this study was 1 hour with a range of 0.5 hours to 50 hours.