Bupivacaine
Generic: BUPIVACAINE
Basic Information
Manufacturer
Jiangsu Hengrui Pharmaceuticals Co., Ltd.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
INFILTRATION
FDA Set ID
0af296bb-1599-4b35-b66b-994924d3e898
Indications & Usage
1.
INDICATIONS AND USAGE 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 Limitations of Use 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 contains bupivacaine, an amide local anesthetic, and is indicated to produce postsurgical: Local analgesia via infiltration in adults ( 1 ).
Regional analgesia via an interscalene brachial plexus nerve block in adults ( 1 ).
Limitations of Use 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.
INDICATIONS AND USAGE 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 Limitations of Use 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 contains bupivacaine, an amide local anesthetic, and is indicated to produce postsurgical: Local analgesia via infiltration in adults ( 1 ).
Regional analgesia via an interscalene brachial plexus nerve block in adults ( 1 ).
Limitations of Use 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.
Adverse Reactions
6.
ADVERSE REACTIONS The following serious adverse reactions have been associated with bupivacaine hydrochloride in clinical trials and are described in greater detail in other sections of the labeling: Central Nervous System Reactions [ see Warnings and Precautions ( 5.1 ) ] Cardiovascular System Reactions [ see Warnings and Precautions ( 5.1 ) ] Allergic Reactions [ see Warnings and Precautions ( 5.1 ) ] Chondrolysis [ see Warnings and Precautions ( 5.1 ) ] Methemoglobinemia [ see Warnings and Precautions ( 5.1 ) ] Accidental intravascular injection [ see Warnings and Precautions ( 5.2 ) ] Adverse reactions reported with an incidence greater than or equal to 10% following bupivacaine liposome injectable suspension administration via: Infiltration in adults were nausea, constipation, and vomiting ( 6.1 ).
Nerve block in adults were nausea, pyrexia, headache, and constipation ( 6.1 ).
To report SUSPECTED ADVERSE REACTIONS, contact eVenus Pharmaceutical Laboratories, Inc.
at 1-609-395-8625 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1 Clinical Trials 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.
Adverse Reactions Reported in All Local Infiltration Clinical Studies in Adults The safety of bupivacaine liposome injectable suspension (local administration into the surgical site) was evaluated in 10 randomized, double-blind, clinical studies (including Studies 1 and 2 [ see Clinical Studies ( 14.2 ) ]) that included 823 adult patients who had various surgical procedures.
Patients were administered a bupivacaine liposome injectable suspension dose ranging from 66 to 532 mg (two times the maximum recommended dose of 266 mg).
In these studies, following bupivacaine liposome injectable suspension administration, the: Most common adverse reactions (incidence greater than or equal to 10%) were nausea, constipation, and vomiting.
Common adverse reactions (incidence greater than or equal to 2% to less than 10%) were pyrexia, dizziness, peripheral edema, anemia, hypotension, pruritus, tachycardia, headache, insomnia, postoperative anemia, muscle spasms, hemorrhagic anemia, back pain, somnolence, and procedural pain.
Less common adverse reactions (incidence less than 2%) were chills, erythema, bradycardia, anxiety, urinary retention, pain, edema, tremor, postural dizziness, paresthesia, syncope, incision site edema, procedural hypertension, procedural hypotension, procedural nausea, muscular weakness, neck pain, generalized pruritus, pruritic rash, hyperhidrosis, cold sweat, urticaria, palpitations, sinus bradycardia, supraventricular extrasystoles, ventricular extrasystoles, ventricular tachycardia, hypertension, pallor, anxiety, confusional state, depression, agitation, restlessness, hypoxia, laryngospasm, apnea, respiratory depression, respiratory failure, increased body temperature, increased blood pressure (BP),decreased BP, decreased oxygen saturation, urinary incontinence, blurred vision, tinnitus, drug hypersensitivity, and hypersensitivity.
Neurological and Cardiac Adverse Reactions In the bupivacaine liposome injectable suspension surgical site infiltration studies, following bupivacaine liposome injectable suspension administration adverse reactions with an incidence greater than or equal to 1% in the: Nervous System Disorders system organ class were dizziness (6.2%), headache (3.8%), somnolence (2.1%), hypoesthesia (1.5%), and lethargy (1.3%).
Cardiac Disorders system organ class were tachycardia (3.9%) and bradycardia (1.6%).
Adverse Reactions Reported in All Local Infiltration Placebo-Controlled Trials in Adults Adverse reactions with an incidence greater than or equal to 2% reported by adult patients in clinical studies who underwent a bunionectomy (Study 1) or hemorrhoidectomy (Study 2) [ see Clinical Studies ( 14.2 ) ] that compared 106 mg of bupivacaine liposome injectable suspension (8 mL) to placebo and 266 mg of bupivacaine liposome injectable suspension (20 mL) to placebo are shown in Table 1.
Table 1: Treatment-Emergent Adverse Reactions with an Incidence Greater than or Equal to 2%: Local Infiltration Placebo-Controlled Studies in Adults (Studies 1 and 2) a Study 1: Bunionectomy b Study 2: Hemorrhoidectomy; TEAE = treatment-emergent adverse event.
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.
STUDY 1 a STUDY 2 b Bupivacaine Liposome Injectable Suspension Placebo Bupivacaine Liposome Injectable Suspension Placebo System Organ Class Preferred Term (106 mg) (N=97) n (%) (N=96) n (%) (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) Generalized Pruritus 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) Increased Alanine Aminotransferase 3 (3.1) 3 (3.1) 1 (1.1) 0 (0.0) Increased Aspartate Aminotransferase 3 (3.1) 2 (2.1) 0 (0.0) 0 (0.0) Increased Blood Creatinine 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0) Increased Body Temperature 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) Adverse Reactions Reported in Placebo-Controlled Nerve Block Clinical Studies in Adults The safety of bupivacaine liposome injectable suspension was evaluated in four randomized, double-blind, placebo-controlled nerve block clinical studies (Studies 3, 6, 7, 8) [ see Clinical Studies ( 14.3 , 14.4 )] involving 469 bupivacaine liposome injectable suspension-treated adult patients and 357 placebo-treated patients who had various surgical procedures.
Patients were administered placebo or a bupivacaine liposome injectable suspension dose of either 133 or 266 mg (two times the maximum recommended dose for these nerve blocks).
In these studies, following bupivacaine liposome injectable suspension administration via nerve block (perineural use) the: Most Common adverse reactions (incidence greater than or equal to 10%) were nausea, pyrexia, and constipation.
Common adverse reactions (incidence greater than or equal to 2% to less than 10%) were muscle twitching, dysgeusia, urinary retention, fatigue, headache, confusional state, hypotension, hypertension, oral hypoesthesia, generalized pruritus, hyperhidrosis, tachycardia, sinus tachycardia, anxiety, fall, increased body temperature, peripheral edema, sensory loss, increased hepatic enzyme, hiccups, hypoxia, and post-procedural hematoma.
Less common adverse reactions (incidence less than 2%) were arrhythmia, atrial fibrillation, first degree atrioventricular block, bradycardia, left bundle branch block, right bundle branch block, cardiac arrest, impaired hearing, blurred vision, visual impairment, asthenia, chills, hyperthermia, cellulitis, lung infection, pneumonia, procedural nausea, wound dehiscence, wound secretion, electrocardiogram QT prolonged, white blood cell count increased, arthralgia, back pain, joint swelling, decreased mobility, muscle spasms, muscular weakness, musculoskeletal pain, paraesthesia, presyncope, sedation, somnolence, syncope, delirium, dysuria, urinary incontinence, atelectasis, cough, dyspnea, lung infiltration, blister, drug eruption, erythema, rash, urticaria, deep vein thrombosis, hematoma, and orthostatic hypotension.
The most common and common adverse reactions for the four randomized, double-blind, placebo-controlled nerve block clinical studies (Studies 3, 6, 7, 8) are shown in Table 3.
Neurological and Cardiac Adverse Reactions In the bupivacaine liposome injectable suspension nerve block placebo-controlled studies, following bupivacaine liposome injectable suspension administration adverse reactions with an incidence greater than or equal to 1% in the: Nervous System Disorders system organ class were motor dysfunction (14.9%), dysgeusia (7.2%), headache (5.1%), hypoesthesia (2.3%), and sensory loss (2.3%).
Cardiac Disorders system organ class were tachycardia (3%), sinus tachycardia (2.3%), and bradycardia (1.3%).
Table 3: Treatment-Emergent Adverse Reactions with an Incidence Greater than or Equal to 2%: Nerve Block Placebo-Controlled Studies (Studies 3, 6, 7, and 8) 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.
SYSTEM ORGAN CLASS Preferred Term Bupivacaine Liposome Injectable Suspension 133 mg (N=168) n (%) Bupivacaine Liposome Injectable Suspension 266 mg (N=301) n (%) Placebo (N=357) n (%) Number of Patients with at Least One TEAE 152 (90.5) 260 (86.4) 299 (83.8) Blood and Lymphatic System Disorders 2 (1.2) 22 (7.3) 15 (4.2) Anemia 2 (1.2) 18 (6.0) 13 (3.6) Cardiac Disorders 13 (7.7) 34 (11.3) 38 (10.6) Atrial Fibrillation 1 (0.6) 4 (1.3) 8 (2.2) Sinus Tachycardia 3 (1.8) 8 (2.7) 4 (1.1) Tachycardia 3 (1.8) 11 (3.7) 10 (2.8) Gastrointestinal Disorders 84 (50.0) 154 (51.2) 184 (51.5) Constipation 29 (17.3) 66 (21.9) 68 (19.0) Dyspepsia 3 (1.8) 7 (2.3) 7 (2.0) Oral Hypoesthesia 6 (3.6) 8 (2.7) 7 (2.0) Nausea 62 (36.9) 111 (36.9) 133 (37.3) Vomiting 17 (10.1) 55 (18.3) 73 (20.4) General Disorders and Administration Site Conditions 52 (31.0) 102 (33.9) 91 (25.5) Fatigue 7 (4.2) 15 (5.0) 15 (4.2) Feeling Cold 0 10 (3.3) 8 (2.2) Peripheral Edema 4 (2.4) 6 (2.0) 8 (2.2) Peripheral Swelling 3 (1.8) 8 (2.7) 4 (1.1) Pyrexia 36 (21.4) 70 (23.3) 64 (17.9) Injury, Poisoning and Procedural Complications 18 (10.7) 44 (14.6) 32 (9.0) Postoperative Anemia 0 8 (2.7) 10 (2.8) Contusion 4 (2.4) 1 (0.3) 0 Fall 4 (2.4) 8 (2.7) 1 (0.3) Post Procedural Hematoma 4 (2.4) 1 (0.3) 0 Procedural Hypotension 2 (1.2) 13 (4.3) 7 (2.0) Investigations 18 (10.7) 31 (10.3) 31 (8.7) Increased Body Temperature 1 (0.6) 10 (3.3) 4 (1.1) Increased Hepatic Enzyme 7 (4.2) 1 (0.3) 3 (0.8) Metabolism and Nutrition Disorders 13 (7.7) 18 (6.0) 25 (7.0) Hypokalemia 7 (4.2) 9 (3.0) 14 (3.9) Musculoskeletal and Connective Tissue Disorders 22 (13.1) 47 (15.6) 41 (11.5) Decreased Mobility 0 6 (2.0) 5 (1.4) Muscle Twitching 14 (8.3) 21 (7.0) 25 (7.0) Nervous System Disorders 72 (42.9) 101 (33.6) 112 (31.4) Dizziness 8 (4.8) 28 (9.3) 40 (11.2) Dysgeusia 12 (7.1) 22 (7.3) 21 (5.9) Headache 14 (8.3) 10 (3.3) 10 (2.8) Hypoesthesia 6 (3.6) 5 (1.7) 2 (0.6) Motor Dysfunction 35 (20.8) 35 (11.6) 37 (10.4) Sensory Loss 4 (2.4) 7 (2.3) 1 (0.3) Psychiatric Disorders 10 (6.0) 33 (11.0) 44 (12.3) Anxiety 3 (1.8) 9 (3.0) 6 (1.7) Confusional State 3 (1.8) 15 (5.0) 14 (3.9) Insomnia 5 (3.0) 10 (3.3) 19 (5.3) Renal and Urinary Disorders 9 (5.4) 31 (10.3) 31 (8.7) Urinary Retention 5 (3.0) 23 (7.6) 22 (6.2) Respiratory, Thoracic and Mediastinal Disorders 18 (10.7) 30 (10.0) 31 (8.7) Dyspnea 2 (1.2) 4 (1.3) 8 (2.2) Hiccups 4 (2.4) 4 (1.3) 1 (0.3) Hypoxia 4 (2.4) 3 (1.0) 3 (0.8) Skin and Subcutaneous Tissue Disorders 24 (14.3) 63 (20.9) 84 (23.5) Hyperhidrosis 1 (0.6) 14 (4.7) 15 (4.2) Pruritus 10 (6.0) 45 (15.0) 55 (15.4) Generalized Pruritus 6 (3.6) 7 (2.3) 14 (3.9) Vascular Disorders 16 (9.5) 30 (10.0) 44 (12.3) Hypertension 3 (1.8) 15 (5.0) 21 (5.9) Hypotension 11 (6.5) 8 (2.7) 19 (5.3) 6.2 Postmarketing Experience Because adverse reactions reported during postmarketing are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
These adverse reactions are consistent with those observed in clinical studies and most commonly involve the following system organ classes: Injury, Poisoning, and Procedural Complications (e.g., drug-drug interaction, procedural pain), Nervous System Disorders (e.g., palsy, seizure), General Disorders And Administration Site Conditions (e.g., lack of efficacy, pain), Skin And Subcutaneous Tissue Disorders (e.g., erythema, rash), and Cardiac Disorders (e.g., bradycardia, cardiac arrest).
ADVERSE REACTIONS The following serious adverse reactions have been associated with bupivacaine hydrochloride in clinical trials and are described in greater detail in other sections of the labeling: Central Nervous System Reactions [ see Warnings and Precautions ( 5.1 ) ] Cardiovascular System Reactions [ see Warnings and Precautions ( 5.1 ) ] Allergic Reactions [ see Warnings and Precautions ( 5.1 ) ] Chondrolysis [ see Warnings and Precautions ( 5.1 ) ] Methemoglobinemia [ see Warnings and Precautions ( 5.1 ) ] Accidental intravascular injection [ see Warnings and Precautions ( 5.2 ) ] Adverse reactions reported with an incidence greater than or equal to 10% following bupivacaine liposome injectable suspension administration via: Infiltration in adults were nausea, constipation, and vomiting ( 6.1 ).
Nerve block in adults were nausea, pyrexia, headache, and constipation ( 6.1 ).
To report SUSPECTED ADVERSE REACTIONS, contact eVenus Pharmaceutical Laboratories, Inc.
at 1-609-395-8625 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1 Clinical Trials 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.
Adverse Reactions Reported in All Local Infiltration Clinical Studies in Adults The safety of bupivacaine liposome injectable suspension (local administration into the surgical site) was evaluated in 10 randomized, double-blind, clinical studies (including Studies 1 and 2 [ see Clinical Studies ( 14.2 ) ]) that included 823 adult patients who had various surgical procedures.
Patients were administered a bupivacaine liposome injectable suspension dose ranging from 66 to 532 mg (two times the maximum recommended dose of 266 mg).
In these studies, following bupivacaine liposome injectable suspension administration, the: Most common adverse reactions (incidence greater than or equal to 10%) were nausea, constipation, and vomiting.
Common adverse reactions (incidence greater than or equal to 2% to less than 10%) were pyrexia, dizziness, peripheral edema, anemia, hypotension, pruritus, tachycardia, headache, insomnia, postoperative anemia, muscle spasms, hemorrhagic anemia, back pain, somnolence, and procedural pain.
Less common adverse reactions (incidence less than 2%) were chills, erythema, bradycardia, anxiety, urinary retention, pain, edema, tremor, postural dizziness, paresthesia, syncope, incision site edema, procedural hypertension, procedural hypotension, procedural nausea, muscular weakness, neck pain, generalized pruritus, pruritic rash, hyperhidrosis, cold sweat, urticaria, palpitations, sinus bradycardia, supraventricular extrasystoles, ventricular extrasystoles, ventricular tachycardia, hypertension, pallor, anxiety, confusional state, depression, agitation, restlessness, hypoxia, laryngospasm, apnea, respiratory depression, respiratory failure, increased body temperature, increased blood pressure (BP),decreased BP, decreased oxygen saturation, urinary incontinence, blurred vision, tinnitus, drug hypersensitivity, and hypersensitivity.
Neurological and Cardiac Adverse Reactions In the bupivacaine liposome injectable suspension surgical site infiltration studies, following bupivacaine liposome injectable suspension administration adverse reactions with an incidence greater than or equal to 1% in the: Nervous System Disorders system organ class were dizziness (6.2%), headache (3.8%), somnolence (2.1%), hypoesthesia (1.5%), and lethargy (1.3%).
Cardiac Disorders system organ class were tachycardia (3.9%) and bradycardia (1.6%).
Adverse Reactions Reported in All Local Infiltration Placebo-Controlled Trials in Adults Adverse reactions with an incidence greater than or equal to 2% reported by adult patients in clinical studies who underwent a bunionectomy (Study 1) or hemorrhoidectomy (Study 2) [ see Clinical Studies ( 14.2 ) ] that compared 106 mg of bupivacaine liposome injectable suspension (8 mL) to placebo and 266 mg of bupivacaine liposome injectable suspension (20 mL) to placebo are shown in Table 1.
Table 1: Treatment-Emergent Adverse Reactions with an Incidence Greater than or Equal to 2%: Local Infiltration Placebo-Controlled Studies in Adults (Studies 1 and 2) a Study 1: Bunionectomy b Study 2: Hemorrhoidectomy; TEAE = treatment-emergent adverse event.
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.
STUDY 1 a STUDY 2 b Bupivacaine Liposome Injectable Suspension Placebo Bupivacaine Liposome Injectable Suspension Placebo System Organ Class Preferred Term (106 mg) (N=97) n (%) (N=96) n (%) (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) Generalized Pruritus 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) Increased Alanine Aminotransferase 3 (3.1) 3 (3.1) 1 (1.1) 0 (0.0) Increased Aspartate Aminotransferase 3 (3.1) 2 (2.1) 0 (0.0) 0 (0.0) Increased Blood Creatinine 2 (2.1) 0 (0.0) 0 (0.0) 0 (0.0) Increased Body Temperature 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) Adverse Reactions Reported in Placebo-Controlled Nerve Block Clinical Studies in Adults The safety of bupivacaine liposome injectable suspension was evaluated in four randomized, double-blind, placebo-controlled nerve block clinical studies (Studies 3, 6, 7, 8) [ see Clinical Studies ( 14.3 , 14.4 )] involving 469 bupivacaine liposome injectable suspension-treated adult patients and 357 placebo-treated patients who had various surgical procedures.
Patients were administered placebo or a bupivacaine liposome injectable suspension dose of either 133 or 266 mg (two times the maximum recommended dose for these nerve blocks).
In these studies, following bupivacaine liposome injectable suspension administration via nerve block (perineural use) the: Most Common adverse reactions (incidence greater than or equal to 10%) were nausea, pyrexia, and constipation.
Common adverse reactions (incidence greater than or equal to 2% to less than 10%) were muscle twitching, dysgeusia, urinary retention, fatigue, headache, confusional state, hypotension, hypertension, oral hypoesthesia, generalized pruritus, hyperhidrosis, tachycardia, sinus tachycardia, anxiety, fall, increased body temperature, peripheral edema, sensory loss, increased hepatic enzyme, hiccups, hypoxia, and post-procedural hematoma.
Less common adverse reactions (incidence less than 2%) were arrhythmia, atrial fibrillation, first degree atrioventricular block, bradycardia, left bundle branch block, right bundle branch block, cardiac arrest, impaired hearing, blurred vision, visual impairment, asthenia, chills, hyperthermia, cellulitis, lung infection, pneumonia, procedural nausea, wound dehiscence, wound secretion, electrocardiogram QT prolonged, white blood cell count increased, arthralgia, back pain, joint swelling, decreased mobility, muscle spasms, muscular weakness, musculoskeletal pain, paraesthesia, presyncope, sedation, somnolence, syncope, delirium, dysuria, urinary incontinence, atelectasis, cough, dyspnea, lung infiltration, blister, drug eruption, erythema, rash, urticaria, deep vein thrombosis, hematoma, and orthostatic hypotension.
The most common and common adverse reactions for the four randomized, double-blind, placebo-controlled nerve block clinical studies (Studies 3, 6, 7, 8) are shown in Table 3.
Neurological and Cardiac Adverse Reactions In the bupivacaine liposome injectable suspension nerve block placebo-controlled studies, following bupivacaine liposome injectable suspension administration adverse reactions with an incidence greater than or equal to 1% in the: Nervous System Disorders system organ class were motor dysfunction (14.9%), dysgeusia (7.2%), headache (5.1%), hypoesthesia (2.3%), and sensory loss (2.3%).
Cardiac Disorders system organ class were tachycardia (3%), sinus tachycardia (2.3%), and bradycardia (1.3%).
Table 3: Treatment-Emergent Adverse Reactions with an Incidence Greater than or Equal to 2%: Nerve Block Placebo-Controlled Studies (Studies 3, 6, 7, and 8) 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.
SYSTEM ORGAN CLASS Preferred Term Bupivacaine Liposome Injectable Suspension 133 mg (N=168) n (%) Bupivacaine Liposome Injectable Suspension 266 mg (N=301) n (%) Placebo (N=357) n (%) Number of Patients with at Least One TEAE 152 (90.5) 260 (86.4) 299 (83.8) Blood and Lymphatic System Disorders 2 (1.2) 22 (7.3) 15 (4.2) Anemia 2 (1.2) 18 (6.0) 13 (3.6) Cardiac Disorders 13 (7.7) 34 (11.3) 38 (10.6) Atrial Fibrillation 1 (0.6) 4 (1.3) 8 (2.2) Sinus Tachycardia 3 (1.8) 8 (2.7) 4 (1.1) Tachycardia 3 (1.8) 11 (3.7) 10 (2.8) Gastrointestinal Disorders 84 (50.0) 154 (51.2) 184 (51.5) Constipation 29 (17.3) 66 (21.9) 68 (19.0) Dyspepsia 3 (1.8) 7 (2.3) 7 (2.0) Oral Hypoesthesia 6 (3.6) 8 (2.7) 7 (2.0) Nausea 62 (36.9) 111 (36.9) 133 (37.3) Vomiting 17 (10.1) 55 (18.3) 73 (20.4) General Disorders and Administration Site Conditions 52 (31.0) 102 (33.9) 91 (25.5) Fatigue 7 (4.2) 15 (5.0) 15 (4.2) Feeling Cold 0 10 (3.3) 8 (2.2) Peripheral Edema 4 (2.4) 6 (2.0) 8 (2.2) Peripheral Swelling 3 (1.8) 8 (2.7) 4 (1.1) Pyrexia 36 (21.4) 70 (23.3) 64 (17.9) Injury, Poisoning and Procedural Complications 18 (10.7) 44 (14.6) 32 (9.0) Postoperative Anemia 0 8 (2.7) 10 (2.8) Contusion 4 (2.4) 1 (0.3) 0 Fall 4 (2.4) 8 (2.7) 1 (0.3) Post Procedural Hematoma 4 (2.4) 1 (0.3) 0 Procedural Hypotension 2 (1.2) 13 (4.3) 7 (2.0) Investigations 18 (10.7) 31 (10.3) 31 (8.7) Increased Body Temperature 1 (0.6) 10 (3.3) 4 (1.1) Increased Hepatic Enzyme 7 (4.2) 1 (0.3) 3 (0.8) Metabolism and Nutrition Disorders 13 (7.7) 18 (6.0) 25 (7.0) Hypokalemia 7 (4.2) 9 (3.0) 14 (3.9) Musculoskeletal and Connective Tissue Disorders 22 (13.1) 47 (15.6) 41 (11.5) Decreased Mobility 0 6 (2.0) 5 (1.4) Muscle Twitching 14 (8.3) 21 (7.0) 25 (7.0) Nervous System Disorders 72 (42.9) 101 (33.6) 112 (31.4) Dizziness 8 (4.8) 28 (9.3) 40 (11.2) Dysgeusia 12 (7.1) 22 (7.3) 21 (5.9) Headache 14 (8.3) 10 (3.3) 10 (2.8) Hypoesthesia 6 (3.6) 5 (1.7) 2 (0.6) Motor Dysfunction 35 (20.8) 35 (11.6) 37 (10.4) Sensory Loss 4 (2.4) 7 (2.3) 1 (0.3) Psychiatric Disorders 10 (6.0) 33 (11.0) 44 (12.3) Anxiety 3 (1.8) 9 (3.0) 6 (1.7) Confusional State 3 (1.8) 15 (5.0) 14 (3.9) Insomnia 5 (3.0) 10 (3.3) 19 (5.3) Renal and Urinary Disorders 9 (5.4) 31 (10.3) 31 (8.7) Urinary Retention 5 (3.0) 23 (7.6) 22 (6.2) Respiratory, Thoracic and Mediastinal Disorders 18 (10.7) 30 (10.0) 31 (8.7) Dyspnea 2 (1.2) 4 (1.3) 8 (2.2) Hiccups 4 (2.4) 4 (1.3) 1 (0.3) Hypoxia 4 (2.4) 3 (1.0) 3 (0.8) Skin and Subcutaneous Tissue Disorders 24 (14.3) 63 (20.9) 84 (23.5) Hyperhidrosis 1 (0.6) 14 (4.7) 15 (4.2) Pruritus 10 (6.0) 45 (15.0) 55 (15.4) Generalized Pruritus 6 (3.6) 7 (2.3) 14 (3.9) Vascular Disorders 16 (9.5) 30 (10.0) 44 (12.3) Hypertension 3 (1.8) 15 (5.0) 21 (5.9) Hypotension 11 (6.5) 8 (2.7) 19 (5.3) 6.2 Postmarketing Experience Because adverse reactions reported during postmarketing are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
These adverse reactions are consistent with those observed in clinical studies and most commonly involve the following system organ classes: Injury, Poisoning, and Procedural Complications (e.g., drug-drug interaction, procedural pain), Nervous System Disorders (e.g., palsy, seizure), General Disorders And Administration Site Conditions (e.g., lack of efficacy, pain), Skin And Subcutaneous Tissue Disorders (e.g., erythema, rash), and Cardiac Disorders (e.g., bradycardia, cardiac arrest).