Expert Opinion on Drug Safety

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Local Anesthetics Systemic Toxicity Association

with Exparel (Bupivacaine Liposome)- A
Pharmacovigilance evaluation

Nitish Aggarwal

To cite this article: Nitish Aggarwal (2017): Local Anesthetics Systemic Toxicity Association with
Exparel (Bupivacaine Liposome)- A Pharmacovigilance evaluation, Expert Opinion on Drug Safety,
DOI: 10.1080/14740338.2017.1335304

To link to this article: http://dx.doi.org/10.1080/14740338.2017.1335304

Accepted author version posted online: 24

May 2017.

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Download by: [Cornell University Library] Date: 28 May 2017, At: 16:41
 Publisher: Taylor & Francis

Journal: Expert Opinion on Drug Safety

DOI: 10.1080/14740338.2017.1335304

Local Anesthetics Systemic Toxicity Association with Exparel (Bupivacaine

Liposome)- A Pharmacovigilance evaluation

Nitish Aggarwal1, *

Affiliation
1
Ohio State University Wexner Medical Center, 410 W 10th Ave, Columbus, OH 43210

*Corresponding author
Email: Nitish.Aggarwal@osumc.edu; Telephone: 614-736-3359

Abstract

Background: Local Anesthetic Systemic Toxicity (LAST) is a rare life threatening

complication usually from intra-arterial or intravenous injection leading to systemic

absorption of regional anesthesia drug. The objective of this research was to statistically

quantify the association between Exparel (bupivacaine liposome) injectable suspension and

LAST.

Methods: Adverse Event Reporting System database of FDA, which houses public and

industry submitted adverse event case reports, was queried and analyzed to quantify the

1
 passive pharmacovigilance signal for Local Anesthetic Systemic Toxicity as associated with

use of bupivacaine Liposome.

Results: A dis-proportionality analysis of the signals yielded a significant association

between Local Anesthetic Systemic Toxicity and Exparel. The Chi-Squared with Yates'

correction was 596.66 and Proportional Reporting Ratio =6.23 [95% CI: 5.41-7.18]).

Conclusion: The health care provider, including anesthetists, should be made aware that as

with bupivacaine HCl, Local Anesthetic Systemic Toxicity, including seizures and cardiac

arrest, could be induced by Exparel as well.

Keywords:

Pharmacovigilance analysis, Exparel , Bupivacaine liposomal , adverse events

1 Introduction

Local Anesthetics have been an integral part of medical care for over 120 years. One of

the local anesthetics, bupivacaine HCl, synthesized in 1957, has been in the clinical market since

1963. It is also on the list of WHO Model list of Essential medicines. A new liposomal

formulation of bupivacaine – Exparel® (bupivacaine liposome) injectable suspension was

approved by FDA on October 28, 20111 and has been in the clinical market since 2012. Exparel

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

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 With the use of bupivacaine limited to regional anesthesia, the side effects tend to be

local, such as pain at the site of injection. Instead of being restricted to local effects, the drug

sometimes enters the bloodstream and causes systemic effects. The constellation of systemic

effects after the administration of local anesthetics is known as Local Anesthetic Systemic

Toxicity (LAST). LAST is a rare life threatening complication usually due to intra-arterial or

intravenous injections leading to systemic absorption of regional anesthesia drugs. There have

been numerous reports of estimates of incidence of LAST with local anesthetics. The rate of

LAST for epidural anesthesia between 1993 and 1997 was reported as 1.2–11 per 10,000

anesthetics2. The rate of LAST for peripheral nerve block3 in 2009 was reported as 9.8 per

10,000. The use of ultrasound decreased the incidence in some of the studies4 and was reported

to be 8.7 per 10,000 in 2013. Summarizing, in most cases, rates of severe systemic toxicity

(seizures with or without cardiac arrest) occur in the order of 1:10,000 to 10:10,000 for epidurals

and 10:10,000 for peripheral nerve blocks (PNB), depending on the type of block.

The systemic effects of LAST are usually limited to Central Nervous System (CNS) and

Cardiovascular system (CVS). CNS complications include seizures, convulsions, agitation,

dizziness and tinnitus. Initial CNS excitation is often followed by rapid CNS depression with

features including unconsciousness, coma, and respiratory depression and arrest. Local

anesthetics also affect the heart and peripheral blood vessels. Cardiovascular manifestations are

chest pain, shortness of breath, palpitations, lightheadedness, diaphoresis and syncope, amongst

others. CVS complications include bradycardia and hypotension. LAST is well known to be

associated with bupivacaine HCl5. In published literature and social media6, LAST has also been

reported to be associated with Exparel (liposomal bupivacaine)7,8. As per one of the reports, a 73

year old male patient who underwent a total hip arthroplasty a day earlier had two episodes of

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syncope preceded with dizziness and hypotension.. His pain had been controlled with liposomal

bupivacaine administered during surgery and by scheduled acetaminophen. The episodes of

syncope were considered to be adverse events due to bupivacaine liposome8.

However, specific clinical studies to analyze Exparel (bupivacaine liposome) induced

LAST could not be located in literature. FDA approved label9 states “Monitoring of

cardiovascular and neurological states, as well as vital signs should be performed during and

after injection of Exparel as with other local anesthetic products”. At present, US Food and Drug

Administration (FDA) does recognize LAST as an associated adverse event for bupivacaine HCl

but not as a bupivacaine liposome associated adverse event. FDA has stated a need to evaluate

regulatory action in this regard10.

Local infiltration of Exparel results in significant systemic plasma levels of bupivacaine

which can persist for 96 hours. These systemic plasma levels are not correlated with local

efficacy but may cause LAST effects. Exparel after being absorbed systemically gets distributed

to some extent to all body tissues, with higher concentrations found in highly perfused organs

such as liver, lungs, heart and brain. Liposomal bupivacaine has the potential to cause LAST,

although the relative frequency and the doses at which it occurs compared to other formulations

of bupivacaine is not well researched and documented.

Study Objective

The clinical anesthesia providers are not fully aware of the potential and significant

safety concerns of Exparel. The objective of this research was to statistically quantify the

association between Exparel (bupivacaine liposome) injectable suspension and LAST based on

post marketing pharmacovigilance data. In this research paper, FDA Adverse Event Reporting

System (FAERS)11 database was used for signal detection of LAST as associated with Exparel

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(bupivacaine liposome). The retrospective data were statistically analyzed to decipher if the

association was significant.

2 Methods

2.1 Data Collection

Spontaneous reports of adverse events and medication errors involving human drugs and

therapeutic biological products are available from FDA Adverse Event Reporting System

(FAERS) as computerized quarterly data reports. FAERS is a self-report, voluntary system. It

does not have any denominators or any regulatory requirement for most participants or reporters

except the manufacturers. The data are publically available at FAERS website11. FAERS has

been used previously to summarize and analyze adverse events related to drugs12,13.

The FDA Adverse Event Reporting System (FAERS) database, used in this study,

contains information on adverse event and medication error reports submitted to FDA by

manufacturers of the drugs, healthcare professionals (such as physicians, pharmacists, nurses and

others) and consumers (such as patients, family members, lawyers and others). The database is

designed to support the FDA's post-marketing safety surveillance program for drug and

therapeutic biologic products. The quarterly data files used in this analysis are available in

ASCII or SGML formats. The files include demographic and administrative information, drug

information from the case reports, reaction information from the reports, patient outcome

information from the reports and information on the source of the reports11.

The adverse events retrospective data for present analysis were obtained from FAERS

website11 for the time-period January 01, 2012 to June 30, 2016. The starting date was selected

as January 01, 2012 as Exparel was approved by FDA on October 28, 2011. The data tables-

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'Demographics', 'Drugs', 'Indications', 'Outcomes, Reactions', 'Report Source' and 'Therapy' were

downloaded and imported in SQL Server (Microsoft SQL Server 2015). The files were

combined using primary key and foreign keys and queried and cleaned as described earlier 14.

2.2 Adverse Event and Exposure Drug

The adverse event investigated was Local Anesthetic Systemic Toxicity (LAST)). In the

FAERS data repository, LAST is not a term in the adverse reactions. As such, the systemic CNS

and CVS symptoms have been combined into an entity “LAST”. Central Nervous System and

Cardiovascular symptoms of LAST investigated were as follows:

Central Nervous System: Agitation, dizziness, tinnitus, seizure, and convulsion. Respiratory

depression and arrest were also included if followed after CNS excitation.

Cardiovascular System: bradycardia and hypotension. Cardiovascular depression and collapse

were also included if followed after other LAST symptoms.

Exparel (bupivacaine liposome) was investigated as the exposure drug being associated with

LAST. Computer algorithm was used to search the ‘LAST’ cases based upon the CNS and CVS

symptoms selected above. The adverse events on FAERS database were individually confirmed

to meet the clinical definition of LAST and corroborated by a secondary investigator. The

analysis was restricted to cases where the drug was specified as the “prime suspect” drug.

2.3 Analysis

Disproportionality analysis can be used to identify statistical associations between

products and events in their respective databases of safety reports15,16. Such analysis compares

the observed count for a product-event combination with an “expected” count for a product-

event combination with an ‘expected’ count if there were no association between the product and

6
the event. This gives a ratio of observed to expected reports, or proportional reporting ratio.

Unexpectedly high reporting associations “signal” that there may be a causal association between

the particular adverse event and the product17,18. This analysis can also identify increased

reporting rates for low frequency. Disproportionality analysis methodologies use frequency

analysis of 2×2 contingency tables (or stratified versions thereof) to quantify the degree to which

a drug-event combination co-occurs disproportionally compared to what would be expected if

there were no association19.

Disproportionality analysis was used to quantify pharmacovigilance signals in FAERS to

provide a picture of the drug-related risk. The association of the adverse events to the drug of

interest was evaluated using chi-squared value with Yates' correction. Chi square values greater

than 4 are considered statistically significant18. Measurements of disproportionality (observed-

expected ratios): Relative Reporting Ratio (RRR), Proportional Reporting Ratio (PRR) and

Reporting Odds Ratio (ROR), and their 95% confidence intervals were also calculated.

Generally, the higher the ratios, the more likely an association between drug(s) and adverse

event(s). The PRR involves the calculation of the rate of reporting of one specific event among

all events for a given drug, the comparator being this reporting rate for all drugs present in the

database (including the drug of interest)20.

According to the criteria of Evans18 if (number of events > 3, chisquare > 4 and PRR >

2), the combination of drug(s) and adverse event(s) is considered 'likely an adverse reaction. The

ROR is the ratio of the odds of reporting of one specific event versus all other events for a given

drug compared to this reporting odds for all other drugs present in the database. A signal is

considered when the lower limit of the 95% confidence interval (CI) of the ROR is greater than

one20.

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 3 Results

3.1 Analysis Results

The major local anesthesia drugs, reported in FAERS database, to have been associated

with LAST during the analyzed period (1st quarter of 2012 to 2nd quarter of 2016) are

summarized in Table 1. A drug may have been administered as a single drug or local anesthetic

combinations. In the FAERS data, a total of 214,716 cases with LAST type symptoms as an

adverse event were reported during the four and a half year period (1st quarter of 2012 to 2nd

quarter of 2016) with the use of any drug (including local anesthetics). 95,283 cases were

reported by health care professionals and 104,970 by consumers/non-health professionals.

Lawyers reported 2,151. The source of the remaining 12,312 cases was missing from the

database.

There were 346 LAST cases associated with bupivacaine HCl as the prime suspect drug

and 130 LAST case reports associated with Exparel (bupivacaine liposome) as the prime suspect

drug. Demographics and a brief summary of some of the Exparel associated critical adverse

events related to LAST are presented in Table 2. 12 cases involved seizures: 3 cases with

Generalized tonic-clonic seizures and 9 cases with the adverse event specified as ‘seizure’. There

was one death and 6 of the 12 seizure cases were coded as life-threatening. Bradycardia was

reported in 8 cases, 4 of which were coded as life-threatening. Cardiac arrest was reported in 7

cases out of which death was reported for 4 cases and one additional case was coded as life-

threatening. Cardiopulmonary arrest was reported in 6 patients. In three of these cases mortality

was the end result and an additional two cases were coded as life threatening.

The FAERS disproportionality analysis was initially carried out for bupivacaine HCl and

subsequently for bupivacaine liposome associated LAST to provide a comprehensive picture.

8
The adverse events for the two are not to be compared one–to-one as FAERS is not intended or

suitable for the purpose.

a) Bupivacaine HCl

The data from FAERS related to bupivacaine HCl associated LAST events are

summarized in a 2 x 2 table (Table 3) and the statistical analysis results are tabulated in

Table 4. The Chi-Squared with Yates' correction was calculated to be 599.98. Comparing

the results of the analysis of passive pharmacovigilance using FAERS data (n =346; chi-

squared (chisq) =599.98 and PRR =3.36 [95% CI: 3.05-3.69]) and Evans18 criteria (n > 3,

chisq > 4, PRR > 2), the Local Anesthetic Systemic Toxicity is statistically significantly

associated with bupivacaine HCl.

Subsequently, the data were stratified by CNS and CVS related adverse events and the

corresponding disproportionality results were obtained. A 2 x 2 table of the queried

stratified results is provided in Table 3 and corresponding statistical analysis results are

tabulated in Table 4. The stratified results show that the Local Anesthetic Systemic

Toxicity is statistically associated with bupivacaine HCl as an adverse event for CNS

manifestations (n=158; chisq =72.28; PRR =1.93 [95% CI: 1.66-2.24]). The significant

association is seen for CVS manifestations, but to a greater extent (n=212; chisq

=1430.04; PRR =8.61[95% CI: 7.58-9.78]).

b) Bupivacaine Liposome (Exparel)

A similar analysis was performed to analyze Exparel associated LAST.

The data from FAERS related to bupivacaine liposome associated LAST events are

summarized in a 2 x 2 table (Table 5) and the statistical analysis results are tabulated in

9
 Table 7. The Chi-Squared with Yates' correction was calculated to be 596.66. Comparing

the results of the analysis of passive pharmacovigilance using FAERS data (n =130; chi-

squared (chisq) =596.66 and PRR =6.23 [95% CI: 5.41-7.18]) and Evans18 criteria (n > 3,

chisq > 4, PRR > 2), the Local Anesthetic Systemic Toxicity is statistically significantly

associated with Exparel (bupivacaine liposome).

Subsequently, the data were stratified by CNS and CVS related adverse events and the

corresponding disproportionality results were obtained. A 2 x 2 table of the queried

stratified results is provided in Table 5 and corresponding statistical analysis results are

tabulated in Table 6. The stratified results show that the Local Anesthetic Systemic

Toxicity is statistically significantly associated with bupivacaine liposome as an adverse

event for CNS manifestations (n=66; chisq =150.39; PRR =3.98 [95% CI: 3.19-4.96]).

The significant association is also seen for CVS manifestations, but to a greater extent

(n=64; chisq =693.89; PRR =12.83[95% CI: 10.24-16.06]).

The results show that LAST is statistically significantly associated with Exparel (bupivacaine

liposome) on the basis of FAERS signal analysis. This association is confirmed for CVS as well

as CNS manifestations, when the data were stratified.

4 Discussion

4.1 Limitations of Analysis

FAERS provides a passive pharmaco-vigilance risk signal and shows an association.

Regulatory actions in response to emerging drug safety concerns often depend on an accurate

assessment of risks using multiple sources of data and the consideration of overall benefits and

risks of the agent21. The submissions can be made by public or patients which may be of

10
questionable accuracy, especially in terms of the suspect drug if multiple drugs are implicated.

Further FAERS is a passive report system. FDA does not receive reports for every adverse event

or medication error that occurs with a product. Therefore, FAERS data cannot be used to

calculate the incidence of an adverse event or medication error in the population11,14. Post-

marketing vigilance such as FAERS, has advantages in identifying the signals in real world

situations with multi-drug regimes, identifying reactivation of adverse events after

discontinuation of drugs and identifying global differences in occurrence of adverse events14.

Further, there have been concerns that when new drugs are introduced on the market, the

frequency with which adverse events are reported to FAERS increases- the so called Weber

Effect22. In addition, it is widely assumed that reporting increases (simulated reporting) because

of FDA alerts, media reports, lawsuits or other outside factors cause certain drugs to receive

larger than normal amounts of adverse reports. However, the Weber Effect theory was debunked

based upon absence of significant bias in pharmacovigilance data analyzed for sixty two drugs

approved by FDA from 2006 to 201023. It was also demonstrated that modern FAERS does not

generally suffer from the biases of simulated reporting24.

4.2 General Discussion

Bupivacaine has been used in clinical practice for over 50 years. It acts by inactivating

the sodium channels inside the inner membrane of the neuron. To accomplish this, bupivacaine is

transferred across the cell membrane in an uncharged state25. Bupivacaine in HCl formulation is

a quaternary water soluble molecule26. Only recently, has there been a change to the delivery

system of the drug. Liposomal bupivacaine consists of bupivacaine molecules that are

encapsulated by a lipid layer, which allows for an easier passage across the membrane due to

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lipid-lipid interactions. This results in an increase in the duration of action, as reflected by its 3.8

times larger AUC at the 266 mg dose compared to that of bupivacaine HCl27,28.

The recommended bupivacaine dose of 266 mg (3.8 mg/kg) is at least 20% higher than

that of bupivacaine HCl. This difference has the potential to increase adverse events including

LAST. Once the drug is in the bloodstream, it causes neuro and cardio effects due to the

abundance of sodium channels in those sites. This affects the normal physiology and causes

symptoms such as seizures or bradycardia. Liposome bupivacaine has clinically meaningful

interactions with other local anesthetics, including lidocaine, ropivacaine, mepivacaine, and

bupivacaine HCl, which result in substantial displacement and release of free bupivacaine from

liposomes29. The manufacturer of Exparel warns that injection of bupivacaine Liposome must

not occur within 20 minutes after the administration of non-bupivacaine local anesthetics, such

as lidocaine, because it could cause the immediate release of bupivacaine from the liposomes30.

If the liposomal bupivacaine is injected into the surgical site within 20 minutes of administration

of another non-bupivacaine local anesthetic, the systemic absorption of local anesthetic

increases26. Bupivacaine HCl, when injected immediately before Exparel, may impact the

pharmaco-kinetics of the drugs if the milligram dose of bupivacaine HCl solution exceeds 50%

of the Exparel dose. The toxic effects of these drugs are additive.

The long acting anesthetics tend to be given either right before the patient is rolled out of

the operating room or at the beginning of the procedure. Even though liposomal bupivacaine has

3% free bupivacaine it is not sufficient to work for the period between perioperative analgesia

and postoperative analgesia. Clinically, this implies a need to cover the liposomal bupivacaine.

This is attained by injecting a bolus of local anesthetic before the patient leaves the operating

room or having a catheter with continuous local anesthetic. Regardless of the option, a local

12
anesthetic, such as bupivacaine HCl or ropivacaine, is given. However, this releases the bound

bupivacaine from the liposomal molecule, thus negating the prolonged efficacy benefit of

Exparel by increasing immediate bupivacaine plasma concentration. This compounds the risk of

adverse events including LAST as the patient is subjected to not only bupivacaine from Exparel

but also additive effects of the concomitant local anesthesia and any liposomal bupivacaine

released from the liposomes as a result of interacting with the other local anesthetic. Co-

administration of Exparel with bupivacaine HCl or other local anesthetics increases the exposure

to Bupivacine31 or local anesthetics, respectively, and the risk for LAST increases substantially.

This is a practical logistic concern, as local anesthetics such as lidocaine and bupivacaine are

mixed in clinical practice in order to get immediate onset of lidocaine with duration of

bupivacaine activity32.

At blood concentrations achieved with normal therapeutic doses, changes in cardiac

conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are

generally minimal. However, at the doses and clinical practices as described in the preceding

paragraph, toxic blood concentrations depress cardiac conduction 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.

The statistically significant findings from FAERS signal analysis indicate the signal

generated by FAERS is not a false positive. Published reports and cases7,8, clinical plausibility

and FAERS signals confirm a cause-effect relationship between Bupivacaine Liposome and

LAST. Liposomal bupivacaine has been shown to affect the neurological system causing altered

mental status, seizures, local- irreversible neuropathy, cardiac arrest and even death8. The most

13
commonly observed adverse effects associated with bupivacaine liposomal reported by the

manufacturer33 include tachycardia at 3.9%.

Warnings of safety concerns following use of Exparel (liposomal bupivacaine) have also

been published in peer-reviewed literature30. Clinically, the interaction between Exparel and

local anesthetics and immediate release of bupivacaine from liposomes in case of concomitant

administration increases the risk of adverse events including LAST. If the efficacy of liposomal

bupivacaine is higher than the bupivacaine HCl, it may be able to balance benefit-risk ratio.

However, eleven studies comparing the two formulations of bupivacaine have not shown a

clinical benefit for the use of the liposomal formulation but only clinical equivalence34. Further a

well-controlled study35 was performed comparing use of the liposomal bupivacaine product

Exparel, to an unencapsulated form of ropivacaine as a periarticular injection in 150 consecutive

patients. The authors35 concluded, “This study found no benefit to intra-articular injection of

liposomal bupivacaine, with the possible negative effect of increased pain throughout the

remaining hospital course after the initial 24 hours pain control. In addition, the additional cost

of liposomal bupivacaine does not appear to be warranted over the less expensive ropivacaine

injection35”. Clinical outcomes of Exparel in active comparator trials have not been improved as

evidenced by no statistical difference in AUC pain scores32.

The adverse events and LAST effects are similar to lower cost bupivacaine HCl. Clinically,

the interaction between Exparel and local anesthetics and immediate release of bupivacaine from

liposomes in case of concomitant administration increases the risk of adverse events including

LAST. It is important to evaluate the economics and risk benefit ratio of liposomal bupivacaine.

In addition, it is important to educate all healthcare providers including non-anesthesiologists

14
who are less likely to be aware of the potential risks of Exparel associated LAST and knowledge

of its management.

5 Conclusion

The results from passive retrospective pharmacovigilance data analysis confirm a

statistically significant association between LAST and Exparel (liposomal bupivacaine). It is

suggested that FDA considers adding a warning on the label for bupivacaine liposome about the

risk of the drug related Local Anesthetic Systemic Toxicity. LAST is rare but may be fatal.

While such events are generally unpredictable, many are preventable. The medical health

community must be made aware of the risk of LAST as induced by bupivacaine liposome. If

LAST occurs, the key is to recognize it immediately and institute appropriate management.

Funding
This paper has not been funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity
with a financial interest in or financial conflict with the subject matter or materials discussed in
the manuscript. This includes employment, consultancies, honoraria, stock ownership or options,
expert testimony, grants or patents received or pending, or royalties.

15
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 Table 1: Local Anesthetic Systemic Toxicity cases for local anesthetics reported in FDA-
FAERS between 01 January 2012 and 30 June 2016.

Drug Number of reported

LAST cases
Chloroprocaine 1
Procaine 9
Cocaine 129
Tetracaine 9
Lidocaine 1050
Mepivacaine 50
Prilocaine 85
Bupivacaine HCl* 346
Ropivacaine 131
Bupivacaine
Liposome* (Exparel) 130
*
Prime suspect only. All others report numbers are for the adverse event with the drug reported
as suspect or concomitant drug.

Table 2: Demographics and a brief summary of some of the of Exparel associated critical
adverse events related to Local Anesthetic Systemic Toxicity reported in FDA- FAERS
between 01 January 2012 and 30 June 2016.

Adverse event Cases Gender Age Mortality Life threatening

Range (not counting
(years) mortal cases)
Male Female
Seizures 12 6 6 30-86 1 6
Bradycardia 8 2 6 29-69 0 4
Cardiac arrest 7 1 6 50-87 4 1
Cardio- 6 3 3 62-87 3 2
pulmonary arrest
Arrhythmia 3 1 2 50-60 2 1
Atrioventricular 2 1 1 78-83 0 0

20
block
Atrial fibrillation 3 1 2 58-87 1 0
Peripheral 1 0 1 42 0 0
ischemia
Bigeminy 2 0 2 60-65 0 0
(Extrasystoles)

Table 3 : 2 x 2 Contingency tables for reported Bupivacaine HCl associated Local

Anesthetic Systemic Toxicity (01 January 2012 and 30 June 2016)

Bupivacaine
HCl All other drugs Total
All Local Anesthetic Systemic 346 214370 214716
Toxicity
All other adverse events 1643 3920644 3922287

Total adverse events 1989 4135014 4137003

Central Local Anesthetic Systemic

Nervous Toxicity 158 170592 170750
system All other adverse events 1831 3964422 3966253
Total adverse events 1989 4135014 4137003

Cardio Local Anesthetic Systemic

Vascular Toxicity 212 51195 51407
system All other adverse events 1777 4083819 4085596
Total adverse events 1989 4135014 4137003

Table 4: Disproportionality analysis results for reported Bupivacaine HCl associated Local
Anesthetic Systemic Toxicity (01 January 2012 and 30 June 2016)

Measure Ratio 95% Confidence 95% Confidence

Interval (lower Interval (upper
limit) limit)
All Proportional Reporting 3.36 3.05 3.69
Ratio (PRR)
Relative Odds Ratio 3.85 3.43 4.33
Relative Reporting Ratio 3.35 3.05 3.69
Chi-Squared with Yates' correction: 599.98

Central Proportional Reporting 1.93 1.66 2.24

Nervous Ratio
21
system Relative Odds Ratio 2.01 1.70 2.36
Relative Reporting Ratio 1.92 1.66 2.24
Chi-Squared with Yates' correction: 72.28

Cardio- Proportional Reporting 8.61 7.58 9.78

Vascular Ratio
system Relative Odds Ratio 9.52 8.25 10.98
Relative Reporting Ratio 8.58 7.55 9.74
Chi-Squared with Yates' correction: 1430.04
Table 5: 2 x 2 Contingency tables for reported Exparel associated Local Anesthetic Systemic
Toxicity (01 January 2013 and 30 June 2016)

Exparel All other drugs Total

All Local Anesthetic Systemic 130 214586 214716
Toxicity
All other adverse events 272 3922015 3922287
Total adverse events 402 4136601 4137003

Central Local Anesthetic Systemic

Nervous Toxicity-CNS 66 170684 170750
system All other adverse events 336 3965917 3966253
Total adverse events 402 4136601 4137003

Cardio Local Anesthetic Systemic

Vascular Toxicity-CVS 64 51343 51407
system All other adverse events 338 4085258 4085596
Total adverse events 402 4136601 4137003

Table 6: Disproportionality analysis results for reported Exparel associated Local Anesthetic
Systemic Toxicity (01 January 2012 and 30 June 2016)

Measure Ratio 95% Confidence 95% Confidence

Interval (lower Interval (upper
limit) limit)
All Proportional Reporting 6.23 5.41 7.18
Ratio (PRR)
Relative Odds Ratio 8.74 7.09 10.77
Relative Reporting Ratio 6.23 5.41 7.18
Chi-Squared with Yates' correction: 596.66

Central Proportional Reporting

Nervous Ratio 3.98 3.19 4.96
system Relative Odds Ratio 4.56 3.51 5.94
Relative Reporting Ratio 3.98 3.19 4.96

22
 Chi-Squared with Yates' correction: 150.39

Cardio Proportional Reporting

Vascular Ratio 12.83 10.24 16.06
system Relative Odds Ratio 15.07 11.53 19.68
Relative Reporting Ratio 12.81 10.23 16.04
Chi-Squared with Yates' correction: 693.89

23