Transcript Promotional Slide Deck - National Association of

A Non-Opioid, Non-NSAID Analgesic
for Perioperative Pain Management
The speaker has been asked to present on the following topic by
Mallinckrodt Pharmaceuticals. However, the thoughts and opinions
expressed by the Speaker do not necessarily reflect the position or
positions of Mallinckrodt.
Acute Perioperative Pain
■ Perioperative pain
 Approximately 46 million inpatient procedures and 35 million outpatient
surgeries were performed in the US in 20061,2
 Despite new treatment standards, guidelines, and educational efforts, acute
postoperative pain continues to be undertreated, with up to 75% of patients
in the US still failing to receive adequate postoperative pain relief3,4
 With the advent of Hospital Consumer Assessment of Healthcare Providers
and Systems (HCAHPS) surveys, patients are now able to make decisions
on hospitals based on quality of care, including quality of pain management
1. DeFrances CJ, Lucas CA, Buie VC, Golosinkskiy A. Natl Health Stat Report. 2008 Jul 30; (5): 1-20. 2. Cullen KA,
Hall MJ, Golosinkskiy. Natl Health Stat Report. 2009 Jan 28; (11): 1-25. 3. Wu CL, Raja SN. Lancet. 2011; 377: 22152225. 4. Phillips DM. JAMA. 2000; 284(4): 428-429.
2
The Historical Acute Pain Paradigm
+++
Severe Pain
Opioids
Moderate Pain
++
Opioids
+
Mild Pain
Opioids
Aubrun et al., 2003
Aubrun F, Langeron O, Quesnel C, Coriat P, Riou B. Anesthesiology. 2003; 98(6): 1415-1421.
3
The Joint Commission Sentinel Event Alert
■ Joint Commission Sentinel Event Alert Entitled “Safe use of opioids in
hospitals”
 Focuses on the need for assessing and managing pain to help avoid accidental
opioid overdose among hospital inpatients
 Provides a number of actions that can be taken to avoid the unintended
consequences
■ Recommendations include advising clinicians who prescribe pain
medications to use both non-pharmacologic and pharmacologic alternatives
 Non-pharmacologic therapies: physical therapy, acupuncture, manipulation or
massage, ice, etc.
 Pharmacologic treatment: non-opioid analgesics, such as acetaminophen,
NSAIDs, antidepressants, anticonvulsants, and muscle relaxants, can be used
before prescribing an opioid
 When used in combination with opioids, these non-opioid pharmacologic
treatments may reduce the dose of opioids required to effectively manage pain
The Joint Commission Sentinel Event Alert. Safe use of opioids in hospitals. Issue 49; August 8, 2012.
http://www.jointcommission.org.
4
Multimodal Techniques for Perioperative Pain
Management
■ Multimodal analgesia combines two or more analgesic agents or
techniques that act by different mechanisms to provide analgesia1
■ ASA, WHO, ASPMN, and The Joint Commission recommend use of a
multimodal approach1-4
■ Opioid dose-sparing effects can be achieved via the use of non-opioid
agents and regional blocks1
■ ASA Task Force recommendations:
 Unless contraindicated, all patients should receive an around-the-clock
regimen of a non-opioid agent
 Non-steroidal anti-inflammatory drugs (NSAIDs)
 Cyclooxygenase-2 specific drugs (COXIBs)
 Acetaminophen
 Consider supplemental regional anesthesia techniques
1. ASA Task Force. Anesthesiology. 2012; 116(2): 248-273. 2. World Health Organization. Pain relief ladder.
http://www.who.int/cancer/palliative/painladder/en/. Accessed September 10, 2014. 3. Jarzyna D, et al. Pain Manage Nurs
2011; 12: 118-145. 4. The Joint Commission Sentinel Event Alert. Safe use of opioids in hospitals. Issue 49; August 8,
2012. www.jointcommission.org/assets/1/18/SEA_49_opioids_8_2_12_finalpdf.
5
Multimodal Approach to Analgesia
Opioids1
2-agonists1
Acetaminophen2
NMDA antagonists3
Local anesthetics1
Opioids1
2-agonists1
NMDA antagonists3
Trauma
Local anesthetics1
NSAIDs1
COXIBs1
NMDA=N-methyl-D-aspartate.
1. Gottschalk A, Smith DS. Am Fam Physician. 2001; 63: 1979-1984 2. Smith HS. Pain Physician. 2009; 12: 269-280.
3. Sinatra RS, Jahr JS, eds. The Essence of Analgesia and Analgesics. New York, NY: Cambridge University Press; 2011.
6
Multimodal Approach to Acute Pain
Management
STEP 3
Severe Pain
STEP 2
and
Higher doses of opioids
STEP 2
Moderate Pain
STEP 1
and
Low doses of opioids
STEP 1
Mild Pain
Acetaminophen, NSAIDs, or COXIBs
and
Local/regional anesthesia
1. Crews JC. JAMA. 2002; 288: 629-632. 2. World Health Organization. Pain relief ladder.
http://www.who.int/cancer/palliative/painladder/en/. Accessed September 10, 2014. 3. Ventafridda V, Tamburini M,
Caraceni A, De Conno F, Naldi F. Cancer. 1987; 59: 850-856. 4. ASA Task Force. Anesthesiology. 2004; 100: 1573-1581.
7
Focus of HCAHPS on Pain and Patient Satisfaction
■ Pain
 Establishing and maintaining an institutional pain performance improvement
plan is a Joint Commission requirement1
■ Patient satisfaction
 Local, regional, or national patient satisfaction data are now being reported
via Hospital Consumer Assessment of Healthcare Providers and Systems
(HCAHPS, also known as CAHPS® hospital survey)2
 As part of the Affordable Care Act 2010, the Centers for Medicare and
Medicaid (CMS) have established hospital reimbursement based on
HCAHPS scores3
 Effective beginning October 1, 2012
1. Wells N, Pasero C, McCaffery M. In: Hughes RG, ed. Patient Safety and Quality: an Evidence-Based Handbook for Nurses.
AHRQ Publication No. 80-0043. 2. US Department of Health and Human Services, Centers for Medicare and Medicaid.
HCAHPS: Patients' Perspectives of Care Survey. http://www.cms.gov/HospitalQualityInits/30_HospitalHCAHPS.asp. Accessed
September 10, 2014. 3. American Hospital Association (AHA) Hospital-based purchasing program: the final rule. May 24, 2011.
http://www.americangovernance.com/americangovernance/webinar/policy/pdf/final_rule_vbp_regulatory_advisory.pdf.
8
Accessed September 10, 2014.
OFIRMEV® (acetaminophen)
Injection Overview
OFIRMEV® (acetaminophen) Injection
INDICATIONS AND USAGE
■
OFIRMEV (acetaminophen) injection is indicated for the:

management of mild to moderate pain

management of moderate to severe pain with adjunctive opioid analgesics

reduction of fever
IMPORTANT RISK INFORMATION
WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY
Take care when prescribing, preparing, and administering OFIRMEV injection to avoid dosing
errors which could result in accidental overdose and death. In particular, be careful to ensure
that:
• the dose in milligrams (mg) and milliliters (mL) is not confused;
• the dosing is based on weight for patients under 50 kg;
• infusion pumps are properly programmed; and
• the total daily dose of acetaminophen from all sources does not exceed maximum daily
limits.
OFIRMEV contains acetaminophen. Acetaminophen has been associated with cases of acute
liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are
associated with the use of acetaminophen at doses that exceed the recommended maximum
daily limits, and often involve more than one acetaminophen-containing product.
OFIRMEV® [package insert]. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company; 2013.
10
Important Risk Information for OFIRMEV®, cont.
CONTRAINDICATIONS
■
Acetaminophen is contraindicated in patients with:

known hypersensitivity to acetaminophen or to any of the excipients in the intravenous (IV)
formulation.

severe hepatic impairment or severe active liver disease.
WARNINGS AND PRECAUTIONS
■
Administration of acetaminophen in doses higher than recommended may result in hepatic
injury, including the risk of liver failure and death. Do not exceed the maximum recommended
daily dose of acetaminophen. The maximum recommended daily dose of acetaminophen
includes all routes of acetaminophen administration and all acetaminophen-containing products
administered, including combination products. Dosing errors could result in accidental overdose
and death.
■
Use caution when administering acetaminophen in patients with the following conditions: hepatic
impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia
(e.g., due to dehydration or blood loss), or severe renal impairment (creatinine clearance ≤30
mL/min).
OFIRMEV® [package insert]. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company; 2013.
11
Important Risk Information for OFIRMEV®, cont.
WARNINGS AND PRECAUTIONS, cont.
■
Rarely, acetaminophen may cause serious skin reactions such as acute generalized
exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal
necrolysis (TEN), which can be fatal.
■
Hypersensitivity and anaphylaxis associated with the use of acetaminophen have been
reported. Clinical signs included swelling of the face, mouth, and throat, respiratory distress,
urticaria, rash, and pruritis.
■
The antipyretic effects of OFIRMEV may mask fever.
ADVERSE REACTIONS
■
Serious adverse reactions may include hepatic injury, serious skin reactions, hypersensitivity,
and anaphylaxis.
■
Common adverse reactions in adults include nausea, vomiting, headache, and insomnia.
Common adverse reactions in pediatric patients include nausea, vomiting, constipation, pruritus,
agitation, and atelectasis.
OFIRMEV® [package insert]. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company; 2013.
12
Important Risk Information for OFIRMEV®, cont.
USE IN SPECIFIC POPULATIONS
■
Pregnancy: Pregnancy Category C. OFIRMEV should be given to a pregnant woman only if
clearly needed.
■
Breast Feeding: While studies with OFIRMEV have not been conducted, acetaminophen is
secreted in human milk in small quantities after oral administration.
■
Pediatrics: The effectiveness of OFIRMEV for the treatment of acute pain and fever has not
been studied in pediatric patients <2 years of age.
OFIRMEV® [package insert]. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company; 2013.
13
Pharmacokinetics and Metabolism of OFIRMEV®
■ Rapid time to reach Cmax
 Peak levels achieved at 15 minutes of administration in both pain
and fever studies1
 Measurable CSF levels at 15 minutes2
■ Peak effect: within an hour of administration1
 OFIRMEV® should only be administered as a 15 minute infusion
■ Dosing interval: 4 to 6 hours1
■ IV acetaminophen bypasses first-pass liver exposure and
metabolism1
The relationship between OFIRMEV pharmacokinetics and clinical
efficacy has not been established.
1.OFIRMEV® [package insert]. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company; 2013. 2. Singla NK,
Parulan C, Samson R, et al. Pain Pract. 2012; 12(7): 523-532.
14
Absorption of Oral Analgesics May be Compromised in
the Perioperative Setting
■ Absorption of oral
acetaminophen is
diminished due to
compromised gastric
function1,2
■ Significant delays in
gastric emptying occur
with the administration
of IV opioid analgesics1
■ Do not exceed the
maximum daily limits of
acetaminophen by all
routes
1. Berger MM, Berger-Gryllaki M, Wiesel PH, et al. Crit Care Med 2000; 28(7): 2217-2223. 2. Petring OU, Dawson PJ,
Blake DW, Jones DJ, Biorksten AR, Libreri FC. Br J Anaesth 1995; 74: 257-260.
15
Absorption of Oral Acetaminophen May be
Decreased by Postoperative Stress and Opioids
Study of Acetaminophen Plasma Concentrations in
Orthopaedic Surgery Patients
Acetaminophen Plasma Concentration (µg/mL)
Postoperative (following
morphine administration)
Preoperative (at least 12
hours)
Minutes
Methods
 Patients (N=8) received IM
morphine 10 mg upon first
complaint of pain post-op
 Oral acetaminophen solution
20 mg/kg given:
 at least 12 hours pre-op,
and
 30 minutes after morphine
administration
Results
 Administration of morphine
reduced and delayed the
absorption of oral
acetaminophen
(AUC0-120, P < 0.005)
Petring OU, Dawson PJ, Blake DW, Jones DJ, Biorksten AR, Libreri FC. Br J Anaesth 1995; 74: 257-260.
16
Pharmacokinetics of OFIRMEV® vs Oral Acetaminophen
PK study comparing IV to oral acetaminophen in healthy adults; efficacy not
assessed
Acetaminophen Plasma
Concentration (µg/mL)1
30
IV acetaminophen (1 g) (n=38*)
Oral acetaminophen (1 g) (n=38*) †
25
■ Mean maximum concentration
(Cmax) is up to 70% higher in IV than
in oral acetaminophen1,2
■ Overall exposures (area under
the concentration-time curve [AUC])
are very similar for IV
and oral acetaminophen2
20
15
■ The first dose PK differences are
maintained with steady-state dosing
(q6h for 48 h), with no evidence of
drug accumulation
10
5
0
0
2
4
6
Time (h)
*Of the 38 randomly assigned patients, 34 patients who received IV acetaminophen 1 g and 33 patients who
received oral acetaminophen 1 g had plasma concentrations measured.
†Rapid release liquid oral acetaminophen (note that C
3
max and AUC values are lower for caplets or tablets )
1. Data on File. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company. 2. OFIRMEV ® [package insert]. San Diego,
CA: Cadence Pharmaceuticals, a Mallinckrodt company; 2013. 3. Kalantzi L, Reppas C, Dressman JB, et al. J Pharma Sci.
17
2006; 95(1): 4-14.
Study of Acetaminophen Plasma Pharmacokinetics (IV, PO, PR)
(Singla et al., 2012)
Randomized, 3-way, cross-over design in 6 healthy volunteers; efficacy was not assessed
25
Mean Plasma Values
 The IV route produced a 76%
IV acetaminophen 1 g
20
higher mean plasma Cmax
(P=0.0004) than PO, and
256% higher (P<0.0001) than
PR
Oral acetaminophen 1 g
Mean (μg/mL)
Rectal acetaminophen 1 g
15
 The median plasma Tmax was
10
earlier (0.25 h for the IV route)
than PO (1.0 h, P=0.0018) or
PR (2.5 h, P=0.0025)
5
 Note: PR acetaminophen
0
0
2
4
Time (hours)
6
data reflects standardization
of the 1300 mg dose to 1000
mg (linear kinetics)
Modified from Singla N, Parulan C, Samson R, et al. Pain Pract. 2012 12(7): 523-532.
18
Study of Acetaminophen Cerebrospinal Fluid PK (IV, PO, PR)
(Singla et al., 2012), cont.
Randomized, 3-way, cross-over design in 6 healthy volunteers; efficacy was not assessed
Mean Cerebrospinal Fluid Values
6

The mean CSF IV
acetaminophen AUC over
6 h is 75% higher than the
PO group (P=0.0099) and
142% higher than the PR
group (P=0.0004)

Comparing mean CSF Cmax
values, the IV group was
59.7% higher than PO
(P<0.0001) and 86.8%
higher than PR (P<0.0001)

The median CSF Tmax
values were 2.0, 4.0 and
6.0 h for IV, PO and PR,
respectively
IV acetaminophen 1 g
Oral acetaminophen 1 g
Rectal acetaminophen 1 g
Mean (μg/mL)
5
4
3
2
AUC0-6 (SD) (µg•h/mL)
IV APAP: 24.9 (17.4)
1
vs PO APAP: 14.2 (52.1); P<0.001
vs PR APAP: 10.3 (24.5); P<0.001
0
0
2
4
6
Time (hours)
* Note: PR acetaminophen data reflects standardization of the 1300 mg dose to 1000 mg (linear kinetics)
Modified from Singla N, Parulan C, Samson R, et al. Pain Pract. 2012 12(7): 523-532.
19
Clinical Studies of
OFIRMEV®
(acetaminophen) Injection
Study in Major Orthopaedic Surgery
(Sinatra et al., 2005)
■ Randomized, double-blind, placebo-controlled multi-dose study in total hip or
knee arthroplasty
■ 7 US centers, N=101 patients (plus 50 patients treated with propacetamol)
■ Started on postoperative day 1 to allow for anesthesia washout (combinations of
general, spinal or epidural anesthesia allowed) and to ensure a stable baseline
■ Moderate to severe pain; patients randomly assigned to 1 of 3 treatment groups
 1 g OFIRMEV®
 2 g propacetamol IV (Note: Propacetamol is not FDA approved in the United States.)
 Placebo
■ Rescue medication: patient-controlled analgesia (PCA) morphine plus as needed
(PRN) bolus doses available to all patients
■ Endpoints: pain intensity, pain relief, patient satisfaction and morphine use were
measured at selected intervals
IMPORTANT RISK INFORMATION
Serious adverse reactions may include hepatic injury, serious skin reactions, hypersensitivity, and
anaphylaxis. Common adverse reactions in adult patients include nausea, vomiting, headache, and
insomnia; and in pediatric patients include nausea, vomiting, constipation, pruritus, agitation, and atelectasis.
Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois C. Anesthesiology. 2005; 102: 822-831.
21
Study in Major Orthopaedic Surgery
(Sinatra et al., 2005), cont.
Mean Pain Relief Score
1.8
IV acetaminophen 1 g q6h + PCA morphine (n=49)
1.6
1.4
**
**
**
*
1.2
Placebo q6h + PCA morphine (n=52)
**
*P<0.05 vs placebo
**P<0.001 vs placebo
*
1.0
**
0.8
**
**
5
6
0.6
0.4
0.2
0
0
1
2
3
Time (h)
4
IV Acetaminophen
Placebo
P value
40.8%
23.1%
0.004†,2
Median time to first use of rescue
3.0 h
0.8 h
0.0001
Morphine consumption over 24 h‡
38.3 mg (33%)
57.4 mg
<0.01
Patient satisfaction: good to excellent at 24 h
Safety (adverse reactions)
† Based
‡ The
1.
IV acetaminophen is comparable to placebo
on Cochran-Mantel Haenszel Test
clinical benefit of reduced opioid consumption was not demonstrated
Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois C. Anesthesiology. 2005; 102: 822831. 2. Data on File. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company.
22
Study in Total Hip Arthroplasty
(Viscusi et al., 2008)
Randomized, Double-Blind, Placebo-Controlled, Total Hip Arthroplasty (N=69)§
Primary Endpoint: Mean Pain Intensity Difference
(PID) as Measured by 4-Point Categorical Scale
Cumulative Percentage of Pain-Free Subjects
IV acetaminophen (1 g) (n=35)
*
*
PID (Mean Score)
1
IV acetaminophen (1 g) (n=35)
Placebo (n=34)
*
*
*
% Pain-Free Patients
1.2
0.8
*
*
0.6
0.4
*
0.2
45
Placebo (n=34)
40
*
4
5
6
*
20
15
10
0
3
*
*
25
-0.2
2
*
30
5
1
*
35
0
0
*
0.25 0.5 0.75
Time (h)
1
2
3
4
5
6
Time (h)
*P<0.05. Opioid rescue medication was freely available to all patients at all times .
§Study
was prematurely terminated due to visible particulates in placebo vials. Planned enrollment was 140 subjects.
Viscusi E, Royal M, Leclerc A, Fong L, Breitmeyer J. AAPM Annual Meeting. Feb 12-16, 2008 (Orlando, FL).
23
Study in Knee Arthroscopy
(Khan et al., 2007)
Mean Verbal Rating Scale (0-4) 0-4 Hours
Mean VRS Score
IV acetaminophen 1 g (n=43)
IV morphine 0.1 mg/kg (n=41)
 Randomized, double-blind
study conducted at a single
site, N=84
 Adult patients undergoing
elective knee arthroscopy
 Prior to general anesthetic
emergence, patients
received single doses of
either:
Adapted from Khan ZU, et al. Pak J Med Sci. 2007; 23(6): 851-853.
 IV acetaminophen 1 g
Pre-Specified Adverse Events
AE
IV acetaminophen
1g
IV morphine
0.1 mg/kg
Nausea
2%
24%
Vomiting
2%
29%
Dizziness
0%
20%
 IV morphine 0.1 mg/kg
 All patients received intraarticular injection of 20 mL
of 0.5% marcaine
Khan ZU, Iqbal J, Saleh H, El Deek AM. Pak J Med Sci. 2007; 23(6): 851-853.
24
Study in General Surgery Requiring ICU Admission
(Memis et al., 2010)
 Randomized, double-blind single site study comparing IV acetaminophen 1 g +
IV meperidine versus placebo plus IV meperidine given q6h for 24 hours
 Patients undergoing major abdominal or pelvic surgery
 Additional IV meperidine given for rescue if BPS or VAS pain >4
Mean Pain Intensity
BPS
VAS
(prior to extubation)
(after extubation)
P <0.01
P <0.01
BPS = behavioral pain scale (3-12)
VAS = visual analog scale (0-10)
IV acetaminophen 1 g q6h + IV meperidine 100 mg/2 mL (n=20)
Placebo + IV meperidine 100 mg/2 mL (n=20)
Memis D, Inal MT, Kavalci G, Sezer A, Sut N. J Critical Care. 2010; 25: 458-62.
25
Study in General Surgery Requiring ICU Admission
(Memis et al., 2010), cont.
Opioid Consumption
Sedation Score
Extubation Time
(mg)
(1-5)
(min)
P <0.05
At Extubation
At 24 Hours
P <0.05
P <0.01
IV acetaminophen 1 g q6h + IV meperidine 100 mg/2 mL (n=20)
Placebo + IV meperidine 100 mg/2 mL (n=20)
Memis D, Inal MT, Kavalci G, Sezer A, Sut N. J Critical Care.
2010; 25: 458-62.
P <0.05
• The difference in the average number of
hours spent in the ICU did not achieve
statistical significance
• The clinical benefit of decreased opioid
consumption has not been evaluated or
demonstrated
26
Study in Renal Colic
(Bektas et al., 2009)
■ A randomized, double-blind, placebo-controlled, single dose clinical
study of adult patients admitted to the ER with suspected renal colic
■ Patients were randomized to receive:
 IV acetaminophen 1 g (n=46)
 IV morphine 0.1 mg/kg – weight self-reported (n=49)
 Placebo (n=51)
■ Analgesia assessed over a 30-minute period
■ Fentanyl available as rescue medication following the 30-minute period
■ Endpoints
 100 mm Visual Analog Scale (VAS)
 4-point Verbal Rating Scale (VRS)
 Amount of rescue consumed
Bektas F, Eken C, Karadeniz O, Goksu E, Cubuk M, Cete Y. Ann Emerg Med. 2009; 54(4): 568-574.
27
Study in Renal Colic
(Bektas et al., 2009), cont.
Median VAS (mm)
Results
VAS (mm)
■ Significant pain
intensity reductions for
IV acetaminophen
(P=0.005) versus
placebo
Time (min) following initiation of study drug
IV acetaminophen 1 g
(n=46)
P=0.005 vs placebo
IV placebo
(n=51)
Percentage
% Patients Requiring Rescue following 30 Minutes
■ The % of patients
requiring rescue
medication was not
significantly different
between IV
acetaminophen and
placebo
P = NS
Bektas F, Eken C, Karadeniz O, Goksu E, Cubuk M, Cete Y. Ann Emerg Med. 2009; 54(4): 568-574.
28
Reduced Opioid Consumption
Total Hip & Knee
Replacement1
Major Abdominal
Surgery2
Total Hip
Replacement3 *
Adult
Tonsillectomy4
(Morphine over 24 h, mg)
(Meperidine, mg)
(Morphine equivalents 0-6 h, mg)
(Meperidine doses)
P<0.05
P<0.01
P=0.016
P<0.001
 33%
 61%
OFIRMEV 1 g
 53%
 78%
Placebo
Note: The clinical benefit of decreased opioid consumption has not been evaluated or demonstrated.
ADVERSE REACTIONS

Serious adverse reactions may include hepatic injury, serious skin reactions, hypersensitivity, and
anaphylaxis.

Common adverse reactions in adults include nausea, vomiting, headache, and insomnia. Common adverse
reactions in pediatric patients include nausea, vomiting, constipation, pruritus, agitation, and atelectasis.
*This study was terminated early due to the detection of particulates in some placebo vials
1. Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois C. Anesthesiology. 2005; 102(4): 822-831.
2. Memis D, Inal MT, Kavalci G, Sezer A, Sut N. J Crit Care. 2010; 25(3): 458-462. 3. Viscusi E, Royal M, Leclerc A, Fong L,
Breitmeyer J. AAPM Annual Meeting. Feb 12-16, 2008 (Orlando, FL). 4. Atef A, Fawaz AA. Eur Arch Otorhinolaryngol. 2008;
265(3): 351-355.
29
Improved Patient Satisfaction
% of Patients Reporting “Good” or “Excellent” Satisfaction
Abdominal Laparoscopy1,4
Total Hip & Knee
Replacement2,4
Total Hip Replacement3,4 *
Patient Satisfaction at 24 h
Satisfaction with Treatment at 24 h
Overall Satisfaction at Bedtime
85.7%
70.3%
P=0.0004
86.9%
P=0.004
P<0.001
40.8%
39.3%
23.1%
All patients had access to IV opioid rescue medication as needed
Placebo
Patient satisfaction was a pre-specified secondary endpoint where subjects were asked to evaluate the
study treatments overall using a 4-point categorical scale.
OFIRMEV
*This study was terminated early due to the detection of particulates in some placebo vials
1. Wininger S, Miller H, Minkowitz HS, et al. Clin Ther. 2010; 32: 2348-2369. 2. Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine
SB, Payen-Champenois C. Anesthesiology. 2005; 102: 822-831. 3. Gimbel J, Royal M, Leclerc A, Smith H, Breitmeyer J. AAPM Annual
Meeting. Feb 12-16, 2008 (Orlando, FL). 4. Data on File. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company.
30
Safety and Tolerability of
OFIRMEV®
(acetaminophen) Injection
Hepatic Safety Data for OFIRMEV®
Liver enzyme elevations were comparable to placebo1
Peak ALT/AST value post-baseline: % of patients in all repeated-dose,
placebo-controlled, all-adult studies
IV Acetaminophen
Placebo
(n=402)
(n=379)
ALT
>3x ULN
>5x ULN
1.1% (n=4)
0.3% (n=1)
1.7% (n=6)
0.6% (n=2)
AST
>3x ULN
>5x ULN
1.0% (n=4)
0.5% (n=2)
1.1% (n=4)
0.8% (n=3)
Data from a pooled analysis of 5 repeated-dose placebo-controlled clinical studies involving adult patients.
IMPORTANT RISK INFORMATION
OFIRMEV contains acetaminophen has been associated with cases of acute liver failure, at times
resulting in liver transplant and death. Most of the cases of liver injury are associated with use of
acetaminophen at doses that exceed the recommended maximum daily limits, and often involve more
than one acetaminophen-containing product.2
1. Data on File. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company. 2. OFIRMEV ® [package insert]. San
Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company; 2013.
32
Treatment-Emergent Adverse Events Occurring ≥3%
in Adults Receiving OFIRMEV® and at a Greater Frequency
Than Placebo in Repeated-Dose Studies
Treatment-Emergent Adverse Event
(TEAE)
OFIRMEV
(n=402)
n (%)
Placebo
(n=379)
n (%)
Nausea
138 (34%)
119 (31%)
Vomiting
62 (15%)
42 (11%)
Pyrexia†
22 (5%)
52 (14%)
Headache
39 (10%)
33 (9%)
Insomnia
30 (7%)
21 (5%)
† Pyrexia
adverse reaction frequency data is included in order to alert healthcare practitioners that the
antipyretic effects of OFIRMEV may mask fever.
The differences between treatment groups were not statistically significant for any reported TEAE.
OFIRMEV® [package insert]. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company; 2013.
33
Recommended Dosing of OFIRMEV®
Dosing of OFIRMEV for Adults, Adolescents, and Children ≥2 Years Old
Age Group
Adults and adolescents
(≥13 years old) ≥50 kg
Dose Given
Every 4 h*
Dose Given
Every 6 h*
Maximum
Single Dose*
Maximum Total Daily
Dose of Acetaminophen
(by all routes)
650 mg
1000 mg
1000 mg
4000 mg in 24 h
15 mg/kg
15 mg/kg
(up to
750 mg)
75 mg/kg in 24 h
(up to 3750 mg)
Adults and adolescents
(≥13 years old) <50 kg
12.5 mg/kg
Children ≥2 to 12 years
old
* Each mL contains 10 mg of OFIRMEV.
WARNINGS AND PRECAUTIONS
Administration of acetaminophen by any route in doses higher than recommended may result
in hepatic injury, including the risk of liver failure and death.
Please see Important Risk Information, including complete boxed warning, in Full Prescribing
Information.
OFIRMEV® [package insert]. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company; 2013.
34
Administration of OFIRMEV®
 OFIRMEV® should be administered only as a 15-minute IV
infusion
 Minimum dosing interval is 4 hours, not to exceed 4 g of
acetaminophen by all routes in 24 hours
 An infusion pump is not required except when delivering
weight-based calculated doses less than 600 mg (60 mL).
Use a syringe pump for administering small volume doses,
particularly in young children
 No dosage adjustment is required when transitioning to oral
acetaminophen
OFIRMEV® [package insert]. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company; 2013.
35
Summary of OFIRMEV® Data
■ OFIRMEV® should be considered as a foundational approach to multimodal
analgesia
■ OFIRMEV has demonstrated:
 Significant reductions in pain intensity1-4
 Reduced opioid consumption1,3,4
 Improved patient satisfaction1,2
■ OFIRMEV has an established safety profile and was well tolerated in clinical
trials1-5
*Note: The clinical benefit of reduced opioid consumption has not been evaluated or demonstrated
IMPORTANT RISK INFORMATION
Do not exceed the maximum recommended daily limit of acetaminophen by all routes.5
Acetaminophen should be used with caution in patients with the following conditions: hepatic
impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia, or
severe renal impairment.5
1. Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois C. Anesthesiology. 2005; 102:
822-831. 2. Wininger SJ, Miller H, Minkowitz, et al. Clin Ther. 2010; 32:2348-69. 3. Memis D, Inal MT, Kavalci G,
Sezer A, Sut N. J Crit Care. 2010; 25: 458-462. 4. Atef A, Fawaz AAl. Eur Arch Otorhinolaryngol. 2008; 265: 351-355.
5. OFIRMEV® [package insert]. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company; 2013.
36
Important Safety Information for OFIRMEV®
(acetaminophen) Injection
INDICATIONS AND USAGE
■
OFIRMEV (acetaminophen) injection is indicated for the:

management of mild to moderate pain

management of moderate to severe pain with adjunctive opioid analgesics

reduction of fever
IMPORTANT RISK INFORMATION
WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY
Take care when prescribing, preparing, and administering OFIRMEV injection to avoid dosing
errors which could result in accidental overdose and death. In particular, be careful to ensure
that:
• the dose in milligrams (mg) and milliliters (mL) is not confused;
• the dosing is based on weight for patients under 50 kg;
• infusion pumps are properly programmed; and
• the total daily dose of acetaminophen from all sources does not exceed maximum daily
limits.
OFIRMEV contains acetaminophen. Acetaminophen has been associated with cases of acute
liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are
associated with the use of acetaminophen at doses that exceed the recommended maximum
daily limits, and often involve more than one acetaminophen-containing product.
OFIRMEV® [package insert]. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company; 2013.
37
Important Risk Information for OFIRMEV®, cont.
CONTRAINDICATIONS
■
Acetaminophen is contraindicated in patients with:

known hypersensitivity to acetaminophen or to any of the excipients in the intravenous (IV)
formulation.

severe hepatic impairment or severe active liver disease.
WARNINGS AND PRECAUTIONS
■
Administration of acetaminophen in doses higher than recommended may result in hepatic
injury, including the risk of liver failure and death. Do not exceed the maximum recommended
daily dose of acetaminophen. The maximum recommended daily dose of acetaminophen
includes all routes of acetaminophen administration and all acetaminophen-containing products
administered, including combination products. Dosing errors could result in accidental overdose
and death.
■
Use caution when administering acetaminophen in patients with the following conditions: hepatic
impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia
(e.g., due to dehydration or blood loss), or severe renal impairment (creatinine clearance ≤30
mL/min).
OFIRMEV® [package insert]. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company; 2013.
38
Important Risk Information for OFIRMEV®, cont.
WARNINGS AND PRECAUTIONS, cont.
■
Rarely, acetaminophen may cause serious skin reactions such as acute generalized
exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal
necrolysis (TEN), which can be fatal.
■
Hypersensitivity and anaphylaxis associated with the use of acetaminophen have been
reported. Clinical signs included swelling of the face, mouth, and throat, respiratory distress,
urticaria, rash, and pruritis.
■
The antipyretic effects of OFIRMEV may mask fever.
ADVERSE REACTIONS
■
Serious adverse reactions may include hepatic injury, serious skin reactions, hypersensitivity,
and anaphylaxis.
■
Common adverse reactions in adults include nausea, vomiting, headache, and insomnia.
Common adverse reactions in pediatric patients include nausea, vomiting, constipation, pruritus,
agitation, and atelectasis.
OFIRMEV® [package insert]. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company; 2013.
39
Important Risk Information for OFIRMEV®, cont.
USE IN SPECIFIC POPULATIONS
■
Pregnancy: Pregnancy Category C. OFIRMEV should be given to a pregnant woman only if
clearly needed.
■
Breast Feeding: While studies with OFIRMEV have not been conducted, acetaminophen is
secreted in human milk in small quantities after oral administration.
■
Pediatrics: The effectiveness of OFIRMEV for the treatment of acute pain and fever has not
been studied in pediatric patients <2 years of age.
OFIRMEV® [package insert]. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company; 2013.
40
References
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(5): 1-20.
Cullen KA, Hall MJ, Golosinkskiy A. Ambulatory surgery in the United States, 2006. Natl Health Stat Report. 2009 Jan 28; (11): 1-25.
Wu CL, Raja SN, Treatment of acute postoperative pain. Lancet. 2011; 377: 2215-2225.
Phillips DM. JCAHO pain management standards unveiled. JAMA. 2000; 284(4): 428-429.
Aubrun F, Langeron O, Quesnel C, Coriat P, Riou B. Relationships between measurement of pain using visual analog score and
morphine requirements during postoperative intravenous morphine titration. Anesthesiology. 2003; 98(6): 1415-1421.
The Joint Commission Sentinel Event Alert. Safe use of opioids in hospitals. Issue 49; August 8, 2012.
www.jointcommission.org/assets/1/18/SEA_49_opioids_8_2_12_finalpdf.
American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in
the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management.
Anesthesiology. 2012; 116(2): 248-273.
World Health Organization. Pain relief ladder. http://www.who.int/cancer/palliative/painladder/en/. Accessed September 10, 2014.
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Gottschalk A, Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician. 2001; 63: 1979-1984.
Smith HS. Potential analgesic mechanisms of acetaminophen. Pain Physician. 2009; 12: 269-280.
Sinatra RS, Jahr JS, eds. The Essence of Analgesia and Analgesics. New York, NY: Cambridge University Press; 2011.
Crews JC. Multimodal pain management strategies for office-based and ambulatory procedures. JAMA. 2002; 288: 629-632.
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Ventafridda V, Tamburini M, Caraceni A, De Conno F, Naldi F. A validation study of the WHO method for cancer pain relief. Cancer.
1987; 59: 850-856.
American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in
the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management.
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Wells N, Pasero C, McCaffery M. Improving the quality of care through pain assessment and management. In: Hughes RG, ed.
Patient Safety and Quality: an Evidence-based Handbook for Nurses. AHRQ Publication No. 08-0043. Rockville, MD: Agency for
Healthcare Research and Quality; March 2008.
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Survey. http://www.cms.gov/HospitalQualityInits/30_HospitalHCAHPS.asp. Accessed September 10, 2014.
American Hospital Association (AHA) Hospital-based purchasing program: the final rule. May 24, 2011.
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September 10, 2014.
OFIRMEV® [package insert]. San Diego, CA: Cadence Pharmaceuticals, a Mallinckrodt company; 2013.
Singla NK, Parulan C, Samson R, et al. Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration
of intravenous, oral, or rectal acetaminophen. Pain Pract. 2012; 12(7): 523-532.
Berger MM, Berger-Gryllaki M, Wiesel PH, et. al. Intestinal absorption in patients after cardiac surgery. Crit Care Med. 2000; 28(7):
2217-2223.
Petring OU, Dawson PJ, Blake DW, Jones DJ, Bjorksten AR, Libreri FC. Normal postoperative gastric emptying after orthopaedic
surgery with spinal anaesthesia and i.m. ketorolac as the first postoperative analgesic. Br J Anaesth. 1995; 74: 257-260.
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42
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Kalantzi L, Reppas C, Dressman JB, et al. Biowaiver monographs for immediate release solid oral dosage forms: Acetaminophen
(paracetamol). J Pharma Sci. 2006; 95(1): 4-14.
Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois C. Efficacy and safety of single and repeated
administration of 1 gram intravenous acetaminophen injection (paracetamol) for pain management after major orthopedic surgery.
Anesthesiology. 2005; 102: 822-831.
Viscusi G, Royal M, Leclerc A, Fong L, Breitmeyer J. Pharmacokinetics, efficacy and safety of IV acetaminophen in the treatment of
pain following total hip arthroplasty: results of a double-blind, randomized, placebo-controlled, single-dose study. Presented at 24th
Annual Meeting of the American Academy of Pain Medicine. February 12-16, 2008 (Orlando, FL).
Khan ZU, Iqbal J, Saleh H, El Deek AM. Intravenous paracetamol is as effective as morphine in knee arthroscopic day surgery
procedures. Pak J Med Sci. 2007; 23(6): 851–853.
Memis D, Inal MT, Kavalci G, Sezer A, Sut N. Intravenous paracetamol reduced the use of opioids, extubation time, and opioidrelated adverse effects after major surgery in intensive care unit. J Crit Care. 2010; 25(3): 458462.
Bektas F, Eken C, Karadeniz O, Goksu E, Cubuk M, Cete Y. Intravenous paracetamol or morphine for the treatment of renal colic: A
randomized, placebo-controlled trial. Ann Emer gMed. 2009; 54: 568574.
Serinken M, Eken C, Turkcuer I, Elicabuk H, Uyanik E, Schultz CH. Intravenous paracetamol versus morphine for renal colic in the
emergency department: a randomised double-blind controlled trial. Emerg Med J. 2012; 29: 902905.
Atef A, Fawaz AA. Intravenous paracetamol is highly effective in pain treatment after tonsillectomy in adults. Eur Arch
Otorhinolaryngol. 2008; 265: 351-355.
Wininger SJ, Miller H, Minkowitz HS, et al. A randomized, double-blind, placebo-controlled, multi-center, repeat-dose study of two
intravenous acetaminophen dosing regimens for the treatment of pain after abdominal laparoscopic surgery. Clin Ther. 2010; 32(14):
23482369.
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Gimbel J, Royal M, Leclerc A, Smith H, Breitmeyer J. Efficacy and safety of IV acetaminophen in the treatment of pain following
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Presented at: 24th Annual Meeting of the American Academy of Pain Management (February 1216, 2008; Orlando, FL).
44
Thank You
Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and other brands are trademarks of a Mallinckrodt company. © 2014 Mallinckrodt.