in Therapeutics InjectableAcetaminophen · in relation to this presentation. Additional Goals ......

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Decisions, Decisions…Debates in Therapeutics

Injectable Acetaminophen:What is its role in postoperative

pain management?p g

Daniel T. Abazia, Pharm.D., BCPSPharmacy Clinical CoordinatorPalos Community Hospital

Disclosures

The speaker has no actual or potential conflict of in relation to this presentation.

Additional Goals

By the end of this knowledge‐based educational activity, participants should be able to:

1. Explain the clinical and economic consequences of inadequate control of postoperative pain.p p p

2. Identify elements of multimodal postoperative analgesia.3. Discuss clinical data for using injectable acetaminophen for management of postoperative pain.

4. Describe the practical aspects of utilizing injectable acetaminophen within the acute care setting.

Palos Community Hospital

• Located in southwest suburbs of Chicago, IL

• Community, non‐teaching• 436 licensed beds• Pharmacy satellite in OR2011 surgical statistics‐ Inpatient procedures: 3,993

‐ Outpatient procedures: 4,575

Impact of Postoperative PainNegative CLINICAL Outcomes: • Cognitive dysfunction• Coronary ischemia / myocardial infarction• Deep vein thrombosis / pulmonary embolism • Insomnia• Pneumonia• Poor wound healing and recovery

Apfelbaum JL, Chen C, Mehta SS, et al. Postoperative pain experience: results of from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003; 97:534‐40.

Kehlet H, Holte K. Effect of postoperative analgesia on surgical outcome. Br J Anaesth. 2001;87:62‐72.

Postop Pain: Link to Chronic Pain

• Retrospective analysis• Evaluated patients undergoing thoracotomy who developed

chronic pain (n = 78) vs. those who did not (n = 71) one week postopP ti t h d l d h i i h d i d• Patients who developed chronic pain had increased...↑ incidence of acute pain (p = 0.002)↑ severity of acute pain (p = 0.0001)↑ total me having pain (p = 0.02)

• Progression to chronic pain increased with intensity of acute postoperative pain

Pluijms WA, Steegers MA, Verhagen AF, et al. Chronic post-thoracotomy pain: a retrospective study. Acta Anaesthesiol Scand. 2006; 50:804-8.

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Impact of Postoperative Pain• Pilot prospective cohort study

• Purpose was to describe postoperative pain and health‐related QOL, and functioning 1 month after hospital discharge

• Participants underwent radical prostatectomy (RP), total hip replacement (THR), or total knee replacement (TKR), and completed the SF‐36 and questions from the Treatment Outcomes of Pain Survey (TOPS) 4 weeks after leaving the hospital

( )– N = 30 ( RP = 15, TKR = 8, THR = 7)

• Postoperative pain interfered with patient's ability to participate in desired activities (42.9% RP, 28.6% THR, 100% TKR), ability to sleep (21.4% RP, 71.4% THR, 75% TKR), and sexual functioning (50% RP, 28.6% THR, 25% TKR). During the first month after surgery, postop pain contributed to diminished health‐related QOL and interfered with activities important to patients. Mean SF‐36 scale scores in each surgical group were lower than US norms for physical functioning, physical roles, bodily pain, vitality and social functioning

Strassels SA, McNicol E, Wagner AK, et al. Persistent postoperative pain, health‐related quality of life, and functioning 1 month after hospital discharge. Acute Pain. 2004; 6(3):95‐104.

Active Learning Assessment

POLL1. How many of you have had an inpatient or outpatient

surgical procedure in your lifetime?2. How many of you have experienced pain following the

procedure?procedure?3. How many of you have experienced one of the negative

clinical outcomes following the procedure?4. How many of you have missed work or school following the

procedure?

Opioid Adverse Events• Historically, opioid monotherapy primary treatment of

postoperative pain• 24 – 48 hours postoperatively: morphine or hydromorphone

PCA followed by oral hydrocodone, morphine, or oxycodoneIn a systematic review of several randomized controlled trials• In a systematic review of several randomized controlled trials analyzing opioid‐associated ADEs in postop patients, more than 30% of patients reported GI ADEs– Most common: vomiting, constipation, and ileus– Most severe ADEs reported: sedation and resp depression

Oderda GM, Said Q, Evans RS, et al. Opioid‐related adverse drug events in surgical hospitalizations: impact on costs and length of stay. Ann Pharmacother. 2007;41(3):400‐406.

Wheeler M, Oderda GM, Ashburn MA, el al. Adverse events associated with postoperative opioid analgesia: a systemic review. J Pain. 2002;3(3):159‐180.

Multimodal Analgesia• Use of different classes of analgesics that employ different

pathways AND receptors to provide pain relief• Ideal components of multimodal analgesia include:

‐ Agents with ability to modulate ≥ mechanism of pain transmission

Agents with an acceptable safety profile‐ Agents with an acceptable safety profile

‐ Availability of an analgesic in a non‐oral formulation

• Multimodal analgesia includes the use of local and systemic pharmaceutical agents in addition to perineural blockade and regional anesthesia

White PF. Multimodal analgesia: its role in preventing postoperative pain. Curr Opin Investig Drugs. 2008; 9(1):76‐82.

Joshi GP. Multimodal analgesia techniques and postoperative rehabilitation. Anesthesiol Clin North Am. 2005;23(1):185‐202.

Multimodal Analgesia

Kehlet H, Dahl JB. Anesth Analg. 1993;77:1048‐1056.

WHO Pain Ladder

Adapted from World Health Organization. Cancer Pain Relief and Palliative Care, Report of a WHO Expert Committee. Geneva: World Health Organization; 1990.

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Multimodal AnalgesiaAmerican Society of Anesthesiologists – 2012 Practice Guideline:

“The consultants and ASA members strongly agree that whenever possible, anesthesiologists should use multimodal pain management therapy. The ASA members agree and the consultants strongly agree that APAP should be considered as part of a postoperative multimodal pain management

i b h h l d b hregimen; both the consultants and ASA members agree that COX‐2 inhibitors, nonselective NSAIDs, and calcium channel ‐2‐ antagonists

(gabapentin and pregabalin) should be considered as part of a postoperative multimodal pain management regimen. Moreover, the ASA members agree and the consultants strongly agree that, unless

contraindicated, patients should receive an around‐the‐clock regimen of NSAIDs, COX‐2 inhibitors, or APAP.”

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; 116:248–73.


Jeopardy

A concept that utilizes multiple classes of medications with acceptable safety profiles that employ different pathwaysacceptable safety profiles that employ different pathways

and receptors to provide relief of pain.

What is multimodal analgesia?

Acetaminophen

• Oral formulation available in US since 1955

• IV formulation approved by FDA in November 2010 for use in (pain fever)

Care needed with IV acetaminophen. Am J Health‐Syst Pharm. 2011; 68:1775‐6.

use in (pain, fever)• Recognized as safe and effective at recommended doses Adapted from:

http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=5836

Pharmacodynamics

• Analgesic effect of APAP involves both central and peripheral actions‐ Inhibition of nitric oxide synthesis pathway

‐ Inhibition of prostaglandin synthesis

• Analgesic effects of paracetamol may also involve the serotonergic system‐ Pickering and colleagues identified agonists of the serotonin 5‐HT3 receptor, granisetron and tropisetron, completely blocked the

analgesic effect of paracetamol in healthy males

Duggan ST, Scott LJ. Intravenous paracetamol (acetaminophen). Drugs. 2009; 69 (1): 101‐113.

Pickering G, Loriot MA, Libert F, et al. Analgesic effect of acetaminophen in humans: first evidence of a centralserotonergic mechanism. Clin Pharmacol Ther. 2006 Apr; 79 (4): 371‐8

PharmacokineticsAbsorption

Peak concentration is observed at the

end of infusion

Distribution

Mean Vd reported in several studies has

d f l

Ofirmev injection prescribing information. San Diego, CA: Cadence Pharmaceuticals, Inc.; Nov 2010. Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd‐9465‐40d8‐861d‐3904496d82b7.

Duggan ST, Scott LJ. Intravenous paracetamol (acetaminophen). Drugs 2009; 69 (1): 101‐113.

ranged from 69.2 ‐ 85 L; not extensively

plasma protein–bound (10% to 25%)

Elimination

Half‐life is 2.4 hours in adults, 2.9 hrs

in adolescents, 1.5 to 3 hrs in children,

4.2 hrs in infants Adapted from: http://www.fda.gov/ohrms/dockets/ac/02/briefing/3882B1_13_McNeil‐Acetaminophen.htm

Dosage and Administration

IV APAP Oral APAP Rectal APAP

Dosage and Administration

50 kg: 1 gm q6h or 650 mg q4h (Max 4 gm/day)< 50 kg or ages 2–12:

Adults: 650 mg or 1 gm q4–6h or 1.3 gm ER tablets q8h PRN (Max 4 gm/day)Children aged < 12:

Adults: 325–650 mg q4h PRNChildren aged 2–12: weight‐adjusted dose

Ofirmev injection prescribing information. San Diego, CA: Cadence Pharmaceuticals, Inc.; Nov 2010. Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd‐9465‐40d8‐861d‐3904496d82b7.

Yeh YC, Reddy P. Clinical and economic evidence for intravenous acetaminophen. Pharmacother. 2012; ; 32(6):559‐79.

15 mg/kg q6h or 12.5 mg/kg q4h (Max 75 mg/kg/day)15 min infusion

Children aged < 12: weight‐adjusted 40–480 mg q4–6 h(Max 5 doses/day)

160–480 mg q4h(Max 5 doses/day)Children aged < 2: individualized

Formulation 1 gm/100 mL SDV Tablet, capsule, suspension, solution

Suppository

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Safety Profile• Amar et al confirmed that doses > 4 grams per day may cause

centrilobular hepatic necrosis in adults‐ Administration of scheduled doses for more than a few days

requires caution

• Singla et al compared the safety profile of IV APAP (1 gm q6h and 650 mg q4h) with the standard‐of‐care in 213 patients. ‐ A lower proportion (~15% vs. 26.7) of patients with elevated

LFTs in the IV APAP groups compared with the control group

Amar PJ, Schiff ER. Acetaminophen safety and hepatotoxicity—where do we go fromhere? Expert Opin Drug Saf. 2007;6(4):341‐355.

Singla N, Ferber L, Bergese S, et al. A phase III, multi‐center, open‐label, prospective, repeated dose, randomized, controlled, multi‐day study of the safety of intravenous acetaminophen in adult inpatients. Proceedings and Abstracts of the 34th Annual American Society of Regional Anesthesia Meeting and Workshops. April 30 to May 3, 2009; Phoenix, AZ. Poster 96.

Meta ‐ Analyses• Rømsing et al1 evaluated the analgesic effect of rectal, IV, and oral

formulations of APAP was evaluated (24 studies, 2023 patients)‐ APAP, given either rectally or IV, was effective for post‐op pain relief

‐ Addition of NSAIDs to APAP predictably improved pain relief, whereas

adding APAP to NSAIDs was less predictable

Remy et al2 and Elia et al3 evaluated outcomes of APAP (IV PO and• Remy et al2 and Elia et al3 evaluated outcomes of APAP (IV, PO, and PR) in combination with PCA after orthopedic and abdominal surgery‐ 7 trials (491 patients) and 10 trials (769 patients), respectively

‐ Compared with placebo, APAP given post‐op significantly reduced

morphine requirements by ~20% (8‐10 mg) on post‐op Day 1

‐ Not associated with a significant reduction in post‐op N/V, sedation,

urinary retention, and respiratory depression


LA is a 92 year old male with a PMH significant for colon polyps, gastric ulcers, hypertension, hyperlipidemia, atrial fibrillation –s/p pacemaker recently diagnosed with early stage colon CA. He is admitted for a partial colectomy and your medical team asks

h h S i l i i ld byou what the BEST postoperative analgesic regimen would be for this patient. He is allergic to morphine (itching).

HINT: Your formulary analgesics include IV and PO APAP, celecoxib, fentanyl IV and TD, hydrocodone, hydromorphone, PO ibuprofen, ketorolac, morphine, and oxycodone.

IV Acetaminophen DUE

• Randomized, retrospective, case‐control evaluation

• Evaluated post‐op pain management 3 months before and 3 months after IV APAP added to PCH formularymonths after IV APAP added to PCH formulary

• 25 patients in each group

• Objective was to investigate if the use of IV APAP reduces the use of opioids and NSAIDs in post‐op general surgical patients

IV Acetaminophen DUEInclusion Exclusion

≥18 year of age

General surgical procedures

Inpatient at least 24 hours post –op

Received min 2 doses of 1gm IV APAP

Allergy or hypersensitivity to APAP

Transaminases > 2 x ULN)

SCr > 2 mg/dL

Uncontrolled chronic disease

Body weight 50‐120 kg

Numeric pain scale used (1‐10)

ASA class 1‐3

History of alcohol or drug abuse

Pregnant or breastfeeding

Treatment of fever

Primary endpoint

Total morphine and NSAID equivalent dose during first 24 hours

Secondary endpoints

PACU LOS and pain score reduction

IV Acetaminophen DUEResults•↓ total opioid use by 24%

•↓ total NSAID use by 100 %

Limitations•Retrospective, observational study

•IV APAP was not available in OR

•Not all patients received IV APAP•↓ their total pain score by 9%

•Did NOT reduce their PACU length of stay

•Not all patients received IV APAP as a scheduled med

•IV APAP group received higher doses of total fentanyl, midazolam, dexamethasone and ketorolac

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Impact on Med‐Use ProcessPrescribing• Which dose...650 mg or 1000 mg (adults)?• Dose calculation required for pediatrics• Scheduled vs. PRN• Restrictions to specialists, units, or patient types?

Dispensing• Doses < 1000 mg require manipulation • Contents of vial must be administered within 6 hrs• Adequate space in automated dispensing machine (ADM)?

Impact on Med‐Use ProcessAdministration• Infusion pump required

‐Errors related to infusion pump programming have been reported to the Institute for Safe Medication Practices (ISMP)

> ISMP recommends use of bothmg andmL dosing when> ISMP recommends use of both mg and mL dosing when prescribing and communicating dose information

• Y‐site compatibility for patients with multiple infusions

Institute for Safe Medication Practices (ISMP).IV acetaminophen and overdoses in kids. ISMP Medication Safety Alert. Apr 2012; 17(8):1,4.

Impact on Med‐Use Process

Monitoring• Ensure use of < 4 grams per day of APAP

‐ Hold use of combo APAP products 24 to 48 hours post‐op

> FDA requiring manufacturers to limit APAP in prescription> FDA requiring manufacturers to limit APAP in prescription products to 325 mg per single dosage unit and add a black‐box warning by 2014

• Cost‐effectiveness‐ IV to PO conversion

‐ Automatic stop dates/times, e.g. 24 hours after 1st dose

Food and Drug Administration. Prescription drug products containing acetaminophen; actions to reduceliver injury from unintentional overdose. Fed Regist. 2011; 76:2691‐7.

Active Learning AssessmentWhich of the following are issues that must be addressed when evaluating IV APAP for formulary addition?

I. Ensuring patients do not receive > 4 gm APAP per 24 hrsII. Manipulation of vials when doses are less than 1 gmIII. Risk of infusion pump errors if doses not ordered in mg and p p g

mLa. I onlyb. III onlyc. I and IId. II and IIIe. I, II, and III

Conclusions

• IV APAP is generally well tolerated at recommended doses

• Clinical trials indicate IV APAP is an effective analgesic in a variety of inpatient and outpatient surgical procedures

• Use should be limited to ≤ 24 hours postoperatively and patients who can not tolerate PO or PR administration

• Institution‐specific strategies are required to ensure safe use of IV APAP

Thank [email protected]

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References

1. Rømsing J, Møiniche S, Dahl JB. Rectal and parenteral paracetamol, and paracetamol in combination with NSAIDs, for postoperative analgesia. Br J Anaesth. 2002;88:215–26.

2. Remy C, Marret E, Bonnet F. Effects of acetaminophen on morphine side‐effects and consumption after major surgery: a meta‐analysis of randomized controlled trials. Br J Anaesth. 2005;94:505–13.

3. Elia N, Lysakowski C, Tramer M. Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase‐2 inhibitors and patient‐controlled analgesia morphine offer advantages over morphine alone? Anesthesiology. 2005;103:1296–304.

2012 ICHP Annual Meeting Injectable Acetaminophen: What is its role in postoperative pain management?

Bibliography

1. Apfelbaum JL, Chen C, Mehta SS, et al. Postoperative pain experience: results of from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003; 97:534-40.

2. Kehlet H, Holte K. Effect of postoperative analgesia on surgical outcome. Br J Anaesth. 2001; 87:62-72.

3. Pluijms WA, Steegers MA, Verhagen AF, et al. Chronic post-thoracotomy pain: a retrospective study. Acta Anaesthesiol Scand. 2006; 50:804-8.

4. Strassels SA, McNicol E, Wagner AK, et al. Persistent postoperative pain, health-related quality of life, and functioning 1 month after hospital discharge. Acute Pain. 2004; 6(3):95-104.

5. Oderda GM, Said Q, Evans RS, et al. Opioid-related adverse drug events in surgical hospitalizations: impact on costs and length of stay. Ann Pharmacother. 2007;41(3):400-406.

6. Wheeler M, Oderda GM, Ashburn MA, el al. Adverse events associated with postoperative opioid analgesia: a systemic review. J Pain. 2002;3(3):159-180.

7. White PF. Multimodal analgesia: its role in preventing postoperative pain. Curr Opin Investig Drugs. 2008; 9(1):76-82.

8. Joshi GP. Multimodal analgesia techniques and postoperative rehabilitation. Anesthesiol Clin North Am. 2005;23(1):185-202.

9. Kehlet H, Dahl JB. The value of multimodal or balanced analgesia in the postoperative pain treatment. Anesth Analg. 1993;77:1048-1056.

10. World Health Organization. Cancer Pain Relief and Palliative Care, Report of a WHO Expert Committee. Geneva: World Health Organization; 1990.

11. 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; 116:248–73.

12. Care needed with IV acetaminophen. Am J Health-Syst Pharm. 2011; 68:1775-6. 13. Duggan ST, Scott LJ. Intravenous paracetamol (acetaminophen). Drugs. 2009; 69 (1): 101-

113. 14. Pickering G, Loriot MA, Libert F, et al. Analgesic effect of acetaminophen in humans: first

evidence of a central serotonergic mechanism. Clin Pharmacol Ther. 2006 Apr; 79 (4): 371-8 15. Ofirmev injection prescribing information. San Diego, CA: Cadence Pharmaceuticals, Inc.;

Nov 2010. Available at: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c5177abd-9465-40d8-861d-3904496d82b7.

16. Yeh YC, Reddy P. Clinical and economic evidence for intravenous acetaminophen. Pharmacother. 2012; 32(6):559-79.

17. Amar PJ, Schiff ER. Acetaminophen safety and hepatotoxicity—where do we go fromhere? Expert Opin Drug Saf. 2007;6(4):341-355.

18. Singla N, Ferber L, Bergese S, et al. A phase III, multi-center, open-label, prospective, repeated dose, randomized, controlled, multi-day study of the safety of intravenous acetaminophen in adult inpatients. Proceedings and Abstracts of the 34th Annual American

Society of Regional Anesthesia Meeting and Workshops. April 30 to May 3, 2009; Phoenix, AZ. Poster 96.

19. Rømsing J, Møiniche S, Dahl JB. Rectal and parenteral paracetamol, and paracetamol in combination with NSAIDs, for postoperative analgesia. Br J Anaesth. 2002;88:215–26.

20. Remy C, Marret E, Bonnet F. Effects of acetaminophen on morphine side-effects and consumption after major surgery: a meta-analysis of randomized controlled trials. Br J Anaesth. 2005;94:505–13.

21. Elia N, Lysakowski C, Tramer M. Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Anesthesiology. 2005;103:1296–304.

22. Institute for Safe Medication Practices (ISMP).IV acetaminophen and overdoses in kids. ISMP Medication Safety Alert. Apr 2012; 17(8):1,4.

23. Food and Drug Administration. Prescription drug products containing acetaminophen; actions to reduce liver injury from unintentional overdose. Fed Regist. 2011; 76:2691-7.

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INTRAVENOUS ACETAMINOPHENA DRUG UTILIZATION EVALUATION

Jamie BrockhouseSt John’s HospitalSpringfield, Il

Conflict of Interest Declaration

The speaker has no actual or potential conflict of interest in

relation to this activity

Learning Objective

• Upon completion of this program, pharmacists should be able to: – Describe the role in therapy for IV acetaminophen

Additional Goal:– Compare the advantages and disadvantages for IV acetaminophen

Question

• Does your organization restrict the use of IV Acetaminophen?

Post Surgical Pain Management:Our Current Approach

• Surgical pain mechanism– Inflammation as a result of tissue trauma– Direct nerve damage

• Multimodal analgesia– Involvement of several different disciplinesInvolvement of several different disciplines– Goal: maximize pain relief, minimizing side effects and contain cost

• Most commonly used pharmacologic agents– Opioids– NSAIDs

Advantages and Disadvantages to Current Approach

• Advantages– Dosing flexibility– Multiple routes of administration– Low cost

• Disadvantagesisadvantages– Nausea and vomiting– Slowing of GI transit

• Constipation/post op ileus– Depression of brainstem control of respiratory drive– Histamine release

• itching

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A New ApproachIV Acetaminophen

• Proposed Benefits– Decreased utilization of morphine equivalents

• Less opioid‐related adverse effects

– Earlier mobilizationEarlier mobilization• Increased physical therapy participation• Decreased risk of DVT

– Decreased length of stay• Reduction of hospital cost

– Increased patient satisfaction


• Disadvantages– Packaging

• Glass bottle‐difficult to store in ADM– Potential for drug waste

• Only available as 1000mg doseOnly available as 1000mg dose• Wt <50kg requires weight based dosing (15mg/kg)• After manipulation stability is 6 hours

– Fluid restricted patients• 100ml of fluid per dose

– Side effects observed• Nausea/vomiting• Headache


• Disadvantages – Kinetics

• Tmax: more predictable than other routes of acetaminophen • Analgesic effect of multiple routes similar• Analgesic effect of rectal formulation prolonged

– Patient selection– Patient selection• Contraindicated with severe liver impairment or acute liver disease• Use with caution:

– Alcoholism, malnutrition, hepatic impairment, renal impairment (CrCl <30ml/min)

– Patient safety• Account for acetaminophen from all sources• Minimum of 4‐6 hours prior to administration of APAP‐containing combination products


• Disadvantages – COST

• 15 minute infusion time– Increase length of stay in PACUg y

• AWP Comparison – 1000mg IV Acetaminophen= $13.68– 500mg Acetaminophen tablet=$0.02– 650mg Acetaminophen suppository=$0.67– 2mg IV Morphine=$1.84– 2mg IV Hydromorphone=$2.22– 30mg IV Ketorolac=$0.92

Our Current PracticeIV Acetaminophen

• Restricted Use – Surgical unit

• Including cesarean sections

– Post‐op orthopedicsPost‐op orthopedics

• Limited duration 24 hours

IV Acetaminophen – Pain Scores

• 100 patients received IV APAP (average of 2.5 doses) during their stay (Feb 2012‐July 2012)

Received IV APAP

Did not receive IV APAP

Average of pre‐surgery pain score

2.4 1.73

Average of pain 2.55 3.8

• 89 patients received no IV APAP during their stay (Oct 2011‐Jan 2012)

score 1‐4 hours after surgery

Average of pain score 5‐12 hours after surgery

4.01 4.7

Average of pain score 12‐24 hours after surgery

5.19 4.1

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IV Acetaminophen – Average Length of Stay and ChargesAverage Length of Stay Average Charges

May 2012, ICD‐9 Code 715.36 (When IV APAP was used)

2.68 days $36,100

May 2011, ICD‐9 Code 715.36(When IV APAP was NOT used)

2.88 days $35,600

May 2012, ICD‐9 Code 715.35(When IV APAP was used)

2.56 days $42,600

May 2011, ICD‐9 Code 715.35(When IV APAP was NOT used)

3 days $42,500

May 2012, ICD‐9 Code 654.21 (When IV APAP was used)

2.56 days $7,700

May 2011, ICD‐9 Code 654.21 (When IV APAP was NOT used)

2.4 days $7,600

IV Acetaminophen – Multiple Dosing

• 15 patients who received multiple doses of IV APAP (average of 3.23

Multiple doses of IV APAP

Single dose of IV APAP

Calculated p-value

Total oral morphine equivalent dose

27.93mg 26.47mg 0.8946

Symptoms of nausea/vomiti

6 patients, receiving total

5 patients, receiving total

1.0 (Fisher’s exact test)

doses) were randomly selected and compared to 15 patients who received a single dose of IV APAP.

ng 0-24 hours after surgery

gof 10 doses of ondansetron 4mg

gof 8 doses of ondansetron 4mg

)

Average lowest oxygen saturation 0-24 hours after surgery

94.2% 94.83%

Average lowest respiratory rate 0-24 hours after surgery

16.2 16.08

Review

• What positives do you see from IV Acetaminophen use?

• What negatives do you see from IV Acetaminophen use?Acetaminophen use?

• What additional research data would you like to see about IV Acetaminophen use?

Conclusion

• Place in therapy is undetermined– Results of our DUE failed to demonstrate that clinical advantages outweigh the economic burden

• Additional research needed – Larger sample size– Time to first physical therapy – Frequency of nausea and vomiting

• Needs to be proven fiscally responsible– Anticipated benefits must be observed

Assessment QuestionWhich of the following statements is/are true regarding the infusion of intravenous acetaminophen?A. Infusion time is 30 minutesB. Cmax occurs at 30 minutesC. Overall AUC is similar to oral administrationD. After penetration of the seal the product should be used within 12 hour

E. All of the above

Questions

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References• Schechter, Leslie N., BS,PharmD. "Multimodal Approach to Pain

Management Focus on Ofirmev (acetaminophen) Injection." U.S. Pharmacist (2012): 1‐12. Apr. 2012. Web.

• Yeh, Yu‐Chen, M.S., and Prabashni Reddy, Pharm.D.,M.Med.Sc. "Clinical and Economic Evidence for Intravenous Acetaminophen." Pharmacotherapy 32.6 (2012): 559‐79. Web.K d li Bh i Sh k MD d J t Ob i MD "REFERENCES "• Kodali, Bhavani‐Shankar, MD, and Jasmeet Oberoi, MD. "REFERENCES." Management of Postoperative Pain. UpToDate, 10 Oct. 2011. Web. 12 Aug. 2012. <http://www.uptodate.com/contents/management‐of‐postoperative‐pain>.

• Zacharoff, Kevin, MD. "The Role of Rational Polypharmacy in Pain Management." PainEDU.org { Articles }. N.p., 11 Mar. 2008. Web. 12 Aug. 2012. <http://www.painedu.org/articles_timely.asp?ArticleNumber=17>.

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Bupivacaine liposomal injection

Will it ti k d?Will it stick around?

Elizabeth Short, Pharm.D.PGY2 Critical Care

Northwestern Memorial Hospital

Conflicts

• I have no conflicts of interest to declare

Additional Goals

• Determine criteria necessary for formulary approval

• Interpret clinical trial data and apply to formulary management

Bupivacaine liposome injectable suspension (Exparel™)

Approved Indication:

F d i i t ti i t th i l it tFor administration into the surgical site to produce postsurgical analgesia1

http://www.drugdevelopment‐technology.com/projects/6855/images/138835/large/1‐bottle.jpg1. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=59067

Formulary Criteria

• Efficacy

• SafetySafety

• Avoid superfluous, expensive additions


• Pacira Pharmaceuticals, Inc.

• FDA Approval: October, 2011

• Intended to provide longer duration of effect

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Multivesicular Liposomes

http://www.exparel.com/images/exparel_how_to_use.jpg

FDA Approval

Based on two clinical trials

• Bunionectomy (Golf 2011)Bunionectomy (Golf 2011)

• Hemorrhoidectomy (Gorfine 2011)

Golf, et al. Adv Ther. 2011;28:776-88

Gorfine et al. Dis Colon Rectum. 2011;54:1552-9.

Efficacy

Primary efficacy endpoint:

Pain intensity score summation over timePain intensity score summation over time

Efficacy

Primary efficacy endpoint:

Pain intensity score summation over timePain intensity score summation over time

No benefit beyond 24 hours

Percentage of Patients Pain‐free vs Hours

Liposomal bupivacaine 120 mg

Placebo


No Opioid Rescue Medications vs Hours


Placebo


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Cumulative Pain Score through 72 Hours

P < 0.0001

ve Pain Score


Cumulativ

Mean Total Amount of Opioids Over 72 Hr

P < 0.006s(m

g)


Milligrams

No Opioid Rescue Medications vs Hours


Placebo


Marketing

“One dose of Exparel provides up to 72 hours of postsurgical pain control with a decrease in opioid consumption without the need foropioid consumption without the need for catheters or pumps.”

FDA Review“Between 24 and 72 hours after study drug administration, there was minimal to no difference between EXPAREL and placebo treatments on mean pain intensity; however, there was an attendant decrease in opioid consumption, the clinical benefit of which was not demonstrated.”

Safety

• No primary safety outcome defined

• Identified opioid‐ related adverse effects

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Error Potential• Inadvertent IV administration

• Institute for Safe Medication Practices (ISMP) issued warning

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8 Unpublished Trialsplain bupivacaine as active comparator

3

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Liposomal bupivacainebetter

No benefit over plain bupivacaine

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suspension (Exparel™)

Recommend to add to formulary

a Yesa. Yesb. NO

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Bupivacaine liposomal injection Will it stick around?

Elizabeth Short, Pharm.D.PGY2 Critical Care

Northwestern Memorial Hospital

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Decisions, Decisions… Debates in Therapeutics

Mupirocin

Sheila Wang, Pharm.D., BCPS AQ-IDAssistant Professor Pharmacy Practice

Midwestern University Chicago College of Pharmacy

Disclosure Statement

• The speaker has no conflicts of interest or relationships with commercial entities that may be referenced in this presentation

Additional Goals

1. Recognize the recent rise in MRSA rates in hospital and community settings and its infectious impact on morbidity and mortality.

2. Describe how Staph aureus carriers increase their risk of infection once entering hospital settingsof infection once entering hospital settings.

3. Name the most common method of decolonization in the United States.

4. Recall the three uses of mupirocin for decolonization discussed in this presentation.

5. Indicate the most concerning consequence of wide spread mupriocin use.

Boucher HW et al. CID 2009Rybak M, AJHP 2009Liu C, et al. CID 2011

Styers D, et al. Ann Clin Microbiol Antimicrob 2006Wyllie DH, et al. BMJ 2006

• In the U.S., MRSA rates range from 50-60% for non-ICU and ICU settings• More morbidity and mortality associated with MRSA versus MSSA infections

- Mortality as high as 25% in some settings.

Staph aureus colonization

• Common site is anterior nares– Carriers of Staph aureus in healthy adults (30%)

– High rates of colonization in hospital inpatients, IVDU, insulin-dependent diabetics, HIV positive and hemodialysis patients

– Extranasal colonization• Throat, perineum, GI tract, cutaneous sites

• Prerequisite to staphylococcal infections– Two to 12 times higher vs. non-colonizers

– Bloodstream, dialysis-associated and surgical site infections

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Decolonization Methods

• Anti-septic body wash therapy– Chlorhexidine, Hexachlorophene, Bleach, Other

• Topical and/or nasal therapy – Mupirocin, Bacitracin, Other

• Oral antimicrobial therapy– Rifampin, TMP/SMX, Clindamycin, Minocycline

Mupirocin• Formally known as pseudomonic acid A

– Major metabolite derived from submerged fermentation by Pseudomonas fluorescens.

• Bacterial RNA and protein synthesis inhibitor– Inhibits bacterial isoleucyl-transfer RNA (tRNA) synthetase

• Bactericidal: topical administration after 24 to 36 hours of exposure

• Highly active (in vitro) against staphylococcal strains (including MRSA) and streptococci (except enterococci)

• Lacks (in vitro) activity against gram-negatives, anaerobes and fungi– Minimal activity against normal skin flora (Micrococcus,

Corynebacterium and Propionibacterium spp.)

Use of Mupirocin for Decolonization

• Nasal Staphylococcal carriage prior to elective surgery

• Inpatient MRSA colonization – Infection control programs

• Recurrent skin and soft tissue infections – Community-yassociated MRSA

Evidence: Surgical Patients

• Kluytmans JA et al. 1996– Single-center, unblinded intervention trial

– Perioperative decolonization with mupirocin nasal ointment reduces surgical-site infection rates (Staph aureus) in

di th icardiothoracic surgery

– ITT analysis: Significant reduction in SSI rate

• 7.3% (control) vs 2.8% (intervention); P < 0.0001

– Limitation: historical controls

Kluytmans JA, et al. Infect Control Hosp Epidemiol 1996


• Van Rijen M et al. 2008

Van Rijen MML, JAC 2008


• Van Rijen M et al. 2008

Van Rijen MML, JAC 2008

• No effectiveness was observed among the non-carriers (RR 1.09, 95% CI 0.52–2.28).

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Evidence: Surgical Patients Evidence: Surgical Patients

Bode L et al. NEJM 2010





Departments included: internal medicine, cardiothoracic surgery, vascular surgery, orthopedics, gastrointestinal surgery, or general surgery

Evidence: Inpatient ICU MRSA Colonization -Infection Control

Fraser TG et al. Infect Control Hosp Epidemiol 2010.


Fraser TG et al. Infect Control Hosp Epidemiol 2010.

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• Forty-five US hospital currently participating in a cluster randomized trial

• Prevention of MRSA infection in ICUs1. Positive screening cultures of ICU admission contact precaution

2. Positive screening cultures of ICU admission decolonization

3. Universal decolonization of ICU admission without screening

Platt R et al. Med Care 2010

Evidence: Recurrent Skin Soft Tissue Infections – Community-associate MRSA

Liu C, et al. CID 2011

Evidence: Recurrent Skin and Soft Tissue Infections – Community-associated MRSA

• Recurrent SSTI despite optimizing wound care/hygiene measures

• Ongoing transmission among household members or close contacts despite optimizing wound care/hygiene measures

Decolonization strategies should be offered in conjunction with

Liu C, et al. CID 2011

• Decolonization strategies should be offered in conjunction with ongoing reinforcement of hygiene measures • Mupirocin twice daily for 5-10 days

• Mupirocin twice daily for 5-10 days and topical body decolonization regimens with a skin antiseptic solution (eg, chlorhexidine) for 5–14 days or bleach baths

• Evidence: CIII

Mupirocin for Decolonization

• Clinical and epidemiological outcomes influencing use– Perioperative eradication of S. aureus colonization

– Controlling for HA-MRSA and transmission

– Incidence of CA-MRSA

• Learning from others– UK – screening includes all hospital admissions

– Utilizing much more mupirocin

– UK - high-level mupriocin resistance ~ 12%• MICs >/= 512 mg/mL

• Independently associated with decolonization failure

• Selection of increased drug resistance in S. aureus– Plasmid carrying resistance determinants to other antimicrobial agents, including

macrolides, gentamicin, tetracycline, and trimethoprim

Mupirocin Resistance in the US

Tenover FC. AAC 2012

References1. Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice L, et al. Bad Bugs, No Drugs: No ESKAPE! An

Update from the Infectious Diseases Society of America. Clinical Infectious Diseases 2009;48:1–12.2. Rybak M, Lomaestro B, Rotschafer JC, Moellering R.,Craig W,Billeter M, et al. Therapeutic monitoring of

vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health-Syst Pharm. 2009; 66:82-98.

3. Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus Aureus Infections in Adults and Children. Clinical Infectious Diseases 2011;1–38.

4. Styers D, Sheehan DJ, Hogan P, Sahm DF. Laboratory-based surveillance of current antimicrobial resistance patterns and trends among Staphylococcus aureus: 2005 status in the United States. Ann Clin Microbiol Antimicrob 2006;5:2.

5. Wyllie DH, Crook D, Peto T. Mortality after Staphylococcus aureus bacteraemia in two hospitals in Oxfordshire, 1997-2003: cohort study. BMJ 2006; BMJ 2006;333:281.

6. Kluytmans JA, Mouton JW, VandenBergh MF, Manders MJ, Maat AP, Wagenvoort JH, et al. Reduction of surgical-site infections in cardiothoracic surgery by elimination of nasal carriage of Staphylococcus aureus. Infect Control Hosp Epidemiol. 1996 Dec;17(12):780-5.

7. van Rijen M, Bonten M, Wenzel RP, Kluytmans J. Intranasal mupirocin for reduction of Staphylococcus aureus infections in surgical patients with nasal carriage: a systematic review. JAC 2008;61:254.

8. Bode LGM, Kluytmans JAJW, Wertheim HFL, Bogaers B, Vandenbroucke-Grauls CM, Roosendaal R, et al. Preventing surgical-site infections in nasal carriers of Staphylococcus aureus. N Engl J Med 2010; 362: 9–17.

9. Fraser TG, Fatica, C, Scarpelli, M, Arroliga, AC, Guzman J, Shrestha,NK. Decrease in Staphylococcus aureus Colonization and Hospital- Acquired Infection in a Medical Intensive Care Unit after Institution of an Active Surveillance and Decolonization Program Infect Control Hosp Epidemiol 2010; 31(8):779-783.

10. Platt R, Takvorian SU, Septimus E, Hickok J, Moody J, Perlin J, et al. Cluster Randomized Trials in Comparative Effectiveness Research: Randomizing Hospitals to Test Methods for Prevention of Healthcare-Associated. Med Care 2010;48: S52–S57.

11. Tenover FC, Tickler IA, Goering RV, Kreiswirth BN, Mediavilla JR, Persing DH. Characterization of Nasal and Blood Culture Isolates of Methicillin-Resistant Staphylococcus aureus from Patients in United States Hospitals Antimicrob. Agents Chemother. 2012, 56(3):1324.

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Post Test Question 1

Which of the following resistant gram‐positive organism has been on the rise in hospital and community settings resulting in mortality as high as 25%?

A. Methicillin‐sensitive Staph aureusB. Methicillin‐resistant Staph aureusC. Vancomycin resistant enterococciD. Multidrug resistant Streptococcus pneumonia


Risk of infection increases when asymptomatic carriers of Staph aureus enter this setting:A. HospitalsB Nursing homeB. Nursing homeC. Rehabilitation centersD. Retirement centers


Which of the following methods of decolonization was found to be the most favorable among infectious diseases consultants?A RifampinA. RifampinB. BleachC. Chlorhexidine with BacitracinD. Mupriocin with or without Chlorhexidine

Post Test Question 4Compelling evidence to support the use of mupirocin as a decontamination agent is largely available for:A. Nasal Staphylococcal carriage prior to elective

surgeryg yB. Inpatient MRSA colonization – Infection control

programsC. Recurrent skin and soft tissue infections –

Community‐associated MRSAD. Elderly long‐term care facility residents colonized

with Staph aureus


Widespread use of mupirocin will likely increase the risk of:A. CostB Allergic reactionsB. Allergic reactionsC. ResistanceD. Tolerance

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