New Drugs & Delivery Techniques

New Drugs & Delivery Techniques

Keith B. Thomasset, PharmD, BCPSClinical Manager – Pharmacy Services

Keith B. Thomasset, PharmD, BCPSClinical Manager – Pharmacy Services

Boston University School of Medicine

May 19, 20063:30- 4:00pm3:30- 4:00pm

2nd Annual Ellison Pierce Symposium Positioning Your ORs For The Future

10%

20%

60%

10%

1 2 3 4

Which of the following is not an approved indication for utilizing morphine sulfate extended release liposomal injection:

Which of the following is not an approved indication for utilizing morphine sulfate extended release liposomal injection:

1. Elective cesarean section

2. Lobectomy

3. Total knee arthroplasty

4. Lower abdominal surgery

1. Elective cesarean section

2. Lobectomy

3. Total knee arthroplasty

4. Lower abdominal surgery

QUESTION:QUESTION:

20%

30% 30%

20%

1 2 3 4

Sugammadex (Org 25969) is a reversal agent for rocuronium and contains what type of carrier matrix?

Sugammadex (Org 25969) is a reversal agent for rocuronium and contains what type of carrier matrix?

1. Lipid emulsion

2. Propylene glycol

3. Cyclodextrin

4. Tween-80

1. Lipid emulsion

2. Propylene glycol

3. Cyclodextrin

4. Tween-80

QUESTION:QUESTION:

70%

10%

20%

0%

1 2 3 4

When administering the first dose of cefazolin as an agent for surgical infection prophylaxis at 6:30AM for a case of 5 hours duration, assuming normal blood loss, the next dose should be administered:

When administering the first dose of cefazolin as an agent for surgical infection prophylaxis at 6:30AM for a case of 5 hours duration, assuming normal blood loss, the next dose should be administered:

1. At 9:00AM

2. At 10:30AM

3. At 2:30 PM

4. Another dose is not required

1. At 9:00AM

2. At 10:30AM

3. At 2:30 PM

4. Another dose is not required

QUESTION:QUESTION:

ObjectivesObjectives

• Describe the advantages of liposomal based morphine sulfate for anesthesia practice

• Appraise the role of Sugammadex (Org 25969) in the reversal of rocuronium muscle relaxation

• Outline the importance of proper antimicrobial timing prior to surgical incision

• Describe the advantages of liposomal based morphine sulfate for anesthesia practice

• Appraise the role of Sugammadex (Org 25969) in the reversal of rocuronium muscle relaxation

• Outline the importance of proper antimicrobial timing prior to surgical incision

DepoDur®

(Morphine sulfate extended release liposomal injection)

DepoDur®

(Morphine sulfate extended release liposomal injection)

• Liposomal formulation of morphine sulfate– Epidural administration – lumbar level– 48 hour pain relief

• Studied in:– Hip arthroplasty– Knee arthroplasty– Lower abdominal surgery– Elective cesarean section

• Liposomal formulation of morphine sulfate– Epidural administration – lumbar level– 48 hour pain relief

• Studied in:– Hip arthroplasty– Knee arthroplasty– Lower abdominal surgery– Elective cesarean section

DepoDur®DepoDur®

SkyePharma. Data on File. Endo Pharmaceuticals Inc.: Chadds Ford, PA; April 21, 2004.

DepoFoam®

Liposomal vs. Conventional Epidural Opioids

Liposomal vs. Conventional Epidural Opioids

• Difficult to provide prolonged pain relief– Multiple injections– Epidural continuous

infusion

• High doses result– Adverse effects

• Indwelling epidural catheter– Infection risk– Spinal hematoma

• Difficult to provide prolonged pain relief– Multiple injections– Epidural continuous

infusion

• High doses result– Adverse effects

• Indwelling epidural catheter– Infection risk– Spinal hematoma

• Liposomal formulation– Single injection– No indwelling catheter

• Decreases post operative pain requirements– PCA– Decrease rescue opioid

doses– Decreased adverse effects

• No indwelling catheter– Decrease infection risk– Decrease spinal

hemoatome risk

• Liposomal formulation– Single injection– No indwelling catheter

• Decreases post operative pain requirements– PCA– Decrease rescue opioid

doses– Decreased adverse effects

• No indwelling catheter– Decrease infection risk– Decrease spinal

hemoatome risk

AdvantagesAdvantages

• Decreased post operative opioid use– Decreased utilization of rescue doses

– Decreased time to rescue therapy• Potential to prevent rescue therapy requirements

• Decrease adverse effects

• Potential decreased post operative nausea and vomiting

• Potential improvement in patient flow– Quicker movement through the system

• Quicker movement through the system

• Decreased post operative opioid use– Decreased utilization of rescue doses

– Decreased time to rescue therapy• Potential to prevent rescue therapy requirements

• Decrease adverse effects

• Potential decreased post operative nausea and vomiting

• Potential improvement in patient flow– Quicker movement through the system

• Quicker movement through the system

Post-Op Opioid UsePost-Op Opioid Use

Anesth Anal 2005;100:1069.

Lower Abdominal SurgeryLower Abdominal Surgery

Time to Rescue TherapyTime to Rescue Therapy

Anesthesiology 2005;102(5):1018.

Hip ArthroplastyHip Arthroplasty

Patients Requiring No Rescue TherapyPatients Requiring No Rescue Therapy

Anesth Anal 2005;100:1155.

Elective Cesarean DeliveryElective Cesarean Delivery

Adverse Effects & PrecautionsAdverse Effects & Precautions

• Greater than 10% incidence– Decreased oxygen saturation– Hypotension– Urinary retention– N/V/H– Constipation– Pruritis– Pyrexia– Dizziness

• Greater than 10% incidence– Decreased oxygen saturation– Hypotension– Urinary retention– N/V/H– Constipation– Pruritis– Pyrexia– Dizziness

• Incidence between 5-10%– Hypoxia– Tachycardia– Insomnia

• Incidence < 5%– Paralytic ileus– Abdominal distention– Hypertension– Bladder spasm

• Potential interaction with epidural anesthetics– Reduced sustained release

activity• Under further investigation

• Incidence between 5-10%– Hypoxia– Tachycardia– Insomnia

• Incidence < 5%– Paralytic ileus– Abdominal distention– Hypertension– Bladder spasm

• Potential interaction with epidural anesthetics– Reduced sustained release

activity• Under further investigation

DepoDur®DepoDur®

• Administration

– Lumbar epidural administration

• prior to surgery

• after clamping of umbilical cord during cesarean section

• Dosing

– Orthopedic surgery of lower extremity – 15mg

– Lower abdominal or pelvic surgery – 10-15mg

– Elective cesarean section – 10mg

• Administration

– Lumbar epidural administration

• prior to surgery

• after clamping of umbilical cord during cesarean section

• Dosing

– Orthopedic surgery of lower extremity – 15mg

– Lower abdominal or pelvic surgery – 10-15mg

– Elective cesarean section – 10mg

Neuromuscular Blockade ReversalNeuromuscular Blockade Reversal

• •

www.medlib.med.utah.edu/ kw/mg/mml/ms_illus002.gif

Common AgentsCommon Agents

Acetylcholinesterase inhibitorAcetylcholinesterase inhibitor

Antimuscarinic agentAntimuscarinic agent

ReversalReversal

Neostigmine0.5-2mg IV

Edrophonium10mg IV

Atropine0.6-1.2mg IV

Glycopyrrolate0.2-0.4 mg IV

Limitations Limitations

• Not agent specific

• Nonselective acetylcholine neurotransmission

– Bradycardia

– Hypersalivation

– Bronchoconstriction

• Interpatient variability of effect

• Lack of effect against profound neuromuscular block

• Require recurrence of first twitch during train-of-four stimulation

• Not agent specific

• Nonselective acetylcholine neurotransmission

– Bradycardia

– Hypersalivation

– Bronchoconstriction

• Interpatient variability of effect

• Lack of effect against profound neuromuscular block

• Require recurrence of first twitch during train-of-four stimulation

Agent Specific ReversalAgent Specific Reversal

Sugammadex (Org 25969)– Cyclodextrin compound

• Encapsulate lipophilic molecules• Highly water soluble• No endogenous targets• Biological tolerance

Sugammadex (Org 25969)– Cyclodextrin compound

• Encapsulate lipophilic molecules• Highly water soluble• No endogenous targets• Biological tolerance

Anesthesiology 99(3) p. 633

J Med Chem 45(9) p. 1807

Agent Specific ReversalAgent Specific Reversal

• Mechanism of Action

– Hydrophillic exterior and hydrophobic interior

• Encapsulation of rocuronium molecule

• Prevention of interactions with nicotinic receptors

– Increased excretion of complex

• 1:1 complex

• Mechanism of Action

– Hydrophillic exterior and hydrophobic interior

• Encapsulation of rocuronium molecule

• Prevention of interactions with nicotinic receptors

– Increased excretion of complex

• 1:1 complex

Anesthesiology 103(4), p. 696

Other Potential Exogenous TargetsOther Potential Exogenous Targets

• Affinity highest with aminosteroid NMBAs

• Others– Atropine– Verapamil– Non-NMBA Steroid Compounds

• Hydrocortisone• Prednisone• Methylprednisone

• Affinity highest with aminosteroid NMBAs

• Others– Atropine– Verapamil– Non-NMBA Steroid Compounds

• Hydrocortisone• Prednisone• Methylprednisone

Anesthesiology 2006; 104(4)

LimitationsLimitations

• Not agent specific

• Non-selective acetylcholine neurotransmission

– Bradycardia

– Hypersalivation

– Bronchoconstriction

• Interpatient variability of effect

• Lack of effect against profound neuromuscular block

• Only effective once partial spontaneous recovery has occurred

• Not agent specific

• Non-selective acetylcholine neurotransmission

– Bradycardia

– Hypersalivation

– Bronchoconstriction

• Interpatient variability of effect

• Lack of effect against profound neuromuscular block

• Only effective once partial spontaneous recovery has occurred

Sugammadex® (Org 25969)Sugammadex® (Org 25969)

• Not agent specific – specific to amniosteroid NMBAs

• Adverse effects

– Bradycardia – not identified to date

– Hypersalivation – not identified to date

– Bronchoconstriction – not identified to date

• Interpatient variability of effect – scant data

• Lack of effect against profound neuromuscular block – scant human data

• Not agent specific – specific to amniosteroid NMBAs

• Adverse effects

– Bradycardia – not identified to date

– Hypersalivation – not identified to date

– Bronchoconstriction – not identified to date

• Interpatient variability of effect – scant data

• Lack of effect against profound neuromuscular block – scant human data

DosingDosing

• •

Anesthesiology 103(4), p. 701

Time to ReversalTime to Reversal

Dose

(mg/kg)Placebo 0.1 0.5 1 2 3 4 8

Avg. time to reversal (min)

15-60 43 1.3-8.5 1.4-31 1-17 0.7-3.2 1-3.3 1-1.2

Anesthesiology 2005; 103(4)

Anesthesiology 2006;104(4)

Br J of Anesthesia 2006;96(1)

Dosing and Data DilemmaDosing and Data Dilemma

• Mostly dose finding studies

– 0.1mg/kg - 8mg/kg

– Single vs. multiple dose per patient

• All human studies with rocuronium

– Intermittent/single bolus or continuous infusion

• All placebo controlled

• Mostly dose finding studies

– 0.1mg/kg - 8mg/kg

– Single vs. multiple dose per patient

• All human studies with rocuronium

– Intermittent/single bolus or continuous infusion

• All placebo controlled

Anesthesiology 2005; 103(4)

Anesthesiology 2006;104(4)

Br J of Anesthesia 2006;96(1)

ConclusionConclusion• Elimination half life is ~ 100 min

– Totally agent removal at 400 min (6.5 hours)

– Renal failure???

• Data suggests no recurarization for 90 minutes

– Any for time period > 90 minutes?

• More safety and efficacy data needed

• Ideal dose yet to be determined

• Impact on daily practice

– Cost effectiveness

STAY TUNED

• Elimination half life is ~ 100 min

– Totally agent removal at 400 min (6.5 hours)

– Renal failure???

• Data suggests no recurarization for 90 minutes

– Any for time period > 90 minutes?

• More safety and efficacy data needed

• Ideal dose yet to be determined

• Impact on daily practice

– Cost effectiveness

STAY TUNED

Decreasing the Risk of Surgical Site Infections

Decreasing the Risk of Surgical Site Infections

• Maintain high levels of inspired oxygen

• Maintain peri-operative normothermia

• Avoid shaving operative site

• Maintain adequate glucose control

• Appropriate use of peri-operative antibiotics

• Maintain high levels of inspired oxygen

• Maintain peri-operative normothermia

• Avoid shaving operative site

• Maintain adequate glucose control

• Appropriate use of peri-operative antibiotics

Goal OutcomesAntimicrobial Specific

Goal OutcomesAntimicrobial Specific

• Evidence-based recommendations

• Correct drug

• Correct dose

• Correct duration

– Including intra-operative dosing

• Evidence-based recommendations

• Correct drug

• Correct dose

• Correct duration

– Including intra-operative dosing

Bratzler, D. W. et al. Arch Surg 2005;140:174-182.

It’s All About TimingIt’s All About Timing

Timing of DosesTiming of Doses

Incision should occur within 60 minutes of antimicrobial administration

• Initial Dosing– Cefazolin, Cefoxitin, Cefotetan, Clindamycin

• Administer over 10-15 minutes

– Vancomycin, Gentamicin, Metronidazole• Administer over at least 1 hour (1 gm/hr for

vancomycin)

Incision should occur within 60 minutes of antimicrobial administration

• Initial Dosing– Cefazolin, Cefoxitin, Cefotetan, Clindamycin

• Administer over 10-15 minutes

– Vancomycin, Gentamicin, Metronidazole• Administer over at least 1 hour (1 gm/hr for

vancomycin)

• Intra-operative Dosing– Redose

• Large amount of intra-operative blood loss (~1500mL)• Approximately 2X half life of antimicrobial

– Cefazolin, Cefoxitin, Clindamycin• Q4 hours intra-op

– Vancomycin• Q6 hours intra-op

– Cefotetan, Levofloxacin, Gentamicin• Not needed intra-op due to prolonged duration

• Intra-operative Dosing– Redose

• Large amount of intra-operative blood loss (~1500mL)• Approximately 2X half life of antimicrobial

– Cefazolin, Cefoxitin, Clindamycin• Q4 hours intra-op

– Vancomycin• Q6 hours intra-op

– Cefotetan, Levofloxacin, Gentamicin• Not needed intra-op due to prolonged duration

Timing of DosesTiming of Doses

Bratzler, D. W. et al. Arch Surg 2005;140:174-182.

Antimicrobial ChoiceAntimicrobial Choice

When to StopWhen to Stop

Bratzler, D. W. et al. Arch Surg 2005;140:174-182.

BMC Antimicrobial Prophylaxis Plan

BMC Antimicrobial Prophylaxis Plan

• Develop agreement– Choice

– Dosing

– Administration

– Redosing

– Intergroup• Surgery• Anesthesia• ID• Pharmacy• ITS

• Develop agreement– Choice

– Dosing

– Administration

– Redosing

– Intergroup• Surgery• Anesthesia• ID• Pharmacy• ITS

• Implementation– Adminstration time– Intraop reminders

• Stickers• Pagers

– Standard Orders• Physician order entry• Orders per guidelines

– Auto stops

• Implementation– Adminstration time– Intraop reminders

• Stickers• Pagers

– Standard Orders• Physician order entry• Orders per guidelines

– Auto stops

Figure based on compliance of the following combined points:

antibiotics (correct agent, correct timing, correct discontinuation)Figure based on compliance of the following combined points:

antibiotics (correct agent, correct timing, correct discontinuation)

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