1. Pharmacy Services Dexmedetomidine (Precedex®) Haley Gill, BSP VCH-PHC Pharmacy Resident 2009-2010

2. Pharmacy Services Outline Current indications Differences & possible advantages over current sedation agents Pharmacology Dosing Cost Review of Literature

3. Pharmacy Services Health Canada Precedex® NOC issued December 2009 Dexmedetomidine (DXM) 100mcg/ml solution Continuous IV infusion

4. Pharmacy Services Health Canada - Approved Indications ICU Sedation: –post-surgical mechanically ventilated patients –Infusion must NOT exceed 24 hours –Not necessary to D/C prior to extubation –↓ dose by 50% after extubation Conscious Sedation (non-intubated patients): –Monitored Anesthesia Care –Awake Fiberoptic Intubation

5. Pharmacy Services DXM vs. Other ICU Sedation Agents Minimal respiratory depression Thought to induce less delirium – does not bind to GABA receptors Analgesic sparing Does not provide adequate & reliable amnesia

6. Pharmacy Services Pharmacology MOA –highly selective α 2 -adrenoreceptor agonist –Similar to clonidine but 8 X more selective for α 2 α 2 -adrenoreceptorsPancreatic β-cells↓ insulin secretion PlateletsAggregation Nerve Terminals↓ release of NE Vascular Smooth muscleContraction

7. Pharmacy Services Pharmacology

8. Pharmacy Services Pharmacology Onset of Action5-10 min Peak effect: 15-30 min Duration of Action60-120 min MetabolismHepatic via N-glucuronidation, N-methylation, & CYP2A6 Elimination t 1/2 ~ 6 min Terminal: ~2 hrs ExcretionUrine 95% Feces 4%

9. Pharmacy Services Drug Interactions EnzymeActionDrugs CYP 2A6substrateamiodarone isoniazid ketoconazole CYP 1A2, 2C9, 3A4 weak inhibitorwarfarin Simvastatin CYP 2D6strong inhibitorcodeine **theoretical interactions – likely of little clinical significance**

10. Pharmacy Services Drug Interactions Beta-blockers: rebound hypertensive effect when the α 2 -agonist is abruptly withdrawn Mirtazapine: α 2 -antagonist (opposing effects)

11. Pharmacy Services Dosing ICU sedation –Load: 1 mcg/kg IV over 10 minutes –Maintenance: 0.2-0.7 mcg/kg/hr IV (0.2-1.4 mcg/kg/hr reported in RCT’s) –titration no more frequently than every 30 minutes may ↓ the incidence of hypotension Procedural sedation –Load: 0.5 – 1 mcg/kg over 10 minutes –Maintenance: 0.6 mcg/kg/hr (usual range: 0.2-1 mcg/kg/hr)

12. Pharmacy Services Dosing No specific recommendations for renal or hepatic dysfunction

13. Pharmacy Services Adverse Effects Hypotension (24- 54%) Bradycardia (5-14%) Respiratory depression (37%; placebo 32%) Atrial fibrillation (4-5%) Hypovolemia (3%) ↓ urine output Pleural effusion Hypocalcemia (1%) Nausea (3-9%) Xerostomia (3-4%) Hyperglycemia

14. Pharmacy Services Cost DrugUnit CostCost/day for 70 kg pt DXM 100mcg/ml2 ml vial = $63$105.84 - $370.44 (0.2 – 0.7mcg/kg/hr) Propofol 10mg/ml100 ml bottle = $8.78$14.75 – $88.50 (1 – 6mg/kg/hr) Midazolam 5mg/ml10 ml vial = $12.25$29.40 – $58.80 (5 – 10mg/hr)

15. Pharmacy Services Effect of Sedation with Dexmedetomidine vs Lorazepam on Acute Brain Dysfunction in Mechanically Ventilated Patients (MENDS) Pandharipande P, et al JAMA 2007;298(22):2644-2653

16. Pharmacy Services MENDS ObjectiveTo determine whether DXM reduces the duration of delirium and coma in mechanically ventilated ICU patients while providing adequate sedation as compared to lorazepam DesignP-MC-DB-RCT Patientsn = 106 medical/surgical ICU patients requiring ventilation for >24 hrs TreatmentDXM 0.15 – 1.5 mcg/kg/hr vs lorazepam 1 – 10 mg/hr ResultsDelirium-free & coma-free days: DXM 7 vs. loraz 3 (p=0.01) Prevalence of delirium or coma: DXM 87% vs. loraz 98% (p=0.03) Time @ target sedation (RASS): 80% vs. 67% (p=0.04) Ventilator-free days: DXM 22 vs. loraz 18 (p=0.22) Length of ICU stay (days): DXM 7.5 vs. loraz 9 (p=0.92)

17. Pharmacy Services MENDS Results28-day mortality: DXM 17% vs. loraz 27% (p=0.18) Open-label fentanyl use (median dose/day): DXM 575 mcg vs. loraz 150 mcg (p=0.006) Bradycardia: DXM 17% vs. loraz 4% (p=0.03) Atrial Fibrillation: DXM 6% vs. loraz 0% (p=0.08) ConclusionDXM patients had more days alive without coma or delirium ↑ bradycardia with DXM ↑ fentanyl use with DXM Max duration of DXM = 120 hr Average dose DXM = 0.74mcg/kg/h

18. Pharmacy Services Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients (SEDCOM) Riker R, et al JAMA 2009;31(5):489-499

19. Pharmacy Services SEDCOM ObjectiveTo compare efficacy & safety of prolonged sedation with DXM vs. midazolam for mechanically ventilated patients DesignP-MC-DB-RCT Patientsn = 366 medical/surgical ICU patients with expected ventilation for >24 hrs TreatmentDXM 0.2 – 1.4 mcg/kg/hr vs midazolam 0.02 – 0.1 mg/kg/hr ResultsTime @ target sedation (RASS): DXM 77.3% vs. midaz 75.1% (p=0.18) Duration of study drug treatment (days): DXM 3.5 vs. midaz 4.1 (p=0.01) Time to extubation (days): DXM 3.7 vs. midaz 5.6 (p=0.01) Length of ICU stay (days): DXM 5.9 vs. midaz 7.6 (p=0.24) Delirium: DXM 54% vs. midaz 76.6% (p<0.001)

20. Pharmacy Services SEDCOM ResultsMean delirium-free days: DXM 2.5 vs. midaz 1.7 (p=0.002) Open-label midazolam use: DXM 63% vs. midaz 49% (p=0.02) Fentanyl use: DXM 73.8% vs. midaz 97% (p=0.25) 30 day mortality: DXM 22.5% vs. midaz 25.4% (p=0.6) Bradycardia: DXM 42.2% vs. midaz 18.9% (p<0.01) Hyperglycemia: DXM 56.6% vs. midaz 42.6% (p=0.02) ConclusionNo difference in time at target sedation level ↓ time to extubation & ↓ delirium in DXM group ↑ use of midazolam in DXM group ↑ bradycardia & ↑ hyperglycemia in DXM group Average dose DXM = 0.83 mcg/kg/h

21. Pharmacy Services Dexmedetomidine versus propofol/midazolam for long-term sedation during mechanical ventilation Ruokonen E, et al Intensive Care Med 2009;35:282-290

22. Pharmacy Services Ruokonen E, et al ObjectiveTo compare DXM with standard care (SC) (propofol or midazolam) for long-term sedation in terms of maintaining target sedation and length of ICU stay DesignP-MC-DB-DD-RCT Patientsn = 85 ICU patients with need for sedation >24 hrs TreatmentDXM ≤1.4 mcg/kg/hr vs propofol or midazolam ResultsTime @ target sedation RASS: DXM 64% vs. SC 63% NSS RASS -4: DXM 42% vs. SC 62% RASS 0 to -3: DXM 74% vs. 64% Length of ICU stay (days): DXM 6.6 vs. SC 6.8 [HR 0.766 (p=0.275)] Duration of ventilation: DXM 77.2 h vs. SC 110.6 h (p=0.109) Delirium: DXM 43.5% vs. SC 25% (p=0.035)

23. Pharmacy Services Ruokonen E, et al ResultsSerious Adverse Events: DXM 100% (3 bradycardia, 1 arrest) vs. SC 95.5% ConclusionDXM comparable to standard sedation when light sedation target DXM less effective when deep sedation target (RASS -4) ↑ delirium in DXM group but more CAM-ICU assessments in this group Average DEX dose 0.8mcg/kg/hr Average duration 40 h (Max duration 14 days)

24. Pharmacy Services The effect of dexmedetomidine on agitation during weaning of mechanical ventilation in critically ill patients Shehabi Y, et al Anaesth Intensive Care 2010;38:82-90

25. Pharmacy Services Shehabi Y, et al ObjectiveTo evaluate the effects of DXM on resolution of agitation during weaning from mechanical ventilation of critically ill patients who failed conventional therapy DesignP-OL-O Patientsn = 28 ICU patients who developed agitation and/or delirium upon weaning from sedation TreatmentDXM 0.4 mcg/kg/hr for 2 hours, titrated up by 0.2 mcg/kg/hr every 30 min to max dose of 1 mcg/kg/hr Results baseline: 77% of patients outside of target MAAS, 23% within target 6 h: 93% within target (p<0.001) 12 h: 87% within target (p<0.001) 73.3% of patients were extubated Median ventilation time after DXM infusion = 70 h ConclusionDXM provided resolution of agitation and facilitated extubation Median infusion time of DXM = 62 h

26. Pharmacy Services Summary of Evidence DXM effective at achieving target sedation DXM not as effective when deep sedation required –↑ use of additional sedation agents in DXM group Higher doses of DXM appear safe –No withdrawal/rebound effects seen –loading dose often not used Duration > 24 hr appears safe Appears safe in non-surgical population May ↓ delirium Main AE ’ s: bradycardia, hyperglycemia, AF

27. Pharmacy Services Place in Therapy Light sedation Medical or surgical patients Patients who may be at increased risk for delirium Patients who are unable to be weaned due to agitation Limited data in dialysis patients, severe liver disease, HR <50

28. Pharmacy Services