Application to Add Propofol to the Model List of Essential Medicines Prepared by Sharline Madera, William Shipman, and Nicole Ramsey Supervised by Marcus M. Reidenberg Weill Cornell Medical College 1300 York Ave. New York, NY 10065 1. Summary: This is a proposal to add propofol as a general anesthetic agent. 2. WHO focal point: 3. Organizations consulted: none 4. INN: Propofol 5. Formulation: 100 ml vials containing 10 mg/ml IV emulsion 6. International Availability: A comprehensive list of suppliers and API manufacturers is appended to this submission (see Appendix 1 & 2). 7. Listing as specific medicine is suggested 8. Public Health relevance: This drug is essential for modern general anesthesia. It is especially useful for induction and procedures of relatively short duration. 9. Treatment details: Dosage Regimen Propofol injectable emulsion (commercially marketed as Diprivan) contains 10mg/mL (1%) propofol, which is ideal for IV injection. However, in certain cases dilution of the propofol emulsion is required, but it is advised that the emulsion is diluted no lower than 0.2% (2mg/mL) with 5% dextrose (American Hospital Formulary Services Drug Information- Propofol, 2010). Duration Since each individual’s reaction to propofol may vary greatly, several factors must be taken into consideration when calculating the specific dosage for each patient. These factors include: individual requirements, age, weight, blood lipid profile, pathological considerations, and premedication/concomitant medications. Propofol is typically used for two purposes: 1) induction and maintenance of general anesthesia for adults and pediatric patients and 2) the initiation and maintenance of Monitored Anesthesia Care (MAC) in adults undergoing diagnostic procedures. Since several variables exist along with these dualistic purposes, a table has been constructed below to outline specific dosages and durations for different patient populations and purposes (American Hospital Formulary Services Drug Information- Propofol, 2010). 1 Patient Population Induction and Maintenance of Anesthesia Initiation and Maintenance of M A C Induction Maintenance Initiation Maintenance 40 mg (2-2.25 mg/kg) IV infusion rate of 100-200 mcg/kg/min (6-12 Initial propofol infusion Initial IV maintenance every 10 seconds until mg/kg/hr), administered concomitantly with of 100-150 mcg/kg/min dosage of 25-75 mcg/kg/min onset of induction. inhaled 60-70% nitrous oxide and oxygen. IV (6-9 mg/kg/hr) for 3-5 (1.5-4.5 mg/kg/hr) for the infusion rates of 50-100 mcg/kg/min are used min. or a slow injection first 10-15 min and then Adult Patients (Younger to optimize recovery time. Alternatively, of 0.5 mg/kg over 3-5 decreased to 25-50 than 55 Years of Age) and patients may receive propofol doses of 20-50 minutes. mcg/kg/min. Alternatively, ASA Physical Status I or II mg by intermittent injection in combination intermittent IV propofol Patients with inhaled nitrous oxide. Additional IV does injections of 10 or 20 mg of 25-50 mg may be given as determined by may be administered. vital signs. Geriatric (55 Years of Age 20 mg (1-1.5 mg/kg) every IV infusion rate of 50-100 mcg/kg/min. (3-6 Dosages similar to Usual adult dosage of and Older), Debilitated 10 seconds until onset of mg/kg/hr) admin. Concomitantly with inhaled healthy adults are propofol for healthy adults induction. 60-70% nitrous oxide and oxygen. required for this should be reduced by 20% Patients, or ASA III or I V population and rapid IV injections Physical Status Patients should be avoided. 2.5-3.5 mg/kg over 20-30 Initial infusion rate is 125-300 mcg/kg/min seconds (3 – 16 years of (7.5-18 mg/kg/hr) admin. concomitantly with Pediatric Patients age). Young ped. patients inhaled 60-70% nitrous oxide and oxygen may req. higher dosages (ASA I or II physical status and 2 months- 16 while patients with ASA years of age). physical status of III or IV may require lower dosage. 20 mg (0.5-1.5 mg/kg) Continuous IV infusion at a rate of 100-150 every 10 seconds by slow mcg/kg/min (supplemented with continuous Adult Patients Undergoing IV injection. (25 infusion of an opiate agonist). When an opiate mcg/kg/min may be used to agonist is used as the primary agent for Cardiac Anesthesia manage anxiolysis prior to maintenance of anesthesia in cardiac surgery, induction.) propofol administration may be reduced to at least 50 mcg/kg/min. Adult Patients Undergoing 20 mg (1-2 mg/kg) of IV infusion rate is 100-200 mcg/kg/min (6-12 propofol IV every 10 mg/kg/hr) Neurosurgery seconds. (American Society of Heath-System Pharmacists Drug Information- Propofol, 2010) 2 In addition, propofol is used for sedation in critical care settings. For patients with residual effects from anesthetic or sedative drugs, propofol should ideally be injected slowly initially at an IV infusion rate of 5 mcg/kg/min (0.3 mg/kg/hr) for at least 5 min. The rate of infusion may then be increased in increments of 5-10 mcg/kg/min (0.3-0.6 mg/kg/hr) for a span of 5-10 minutes. To maintain this sedation, adults are typically administered IV infusions of propofol dosages of 5-50 mcg/kg/min (0.3-3 mg/kg/hr). In patients where development of hypotension is unlikely, rapid IV (“bolus”) administration of 10 or 20 mg doses of propofol may be used to rapidly increase depth of sedation in patients (American Hospital Formulary Service Drug Information- Propofol, 2010). Existing W H O and Other Clinical Guidelines Currently there are no WHO guidelines regarding the clinical administration of propofol. However, in October of 2004, The American Society of Anesthesiologists (ASA) released the “Statement on Safe Use of Propofol” in which they stated that it is optimal to include the involvement of an anesthesiologist in the care of patients receiving propofol. They further state that when an anesthesiologist is not available, non-anesthesia personnel trained to rescue patients via airway management and advanced life support when sedation levels become deeper than intended should be present during the administration of propofol. In addition, they also present guidelines that require the practitioner to be qualified to identify and manage the airway and cardiovascular changes in patients under anesthesia. This practitioner must also be dedicated to the task at hand and be present during the entire procedure. The ASA highlights several physiological parameters that should be consistently monitored during a particular procedure involving propofol such as: level of consciousness, signs of hypotension, bradycardia, apnea, airway obstruction, oxygen saturation/desaturation, ventilation, heart rate and blood pressure. Based on the nature of the patient, the ASA finds that it may also be necessary to monitor for the presence of exhaled carbon dioxide (American Society of Anesthesiologists: Ambulatory Surgical Care Committee, “Statement of Use of Propofol”, 2009). Although propofol has proven to be effective and safe for the use in pediatric patients, as of March 2001, the State Medicines Control Agency (SMCA) of Lithuania has restricted the use of propofol and has deemed it unsuitable for patients less than 16 years of age (State Medicines Control Agency order No. 43 23 March 2001) Special Diagnostic or T reatment Facilities or Skills As stated earlier, during the administration of propofol, practitioners trained in the administration of anesthesia should be present and devoted to the task at all times. In addition, this particular practitioner should not be directly involved in the surgical or diagnostic procedure at hand. Furthermore, in situations where propofol is used for the sedation of intubated mechanically ventilated adult patients in the Intensive Care Unit (ICU), a practitioner who is specifically trained in the management and care of critically ill patients, cardiovascular resuscitation, and airway management should be available during the entire procedure (Astra-Zeneca- Diprivan Drug Information, 2005). Equipment for oxygen enrichment, patent airway, and artificial ventilation must be immediately available for use during the administration of propofol. Specific attention should be given to the retardation of microorganism growth in the propofol emulsion. Stringent aseptic practices should be maintained while handling the propofol emulsion and typically the single-use product contains 0.005% disodium edetate, which impedes microorganism growth. If contamination is suspected all unused portions of the propofol emulsion should be discarded immediately (Astra-Zeneca- Diprivan Drug Information, 2005). 3 10. Summary of comparative effectiveness in a variety of clinical settings 10.1 Identification of clinical evidence (search strategy, systematic reviews identified, reasons for selection/exclusion of particular data) Systematic reviews and meta‐analyses relevant to the terms "propofol effectiveness," were searched on the Database of Abstracts of Reviews of Effectiveness (DARE: www.crd.york.ac.uk/crdweb/). Articles were limited to comparative analyses of propofol, effectiveness in the clinical setting of induction of anesthesia, or short‐term surgical anesthesia. No date restrictions were applied. The Cochrane Library and PubMed were searched for meta‐analyses and relevant randomized clinical trials (RCTs) otherwise not captured. PubMed searches were language‐limited to English, which necessarily limited the scope of this analysis. No date restrictions were applied. A hand search for clinical practice guidelines was done in Anesthesia, Anesthesiology, National Institute for Health