Efficacy and Safety of Sevofran in Patients Scheduled for Elective Surgery Under General Anesthesia
Sevoflurane is currently being used in more than 100 countries worldwide with an estimated 100 million operations having been performed using sevoflurane as a general anesthetic. After the expiry of the patent on sevoflurane as a pharmaceutical drug, a generic product (Sevofran®; Hana pharmacy, Co. Ltd, Seoul, Korea) has been launched. The aims of this study were to investigate the efficacy (mean minimum alveolar concentration), recovery characteristics (time to recovery of consciousness (ROC) and recovery, and BIS values at ROC and orientation), and safety (incidence and severity of adverse events) of generic sevoflurane in patients undergoing elective surgery.
Drug: original sevoflurane
Drug: generic sevoflurane
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Multi-center, Open-Label, Randomized, Active-controlled, Parallel, Phase 4 Clinical Trial to Assess the Efficacy and Safety of Sevofran in Patients Scheduled for Elective Surgery Under General Anesthesia|
- Comparison of mean minimum alveolar concentration between original and generic sevoflurane [ Time Frame: During mainenance of anesthesia under general anesthesia ] [ Designated as safety issue: No ]
Minimum alveolar concentration was determined by end-tidal sevoflurane concentrations. Mean MAC was calculated as following equation,
Mean MAC = (MAC * hour) / (maintenance time from administration of hypnotic agent (propofol) for acquring loss of consciousness to extubation)
- Comparison of secondary efficacy and safety endpoints between two inhalation agents [ Time Frame: During maintenance of anesthesia under general anesthesia ] [ Designated as safety issue: Yes ]
Secondary efficacy and safety characteristics include following items.
- Anesthesia exposure: MAC * hour [Time frame: maintenanane period of anesthesia]
- Bispectral index, BIS [Time frame: time to recovery of consciousnessn, time to recovery of orientation]
- Adverse event [Time frame: maintenanane period of anesthesia]
- Incidence and severity of postopertive nausea and vomiting [Time frame: 24 hours postoperatively]
- Concentrations of compound A, formaldehyde, methanol [Time frame: 30, 60, 90, 120, 150, 180 min after sevoflurane administration]
|Study Start Date:||September 2008|
|Study Completion Date:||March 2010|
|Primary Completion Date:||September 2009 (Final data collection date for primary outcome measure)|
|Experimental: generic sevoflurane||
Drug: generic sevoflurane
Sevoflurane content: 99.99%, compound A: 3.8 ppm, water content (sample was opened, sealed and stored for 2 weeks) : 0.044% w/v
Other Name: Sevofran® (Hana Pharmacy, Co. Ltd, Seoul, Korea)
|Active Comparator: origianl sevoflurane||
Drug: original sevoflurane
Sevoflurane content: 99.9985%, compound A: 4.6 ppm, water content (sample was opened, sealed and stored for 2 weeks): 0.072% w/v
Other Name: Sevorane® (Abott Korea Ltd, Seoul, Korea)
Patients were randomly allocated to experimental group (generic sevoflurane) and active comparator group (original sevoflurane). Once in the operating room, patients were monitored with electrocardiography, non invasive blood pressure, pulse oximetry (Datex-Ohmeda S/5, Planar Systems, Inc., Beaverton, OR, USA) and BIS (Aspect 2000, Aspect Medical Systems, Inc., Newton, MA, USA).
Anesthesia was induced with fentanyl (2 μg/kg) and propofol (2mg/kg). When patients were unconscious, original or generic sevoflurane was administered. Tracheal intubation was facilitated by administering rocuronium 0.6 mg/kg. The lungs of the patients were then ventilated with oxygen in air (1:2), and the ventilation rate was adjusted to maintain the end-tidal carbon dioxide partial pressure between 35 and 45 mmHg. The concentrations of carbon dioxide, sevoflurane, and oxygen were measured continuously using an infrared anesthetic gas analyzer (Datex-Ohmeda S/5, Planar Systems, Inc., Beaverton, OR, USA), which was calibrated before anesthesia for each patient using a standard gas mixture.
The inspired concentration of sevoflurane was adjusted to maintain BIS values < 60 and stable haemodynamics (systolic arterial pressure (SAP) > 80 mmHg and heart rate (HR) > 45 beats/min). Also, it was titrated to prevent signs of inadequate anesthesia (sweating, facial flushing, movement and swallowing, HR > 90 beats/min without evidence of hypovolemia, and a 15 mmHg increase in SAP, compared with baseline SAP). Fentanyl 1 μg/kg was given if needed to resolve of signs of inadequate anesthesia.
Concentration of compound A, formaldehyde, and methadone were measured at preset interval: 30, 60, 90, 120, 150, 180 min after administration of sevoflurane. Blood and urine samples were taken at preset interval for analyzing concentration of inorganic fluoride: 1 hr after administration of sevoflurane and every 2 hr during maintenance of anesthesia.
|Korea, Republic of|
|Asan Medical Center|
|Seoul, Korea, Republic of, 138-736|
|Seoul, Korea, Republic of, 139-707|
|Study Chair:||Gyu Jeong Noh, M.D. & Ph.D.||Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine|
|Principal Investigator:||Sang Seok Lee, M.D.||Department of Anesthesiology and Pain Medicine, Sanggye-Paik Hospital, College of Medicine, Inje University|