Diprivan® (AstraZeneca, Wilmington, DE) is a short-acting hypnotic agent used for the induction and maintenance of anaesthesia and approved by the Food and Drug Administration (FDA) in the United States in 1989. It is a hindered phenol drug with ethylenediaminetetraacetic acid (EDTA) as a bacteriostatic agent . Propofol (Baxter Inc., Deerfield, IL, USA) is one of the generic propofol products available in the US and is formulated with metabisulphite. A pilot study suggested 15% reduced efficacy of generic propofol compared to Diprivan®. Depth of anaesthesia was, however, not sufficiently defined to adequately determine comparative efficacy. FDA approval of generic substitutions stipulates bioequivalent variance within 25% compared to brand name drugs . Concerns over narrow therapeutic indices, drug interaction, dose adjustment requirements, adverse effects and professional liability have limited the use of some generic agents currently available . The objective of this study was to assess whether there are measurable differences in the dose of propofol required to achieve a targeted bispectral index (BIS) score between generic propofol and Diprivan® in female patients undergoing abdominal hysterectomy under general anaesthesia.
Following Duke Institutional Review Board approval and written informed patient consent, 60 ASA I–III women undergoing total abdominal hysterectomy were enrolled. Exclusion criteria included patients on long-term sedative or psychotropic agents; known adverse reactions to propofol or sulphur-containing drugs; asthma; morbid obesity (body mass index > 40 kg cm−2); age > 65 yr; abnormal renal (serum creatinine > 100 μmol L−1) and liver functions (enzyme values > twice the normal limits) and significant cardiac disease. Patients were randomized using a computer randomization generator to receive either Diprivan® or generic propofol for induction and maintenance of anaesthesia. The study drugs were prepared in identical syringes by research personnel not involved in the collection of data.
All patients were given midazolam 0.03 mg kg−1 as a premedication. At induction, anaesthesia was initiated with fentanyl 3 μg kg−1 bolus and propofol 2 mg kg−1 given by infusion over 1 min. A Medfusion 2010i infusion pump (Medex Medical Supplies Inc., Duluth, GA) was used to administer both drugs. Lidocaine 1% 2 mL was added to the propofol bolus during induction to avoid pain on injection. Tracheal intubation was performed using succinylcholine 1.5 mg kg−1.
Anaesthesia was maintained with a propofol infusion 20–200 μg kg−1 min−1 and 70% nitrous oxide in oxygen. The rate of infusion initially started at 100 μg kg−1 min−1 was adjusted up or down by 10–20 μg kg−1 min−1 to a BIS range of 50–65. Analgesia comprised a fentanyl infusion at 0.03 μg kg−1 min−1. Additional bolus of fentanyl 1–2 μg kg−1 was given when (a) blood pressure increased above 20% baseline or systolic pressure was >170 mmHg or (b) heart rate >20% baseline or >110 min−1, in the presence of predefined BIS range. Vecuronium or rocuronium was administered to provide muscle relaxation. Twenty minutes before the expected end of surgery, the propofol infusion was reduced to achieve a BIS level of 65–75 and then discontinued 5 min before the end of surgery or with the last surgical suture placement. The fentanyl infusion was discontinued 20 min before the end of surgery. Neostigmine (50–70 μg kg−1) and glycopyrrolate (10 μg kg−1) were administered to reverse the residual effects of neuromuscular blockade. Intravenous (i.v.) ondansetron 4 mg and ketorolac 30 mg were also given 30 min before the end of surgery.
Non-invasive blood pressure, continuous ECG and pulse oximetry were initiated before induction of anaesthesia. A BIS electrode was placed on the forehead prior to induction and continuously recorded the BIS level. Anaesthesia was maintained at BIS range of 50–65 using the BIS 2000 (Aspect MS Inc., Newton, MA). All patients were ventilated to an end-tidal carbon dioxide of 30–40 mmHg. Core temperature was maintained above 35°C using a life air Bair Hugger™ PD 1000 (Progressive Dynamics Inc., Marshall, MI) and monitored with an oesophageal temperature probe. Time from termination of the propofol infusion to eye opening or appropriate response to command was noted. We auscultated the lungs preoperatively, 5 min after induction and hourly thereafter for signs of bronchospasm (audible wheeze) in the apical, mid-axillary or posterior lung areas.
Venous blood samples were taken from 25 patients in tiger-top serum separator tubes 1 and 2 h after induction of anaesthesia to determine the propofol blood concentration. The infusions were unchanged for 10 min prior to blood sampling. Shortly after blood collection, the blood samples were centrifuged for 15 min at 3000 rpm (1400g) and the plasma stored at −62°C for analysis. To measure plasma propofol concentration, the sample (0.2 mL) was placed in a microfuge tube (1.5 mL). We added 0.05 mL of 1 M sodium hydroxide solution and 0.6 mL of a 1: 1 mixture of ethyl acetate/heptane containing 150 ng of the internal standard, thymol to the plasma. The tubes were agitated by a vortex shaker for 30 s. The emulsion was broken by 3 min of centrifugation at 3000 rpm (1400g) and the organic phase transferred to an auto sample vial with reduced volume insert for analysis using gas chromatography.
Based on the results of a pilot study, a sample size of 30 subjects per group was calculated to be sufficient to allow a detection of 15% difference in mean drug dose with an 80% power at an alpha of 0.05. Groups were compared on descriptive characteristics and outcomes using χ2; and two-sample t-test analysis. A P-value <0.05 was considered to be statistically significant.
A total of 76 patients were recruited into the study but 16 were excluded (surgery cancelled or changed, equipment malfunction, patient withdrew consent, not meeting inclusion criteria). Data from 30 patients in each group were analyzed. A flow diagram illustrating the progress of patients during the clinical trial is shown in Figure 1. Patient characteristics are presented in Table 1. Both groups were similar in age, height and weight. There was no significant difference in the mean total propofol doses delivered (induction and maintenance combined) between Diprivan® and generic propofol groups: 90 (30) μg kg−1 min−1 vs. 90 (20) μg kg−1 min−1 (mean ± standard deviation), nor in time to emergence (end of propofol infusion to extubation) or the incidence of respiratory adverse effects (Table 2). There was also no difference in the mean maintenance propofol doses in both groups: 70 (20) μg kg−1 min−1 vs. 70 (20) μg kg−1 min−1.
There was no statistical difference in the BIS values of the two groups, which are presented in 10% epochs (Fig. 2), nor in the average BIS readings during blood sampling. Fifty plasma samples were collected for propofol analysis. Results of three samples (one from the Diprivan® group and two from the generic propofol group) were eliminated due to the extreme values as a result of possible contamination. There was no statistical difference between mean (SD) plasma propofol levels of Diprivan® and generic propofol at 1 and 2 h after induction of anaesthesia (3.0 (1.0) μg mL−1 vs. 3.6 (1.4) μg mL−1, P = 0.2; and 3.0 (1.9) μg mL−1 vs. 3.4 (1.6) μg mL−1, P = 0.58). As the plasma concentration did not demonstrate a statistical difference, all samples were combined and compared to the BIS readings at the time of sampling (Fig. 3). There was a statistically significant correlation between the plasma propofol concentration and BIS value.
We found no difference in mean dosages between Diprivan® and generic propofol when used for induction and maintenance of general anaesthesia at a specified range of BIS. The study was powered to detect a difference in mean drug dose as small as 15% (0.0135 mg kg−1 min−1). Plasma propofol concentrations at a predefined BIS value were also similar between the two groups.
Physicians and institutions are encouraged to prescribe generic drugs due to their wide availability at reduced cost. Generic substitutions often have altered formulations with differences in carrier molecules that potentially can alter the bioequivalence of its base compound. Despite different antibacterial additives, similar doses of Diprivan® and generic propofol produced the same hypnotic effect in our study. A previous study using Diprivan® (AstraZeneca) and generic propofol (Abbott) to maintain a BIS value of 45 demonstrated no difference in their hypnotic and cardiovascular effects . The two drug formulations were however identical. Diprivan® and generic propofol have the same base compound but a different antibacterial ingredient. No previous study has compared the efficacy of both formulations for both induction and maintenance of anaesthesia.
Pharmacokinetic profiles of brand and generic drugs may differ yet achieve acceptable bioequivalency . Generic propofol differs from the brand product due to the sulphite substitution of EDTA. The pH of generic propofol is low, 4.5–6.5 compared to 7–8.5 for Diprivan®. In a study examining the effect of propofol at induction of anaesthesia, pain on i.v. injection was observed to be less with generic propofol compared to Diprivan® (5% vs. 11%) with no difference in hypnotic effect . Inadvertent arterial injection has however been reported to cause hyperaemia and pain but onset of action seem to be similar to the i.v. route [7–9].
In 1986, the FDA had suggested that alternatives be found for sulphite in drugs due to the growing evidence of allergy related to it. The incidence of sulphite allergy is suggested to be more than 1 in 1000 with varied presentation (dermatitis, bronchospasm, anaphylaxis) . Asthmatics, especially those on corticosteroids, are particularly susceptible with a reported incidence of 5% . Propofol inhibits calcium influx and causes smooth muscle relaxation and has been reported to reverse intubation induced bronchoconstriction [12–13]. This effect was not observed with generic propofol . Generic propofol contains 0.25 mg mL−1 of sodium metabisulphite, a product found in many other drugs, foods, wines and cosmetics. Others however reported no difference in airway resistance between generic propofol and Diprivan® . Despite previous precautionary FDA restrictions and reports of adverse reactions with sulphite, there have been little adverse reports with its use with propofol. We also found no difference in adverse events with both drugs, although our study was not adequately powered to determine this difference. Susceptible patients such as asthmatics were excluded from our study and continue to be a relative contraindication to generic propofol usage.
The results of plasma propofol concentration in our study are similar to other reported studies . Although our study was not powered with respect to this secondary measured endpoint, the differences observed were small enough not to be clinically meaningful, regardless of statistical significance.
The BIS monitor, a tool that measures derived electroencephalogram, has been used to correlate hypnotic depth to propofol blood concentration [16–17]. Significant correlation between both measured and pharmocokinetically derived blood propofol concentration to BIS values have been reported [16–19]. Also, propofol demonstrated stronger correlation to BIS than propofol/fentanyl combination (R = −0.33 vs. −0.18) . Opioids have a synergistic effect with propofol and can contribute to lower propofol requirements . Opioids however are also known to significantly increase the plasma concentration of targeted propofol concentrations [21–23]. The cause of this is uncertain but has been postulated to be secondary to altered distribution or metabolic clearance. Others have demonstrated opioid contribution to the reduction in propofol first pass uptake by the lungs, leading to greater systemic availability of propofol . For a targeted response, the combination of opioid and propofol may therefore require less propofol compared with propofol alone. In the narrow range of BIS during anaesthesia maintenance, the association of BIS and plasma concentration of propofol in our study was not significant (R = −0.16; P = 0.2).
In conclusion, we demonstrated similar efficacy between Diprivan® and generic propofol using the BIS monitor to control for depth of anaesthesia without any difference in adverse effect. Plasma propofol concentrations were also similar in both groups suggesting bioequivalence.
This study was supported in part by a grant from AstraZeneca. Presented in part at the International Society of Anaesthetic Pharmacology (ISAP) 13th Annual Meeting, Las Vegas, NV; October 2004.
(PROPOFOL). Injectable Emulsion Professional Information Brochure, AstraZeneca Pharmaceuticals LP, Wilmington, DE.
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