Objective: The study was conducted to provide information on how consumers would use orlistat 60 mg, especially in terms of product dosing, in a setting without physician supervision.
Methods and Procedures: A 3-month, open-label, naturalistic study was conducted in an over-the-counter (OTC) setting in 18 pharmacies. Consumers ≥18 years were allowed to purchase orlistat packages containing a bottle of orlistat 60 mg plus educational materials, which provided lifestyle information and tools to encourage successful weight loss. Data were collected at pharmacy visits and during telephone interviews at 14, 30, 60, and 90 days after enrollment.
Results: A total of 237 subjects purchased and used the product, and completed at least one interview. Most subjects followed the dosing directions and took two to three capsules per day with meals throughout the study. The majority of subjects took a daily multivitamin, as directed. Approximately, 80% of subjects used the educational materials and found them useful or very useful. Over the study duration, most subjects reported following a diet and 51% of subjects reported more frequent or longer exercise than at enrollment. Approximately, 80% of subjects indicated they were satisfied or very satisfied with the weight loss achieved; measured and self-reported relative median weight loss was ∼5% after ≥60 days of using orlistat. Most common adverse events were gastrointestinal (GI), and majority of subjects did not interrupt or discontinue orlistat due to these GI events.
Discussion: These results demonstrate that orlistat 60 mg can be used appropriately and safely and with high consumer satisfaction without physician supervision or dietary counseling. Collectively, results indicate that orlistat 60 mg is an appropriate weight loss therapy in the OTC environment.
There is currently a major epidemic in overweight and obesity. In the United States alone, it is estimated that 66% of adults aged ≥20 years are either overweight, defined by a BMI of 25–29.9 kg/m2, or obese (BMI ≥30 kg/m2) (1). The prevalence of obesity has more than doubled over the past 30 years, with estimates at 32% of the adult US population (1). Several pharmacotherapy prescription options are available for long-term treatment, including Xenical (orlistat 120 mg) and Meridia (sibutramine) in overweight individuals with a BMI ≥27 and at least one risk factor or in obese patients (2). However, until recently, there were no Food and Drug Administration approved over-the-counter (OTC) weight loss medications. In February 2007, orlistat 60 mg (alli, manufactured by GlaxoSmithKline Consumer Healthcare) was approved by the Food and Drug Administration as an OTC weight loss aid for overweight adults ≥18 years (3), and is currently available in the OTC market.
Orlistat is a lipase inhibitor that is minimally absorbed (<2% bioavailable) and acts non-systemically in the intestinal tract. By binding to pancreatic lipase in the small intestine, it partially prevents dietary triglycerides from being hydrolyzed and absorbed (4). At the proposed 60 mg orlistat dose, ∼25% of ingested fat is excreted within 24–48 h of taking the drug (4). Orlistat has few drug interactions and has a well-established safety profile, based on >100 clinical trials (5).
As a prescription drug, orlistat has been used by individuals under the care and direction of their physician. A number of controlled, randomized blinded trials were conducted to evaluate the long-term efficacy of orlistat, as well as to provide accumulating safety data (2). Several of these long-term studies included a 60 mg orlistat arm (6,7,8) and played an important role in considering the drug for switch from prescription to non-prescription (Rx-to OTC) status.
As part of the Rx-to-OTC approval process, additional clinical trials referred to as actual use trials may be conducted to determine how the study drug is used without the guidance of a health care professional and to assess the safety outcomes within this context (9). To address this issue as it relates to orlistat, a multi-center, pharmacy-based, open-label, 3-month study was conducted to examine how consumers would use orlistat 60 mg under real-world OTC conditions. Specifically, the primary objective was to provide information regarding how consumers use orlistat in the absence of physician supervision, especially in terms of product dosing. In addition, safety and tolerability parameters, consumer perceptions of weight loss and the medication, and assessment of the self-help educational materials included in the package were collected. In contrast to clinical trials, this study was designed to assess consumer behavior, perceptions, and safety under OTC conditions rather than to assess efficacy under controlled conditions.
Methods and procedures
Male and female subjects ≥18 years were screened for the study. There were no screening restrictions with the exception of age (≥18 years). All subjects who agreed to purchase the product were provided a written informed consent before actual purchase and agreed to participate in telephone follow-up interviews. Exclusion criteria included participation in previous orlistat market research studies, previously prescribed orlistat, currently treated with medication for diabetes, warfarin, or cyclosporine, and pregnant or breast-feeding.
The study was designed to simulate a “real-world” OTC setting in which subjects could walk into a pharmacy, purchase medication, and use it without physician supervision. A total of 18 community-based pharmacies in the United States participated in this open-label, 3-month trial. In order to minimize influencing the subject's use and purchase decision, study personnel were limited in what they could say and were instructed to state only very general information to all who inquired about the study.
In-store posters and local newspapers were used to advertise for the study. The advertisements targeted mild to moderately overweight individuals. A potential consumer responding to the advertisement, who was ≥18 years, was provided an OTC orlistat package by the pharmacist and asked to read the outside package label. Consumers were offered an opportunity to purchase the product at the intended market price. Their decision to purchase was based on their reading of the carton label. Study personnel were instructed not to provide consumers any information about the drug, other medications they might or might not take, or other details that could influence their behavior. Subjects interested in purchasing orlistat were taken through the informed consent procedure including inclusion and exclusion criteria.
Subjects were allowed to purchase up to three product packages of 90 count bottles of 60 mg capsules. They were not limited on how often they could return to the pharmacy for additional product packages, but they were not allowed to purchase more than three packages of orlistat at any one time. All subjects were reimbursed for the product at the end of the study, but this was not revealed to them during the study period.
Drug facts label. The study drug was labeled as appropriate for individuals who were mild to moderately overweight and needed to lose up to 30 pounds. This corresponds to an approximate BMI between 25 and 29.9 kg/m2.
The outside of the orlistat package included information on the product usage including what to do when using this product and specific dosage directions. Key communications included:
1. Dosage: take one to two capsules (60 mg) with each meal containing fat, up to three times a day;
2. Diet: eating meals that are low in fat and calories;
3. Adverse effects: may experience gastrointestinal (GI) changes;
4. Multivitamin direction: take a daily multivitamin 2 h before or after taking the product;
5. Duration: can be used for up to 6 months of continuous use.
Orlistat package. The contents of the orlistat package included the following: one bottle of 90 orlistat 60 mg capsules, the orlistat user guide, a personal food diary, a pocket fat gram counter, a fat gram wheel, and a portion size information card. In addition, the orlistat diet success planner was provided to each purchaser with the first purchase. These educational materials were an important aspect of the orlistat package and provided subjects with lifestyle information and tools to encourage successful weight loss. The primary tools are detailed below:
1. Diet success planner: a binder that provided lifestyle information on goal-setting and staying motivated, food preparation and dining out, and physical activity.
2. Fat wheel: a cardboard wheel that provided fat grams and portion sizes for common food classes (dairy, meats, etc.).
3. Fat counter: a pocketsize book, Harriet Roth's Fat Counter (10) that provided information on fat grams and calories for a number of food items and brand name comparisons.
4. How to lose weight with orlistat: a booklet that served as an extension of the labeled directions and usage.
5. Personal food diary: a booklet that allowed subjects to track food intake and physical activities.
Study drug. Study medication was manufactured by Roche Pharmaceuticals as blue and white gelatin capsules containing 60 mg orlistat.
Data collection. Data for this trial were collected at the initial and follow-up pharmacy visits and during the scheduled telephone interviews.
Pharmacy. During the initial enrollment visit, demographic, medical, and diet history questionnaires were collected. Heights and weights were measured using a calibrated scale, from which baseline BMI was calculated. Additional weight measurements were collected in all subjects who returned to the pharmacy to purchase additional medicine. Subjects were weighed wearing light indoor clothes, with no shoes, outerwear, or accessories.
Phone interviews. The follow-up telephone interviews were designed to gather information about the following areas: product use, adverse events, use of educational materials, if any contact with a doctor or pharmacist was made, multivitamin use, and satisfaction with the product. To ensure consistency and reproducibility of GI event reporting, a specifically designed dictionary of standard terms was used to describe orlistat-specific GI changes (6,7,8). At the time a subject stopped using orlistat or completed the 3-month study (final interview), the following additional information was collected: use and evaluation of educational materials, reasons why they did not speak with their doctors (where applicable), questions about diet and physical activity, and perceptions of study drug. In addition, self-reported weight loss was solicited at each interview. Subjects were asked, “Since you started using the study medication have you lost any weight?” Only those who indicated they lost weight were asked the next question, “About how many pounds have you lost?” In order to reflect the entire subject sample, self-reported weight loss data are presented as median weights.
Phone interviews were scheduled at 14, 30, 60, and 90 days after enrollment at the pharmacy. A post-treatment safety interview (14 days after treatment end) was conducted only if a participant stopped using the study medication <14 days before being contacted for a follow-up interview. All interviews were conducted by trained nurses. Computer-assisted telephone interviewing software was used to manage the call schedule and interview process.
The main study endpoints included patterns of use; days on study medicine; use of multivitamin; subject-perceived effectiveness and satisfaction with the study medicine; subjects' use and perceptions of the supplementary educational materials, and weight loss during the study. Dosing patterns included an analysis of the number of capsules used per day, number of doses used per day, and number of capsules used per dose.
The User population was defined as all screened subjects who purchased orlistat, used it at least once, and completed at least one interview. The Safety population was defined as all screened subjects who purchased orlistat at the initial pharmacy visit; this population was used in all safety analyses. The safety population included 22 subjects who purchased study medication, but were excluded from the User population due to serious protocol violations that could have confounded subjects' purchase and use decisions. Since these subjects purchased and used the product, they are included in the safety analysis.
All study endpoints were summarized using descriptive statistics. Pearson's chi-square statistic was used to test the associations between satisfaction and measured weight loss, treatment-related adverse events, and capsules per dosage.
At the 18 pharmacy sites, a total of 703 consumers were screened of which 237 purchased and used the drug. The primary reason provided by ∼60% of subjects who did not want to purchase the product was cost. Other reasons included the drug being unknown (9% of subjects) or the need to speak with a health professional before purchasing (7% of subjects).
Most subjects were employed full or part time and were generally well educated; >95% reported graduating from high school and >80% reported having either some college education or were college graduates or postgraduates. Most subjects (96%) used English as their primary language.
Most subjects (92%) in this study had a BMI ≥25, with ∼60% of subjects with a BMI ≥30 (Table 1). There were no subjects with a BMI <18.5, which is defined as underweight (11). Eighteen subjects (7.5%) had a body weight within the normal range (BMI 18.5–24.9), with 83% in the BMI range of 22–24.9 kg/m2. When asked to rate their degree of overweight (underweight or mildly, moderately, or severely overweight), 97.5% of subjects rated themselves mildly–severely overweight, with 62% considering themselves to be moderately overweight. Approximately, 80% of these subjects desired to lose >20 pounds and ∼40% of subjects desired to lose >30 pounds.
Prior use of weight loss drugs
Approximately, 27% (65/237) of subjects in the users group reported having taken a prescription medication or dietary supplement for weight management in the previous 12 months. Of these subjects, 75.4% were taking dietary supplements and 24.6% were taking prescription medications.
At each phone interview, subjects reported using orlistat for at least 90% (median) of the days since enrollment, and 95% of subjects reported taking orlistat with their meals.
The majority of subjects took two to three capsules per day. This pattern of use remained consistent across all interviews (Table 2). In terms of the number of doses per day, the majority of subjects took two to three doses per day with their meals over the course of the study (two doses/day: 29.5% at day 14 and 37.8% at day 90; three doses/day: 59% at day 14 and 45.3% at day 90). Since most subjects took only one capsule per meal, the number of capsules per day and the number of doses per day are very similar.
Table 2. . Number of capsules used per day
With respect to the capsules per meal, at day 14, 70% of subjects were taking one capsule per meal compared to 60% at day 90; at day 14, 30% of subjects were taking two capsules per meal compared to 40% at day 90.
At the time of enrollment 26% of subjects reported following a diet plan (self-imposed diet, medically supervised program, or commercial/self-help group), whereas at the 14-day interview ∼80% reported following a diet (Table 3). During the study, most subjects' diets consisted of a reduced calorie and low-fat diet (see Table 3).
Table 3. . Type of diet followed during the study
An overwhelming majority of subjects (>90%) who reported following a diet indicated that they were very successful or somewhat successful in maintaining their diet. These results remained consistent at every interview for the duration of the study.
At the time of enrollment, 75% of subjects (177 of 237) reported following an exercise program (self-imposed or supervised). Over the study duration, 51% of subjects reported more frequent or longer exercise relative to enrollment. At each interview, subjects demonstrated a median increase of 30–40 min of exercise per week relative to their enrollment exercise levels.
The majority of subjects (74%) used a multivitamin while taking orlistat. Fifty-five percent of subjects were regularly using a multivitamin before enrollment, and at the 14-day interview 50% of the subjects who were originally not using a multivitamin reported taking one. Nearly all subjects (86%) took one vitamin daily and 50% took a multivitamin >2 h before or after taking orlistat as indicated on the label.
Approximately, 79% of subjects who had a final interview (N = 198) reported using at least one of the educational materials that came with the orlistat package. Maximum usage was observed for the fat counter, which was used by 64% of subjects who reported using the materials. Each of the tools was rated as useful or very useful by ∼80% of subjects who used them (Table 4).
Table 4. . Usefulness ratings of educational materials
Weight change and satisfaction
Measured and self-reported weight loss. A total of 106 subjects returned to the pharmacy and were weighed. The mean weight loss was 2.5 ± 0.4 kg within the first 30 days of using orlistat and 4.6 ± 0.7 kg after at least 60 days of using orlistat. As shown in Figure 2, median relative weight loss (%) for measured and self-reported weight loss was similar. For measured weight loss, the three time intervals coincide with returning to the pharmacy within 1–30 days from enrollment, 31–60 days from enrollment, and >60 days from enrollment. For the self-report data, the time intervals reflect interviews conducted 30, 60, and 90 days after enrollment.
Almost all subjects achieved weight loss at the end of the study period: 83% (45/54) based on measured weight loss and 93% (134/144) based on self-report. Moreover, almost 50% of subjects achieved >5% weight loss at the end of the 3-month study period. For measured weight loss, 46.3% (25/54) of subjects weighed >60 days after enrolling achieved >5% weight loss. For self-reported weight loss, 46.5% (67/144) of subjects interviewed at 90 days achieved >5% weight loss.
Satisfaction with Medication. Approximately, 80% of the subjects indicated they were satisfied or very satisfied with orlistat, and this percentage remained consistent across all four interviews. The main reasons provided for satisfaction were weight loss (63% of subjects) and the drug was working (55% of subjects). Other reasons included the drug helped maintain their diet and provided fat content awareness (30% of subjects) and did not cause side effects (34% of subjects). There was a significant relationship between measured weight loss and satisfaction (p < 0.001), but neither incidence of GI-related adverse events nor capsules per dose were significantly correlated with satisfaction. Across the interviews, only 8–16% of subjects were unsatisfied or not at all satisfied.
A summary of all adverse events by body system identified and documented in this study is presented in Table 5. The most commonly observed adverse events were GI in nature. Most of these GI adverse events were changes associated with the drug's mechanism of action. Specifically, 52% of 284 orlistat users did not experience any orlistat-specific GI changes, and only 8.5% discontinued due to these GI treatment-related effects.
Table 5. . Rates of adverse events by system organ class
Rates are based on the 284 subjects who purchased study medication.
Data are presented for system organ classes with adverse events in at least 10 subjects.
Infections and infestations
Nervous system disorders
Musculoskeletal, connective tissue, and bone disorders
Injury and poisoning
There were six serious adverse events reported. Four were reported by the Medical Investigator as unrelated to the study drug, and two (abdominal pain and chest pain) were identified as being possibly related to the study drug. In both cases, the medical history was unknown and the subject was taking orlistat for ∼1 month.
Behavioral studies conducted under a real-world setting play an increasingly important role in assessing prescription products being considered for OTC status (9). These actual use trials are designed to examine whether consumers can understand the label and use the product appropriately and safely in the absence of physician supervision. Importantly, these studies provide consumer advocates and the regulatory agencies with evidence of how these drugs will be used once they are available OTC.
The results of this 3-month study demonstrated that orlistat 60 mg can be used effectively and with high consumer satisfaction without any physician instruction or dietary counseling. This study provided very useful information on the use of orlistat in an actual use setting with regards to compliance with label instructions, product usage and dosing, compliance with daily diet and physical activity, multivitamin use, educational materials, effectiveness, safety/tolerability, and satisfaction.
This was an “all comers” study in that subjects were allowed to decide if they were interested in purchasing the product, and minimal exclusion criteria were applied for the actual use of the product. Thus, the subjects in this study likely reflect the consumers who may purchase the OTC product. Most subjects in this study were well-educated, employed, white women between the ages of 30 and 59 with a BMI ≥ 25 and who desired to lose >20 pounds. Importantly, the orlistat OTC product did not appeal to underweight individuals since there were no subjects who were underweight (BMI < 18.5) in this study.
Overall, subjects in this study used orlistat appropriately in terms of dosing instructions. Most subjects indicated that they used orlistat for at least 90% of the days since enrollment, and at least 95% of subjects took orlistat with their meals.
The majority of subjects took two to three capsules per day over the course of the study. Responses to dosing questions indicate that subjects took less than the recommended dose when they either skipped a meal or had meals containing minimal or no dietary fat, rather than taking less to avoid potential side effects. Few subjects took more than three doses per day. Only one subject exceeded the maximum dose of six capsules per day, which was reported only at the last interview; the daily recommended dose was taken at all prior interviews. These results suggest the likelihood of misuse is very low. Moreover, doses >120 mg (two capsules) provide little additional efficacy in terms of preventing additional fat absorption (4). This information, which is provided to consumers (12), should further discourage inappropriate use.
Although the label allowed subjects to take one to two capsules with each meal, most subjects chose to take only one capsule per meal. In general, most subjects found a strategy that worked and stayed with it. The majority of subjects used one capsule per dose throughout the study duration and a smaller subset of subjects used two capsules per dose. Only a small increase in capsules/dosage was observed over time. For those subjects who took more than one capsule per meal, ∼70% indicated they did so when eating a large and/or high fat content meal, and only 2% of subjects specifically reported taking more capsules because they felt they were not losing weight (data not shown).
There are several differences between the marketed alli label and the label used in this study (12). In particular, the dosing has been changed to one capsule per meal from one to two capsules per meal; duration is unspecified rather than 6 months, and the indication has been modified to overweight individuals rather than mild to moderately overweight individuals who need to lose up to 30 pounds. The process of Rx-to OTC switches involves testing several labels, which are modified over time based on clinical and consumer research (9). As such, the results of the current study were critical in developing the final label approved by the Food and Drug Administration.
Recommendations on changes in lifestyle behavior were a key focus of the educational materials included with the medication. Most subjects reported using at least one of the educational self-help tools during the study period. Although all components were utilized, the fat counter and personal food diary were used more often (data not shown), and both were seen as “very useful” by a much higher percentage of subjects than the other three components. These results are not surprising given the nature of the materials. Components such as the diet success planner and how to lose weight booklet were designed to be read at the beginning and used as a reference. The fat counter and food diary, on the other hand, were intended to be used as daily tools for monitoring and calculating food intake. It is important to note that the educational materials used in this study served as the primary source for the reference guides that are included in the alli starter package. Although the reference guides differ in presentation and organization, they include all the key concepts and recommendations that were included in the study materials.
As the results demonstrated, subjects not only took the medication as instructed but also made appropriate changes in their diet and physical activity. Once taking the medication, many subjects initiated a diet low in fat and calories, and an overwhelming majority of subjects indicated that they were very successful or somewhat successful in maintaining their diet throughout the duration. Moreover, ∼50% of the subjects reported increasing their physical activity over the study period.
Approximately, 80% of the subjects indicated they were satisfied or very satisfied with orlistat. Not surprisingly, the primary reason for their satisfaction was related to their weight loss outcome. Self-reported and measured weight loss results were consistent, indicated by the similar findings for % median weight loss after 60 days of orlistat treatment, which corresponded to ∼5% weight loss. The percentage of subjects achieving >5% weight loss at the end of the study was also comparable (∼46% of subjects). Given the study was only 3 months in duration, a 10% categorical analysis, which is usually limited to the studies of at least 1 year duration (6,7,8), was not included. The Food and Drug Administration Draft Guidance, Developing Products for Weight Management, specifies only a 5% categorical criterion in their evaluation (13).
Previous studies have demonstrated the importance of prescribing weight loss medications in combination with lifestyle modification (14). These results provide further evidence that, in an OTC environment without medical supervision, self-instructional materials that encourage lifestyle changes in combination with weight loss medication can result in meaningful and satisfying weight loss.
Since orlistat may reduce the absorption of fat-soluble vitamins, it is recommended that patients taking prescription Xenical take a multivitamin daily. Moreover, patients are instructed to take the multivitamin at least 2 h before or after taking orlistat (15). In the current study, a similar instruction was provided; and although 74% of subjects took a multivitamin daily, as directed, subjects were less compliant about when to take the multivitamin (within 2 h of orlistat). This lower rate of adherence may reflect the fact that most multivitamins are labeled to be taken with food (16), and some individuals experience GI discomfort if they do not take their vitamins with food. Importantly, even if consumers were to take a multivitamin along with orlistat, the majority of fat-soluble vitamins will be absorbed (17). The current alli labeling instructs individuals to take a multivitamin once a day at bedtime (12).
The safety profile for orlistat observed in the current study is consistent with the results from randomized, placebo-controlled trials (3). In these studies, adverse event rates were similar to placebo with the exception of GI events, which were the most common adverse event (3). The overall incidence of specific orlistat-related GI adverse events observed in this study was similar to that seen in controlled clinical trials and, in some instances, was actually lower (6). Importantly, for those subjects who experienced GI adverse events, most continued to take orlistat and did not alter their dosing or therapy of orlistat.
In contrast to a randomized blinded clinical trial in which subjects are carefully selected and monitored, methods used in the current study to measure product usage, compliance, and safety outcomes were designed to be as unobtrusive as possible to minimize affecting the behaviors being measured. However, the methodology can be challenging and has limitations. First, asking the subjects questions during their study participation may sensitize them to certain information, which may change their subsequent behavior. Trying to minimize this issue, only usage from the first interview was reported for certain variables. For example, since subjects could have started taking a multivitamin or taken it differently after asking about their usage in the first interview, vitamin usage was only reported on the subjects' response to the 14-day interview.
Another limitation is that the actual use study was not designed to measure efficacy, and thus the weight loss results should be interpreted with caution. First, the measured weight loss data reflect only those subjects who returned to the pharmacy to repurchase the drug. Since subjects could return any time during the 3-month study period, the weight changes reflect fairly wide data windows, i.e., first 30 days, >60 days. Second, subjects who returned to repurchase were likely successful in their weight loss attempt and therefore the sample was somewhat biased. Finally, with respect to self-reported weight loss, since only those subjects who indicated they lost weight reported the actual pounds lost, it was necessary to use self-report median weight change rather than mean change.
In conclusion, the use of orlistat 60 mg in conjunction with self-instructional lifestyle materials and in the absence of physician supervision or counseling resulted in high consumer satisfaction, excellent dosing compliance, and utilization of the in-package materials. Moreover, most subjects showed positive behavioral changes in diet and physical activity and weight loss over the study duration. Together with an acceptable and consistent safety profile, these findings provide assurance that orlistat 60 mg is an appropriate weight loss drug for OTC use.
Several of the authors are employees of GSK and Roche.
We acknowledge and thank Pegus Research, including nursing staff, and Brent Page for conducting the study and for their methodological assistance we also thank the pharmacists who served as investigators at the sites. The study was funded by Hoffmann-La Roche.