|Year : 2016 | Volume
| Issue : 4 | Page : 296-301
Bottle characteristics of topical international glaucoma medications versus local brands in Saudi Arabia
Nasser Al-Jumaian1, Rizwan Malik1, Rajiv Khandekar1, Abdullah Al-Humaidan1, Rana Al-Madany1, Reham Al-Qahtani1, Ahmed Altowairqi1, Abdulwahab Al-Theeb1, Babar Zaman1, Leyla Al-Djasim1, E Randy Craven2, Deepak P Edward2
1 King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
2 King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; Wilmer Eye Institute, Baltimore, Maryland, USA
|Date of Web Publication||15-Nov-2016|
Deepak P Edward
King Khaled Eye Specialist Hospital, P. O. Box 7191, Riyadh 11462, Saudi Arabia
Source of Support: None, Conflict of Interest: None
| Abstract|| |
What Is Known and Objective: Physical bottle characteristics differ of brand name topical glaucoma medications and local generic equivalents. This study compares the bottle characteristics of international topical glaucoma brands versus local brands from the Kingdom of Saudi Arabia.
Methods: Data were collected on bottle drum volume, drop volume, bottle "squeezability," bottle tip diameter, labels and instructions, cap color coding, and clarity of the drug label. Density-based calculations of drops in bottle volume were assessed using an analytic balance. Bottle tip diameter was measured using 0.05 mm Vernier calipers. A Likert scale-based questionnaire was used to evaluate the subjective opinions of patients on bottle squeezability, clarity of usage and storage instructions, and the consistency of the cap color coding.
Results: The volumes of international brands were statistically significantly higher than the local brands (P < 0.001). A number of drops per bottle and tip diameter were comparable between the international local brands. Cap color coding was inconsistent for international and local brands. Patients were dissatisfied with the label font size. Patients reported that the international and local brands were similar in terms of the ease of opening the bottle, instilling a drop, and the clarity of the instructions; but the local brands were subjectively easier to squeeze than international brands.
What Is New and Conclusions: This is the first study to compare bottle characteristics of local Saudi Arabia brands with international brands. The bottle characteristics and patient feedback were similar between the local and international topical glaucoma medications. However, there were differences between the local and international brands in drug volume, bottle squeezability. Hence, patient compliance and drop dosage may differ based on the origin of manufacture.
Keywords: Bottle characteristics, bottle tip diameter, drug volume, glaucoma, glaucoma medication, survey
|How to cite this article:|
Al-Jumaian N, Malik R, Khandekar R, Al-Humaidan A, Al-Madany R, Al-Qahtani R, Altowairqi A, Al-Theeb A, Zaman B, Al-Djasim L, Craven E R, Edward DP. Bottle characteristics of topical international glaucoma medications versus local brands in Saudi Arabia. Middle East Afr J Ophthalmol 2016;23:296-301
|How to cite this URL:|
Al-Jumaian N, Malik R, Khandekar R, Al-Humaidan A, Al-Madany R, Al-Qahtani R, Altowairqi A, Al-Theeb A, Zaman B, Al-Djasim L, Craven E R, Edward DP. Bottle characteristics of topical international glaucoma medications versus local brands in Saudi Arabia. Middle East Afr J Ophthalmol [serial online] 2016 [cited 2017 Aug 19];23:296-301. Available from: http://www.meajo.org/text.asp?2016/23/4/296/194077
| Introduction|| |
The management of glaucoma in the majority of patients involves lowering intraocular pressure, ,,,, with topical medications. The mode of action and dosing varies based on the type of medications. However, topical glaucoma medications are usually solutions/suspensions that are dispensed in a low-density polyethylene bottle in which a "dropper built into the neck (droptainer)."  In the past, the droppers were available separately were to be applied to the bottle after opening medication packet. Recently, generic glaucoma medications have been introduced as alternatives to original brand name topical medications. The standards for a "generic" ophthalmic product and an "innovator" ophthalmic product are well defined under the regulations and policies in the USA. In the Kingdom of Saudi Arabia (KSA), various international (brand name) and local brands of glaucoma medications are available.  The Saudi Food and Drug Administration and drug regulatory agencies in KSA have developed policies regarding local brands that are consistent with international standards. 
What is known and objective
North American studies suggest that there is a difference in the physical characteristics of brand name and generic topical glaucoma bottles. , To the best of our knowledge, no studies have compared the physical characteristics of bottles of topical glaucoma medications manufactured in KSA (generics) with those manufactured internationally. Furthermore, there is a relative paucity of data on patient feedback observations on the physical characteristics of topical glaucoma medication. This information is pertinent for improving the bottle features and may be important for understanding patient compliance. For example, bottle tip diameter, bottle label, and instructions; cap color coding and readability of the label may all influence how a patient uses the medication.
The purpose of this study was to compare the bottle characteristics of international topical antiglaucoma brands versus local brands (KSA) based on patient perspectives.
| Methods|| |
This prospective study was subdivided into two arms: a laboratory-based arm and a patient questionnaire-based arm that were approved by the Institutional Review Board of King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia. Data were collected on drug volume in the bottle, drop volume, bottle "squeezability," bottle tip diameter, bottle label and instructions, cap color coding, and clarity of the drug label.
International branded topical antiglaucoma medication bottles included Xalatan (Latanoprost, Pfizer New York, NY, USA), Xalacom (Timolol/Latanoprost, Pfizer New York, NY, USA), Cosopt (Timolol/Dorzolamide, Merck Kenilworth, NJ USA), Trusopt (Dorzolamide, Merck Kenilworth, NJ, USA), and Alphagan-P (Brimonidine, Allergan Irvine, CA, USA). The local brand included Latano (Latanoprost, Jamjoom Pharma, Jeddah, KSA), Latanocom (Timolol/Latanoprost, Jamjoom Pharma, Jeddah, KSA), Xolamol (Timolol/Dorzolamide, Jamjoom Pharma, Jeddah, KSA), Xola (Dorzolamide, Jamjoom Pharma, Jeddah, KSA), and Brimo (Brimonidine, Jamjoom Pharma, Jeddah, KSA).
Three bottles of each medication were stored at room temperature (22°C) before evaluating their characteristics. All medications bottles were supplied from the pharmacy at the King Khaled Eye Hospital.
Bottle volume and drop volume measurement
Medication volume and drop volume measurement were performed using a densitometric method that has been previously described. , An analytical balance with a lower detectable limit of 0.1 mg and capacity of 240 g was used to determine the drop weight. The drop weight was determined by administering ten drops into a Petri dish, and the weight of the drops determined using the analytical balance. This process was repeated until the bottle was empty. Weighing took place in ten-drop intervals. The final interval, however, may or may not have contained ten drops depending on the remaining volume in the bottle. This process was duplicated for three bottles of each product. The density of bottle medication solution and density of drops was calculated by the total weight of a 100 μL sample divided by 0.1 ml. This process was repeated four times for each product to obtain an average density for each medication. From this, the volume of each medication and each drop was determined by dividing the weight of each drop or medication, respectively, by the calculated density. The number of drops in each bottle was calculated by the summation of the total number of drops for the three samples of each drug and divided by three and variability in drop number (standard deviation) was determined.
Measurement of bottle tip diameter
The bottle tip diameter was measured using 0.05 mm Vernier calipers. 
Assessment of color coding
The American Academy of Ophthalmology (AAO) recommended that a uniform color coding system is established for the caps and labels of all topical ocular medications.  The consistency of color coding of the bottle cap was determined by comparing the bottle cap color to the internationally accepted coding system.  This color coding system is only applicable to single medications. Hence, bottles containing combinations of medications were excluded from the evaluation of the color coding system. The combination drops were Xalacom and Cosopt from the international brands and Xolamol, and Latanocom from the local generic brands.
A previously developed patient questionnaire was used in this survey.  A research coordinator and two medical students administered the questionnaire to patients and health-care providers for feedback on the physical characteristics of the medication bottles. Patients who presented for regular follow-up were randomly selected to participate in the questionnaire. To participate in this part of the study, patients had to be literate or have a literate caretaker. The questionnaire was comprised three sections: (1) patient demographics and glaucoma duration; (2) feedback on bottle label including font size, clarity of instructions, and storage instructions; and (3) feedback on bottle characteristics including ease in squeezing the bottle, ability to open the cap smoothly, ease in expressing a single drop from the bottle, and any similarity with other drops that may lead to instilling the wrong medication. Each of these variables was measured on a Likert rating scale, similar to a previous study.  Patients were given a set of three international brands (Cosopt, Trusopt, and Alphagan) and a set of three local equivalent generic brands (Xolamol, Xola, and Brimo).
The data were analyzed using the Statistical Package for Social Studies Version 16 (IBM Corporation, Armonk, New York, USA). The two-sided t-test was used to compare the physical characteristics of international and local brands. The results of the questionnaire were calculated as frequencies and percentage proportions. The sum of response score in each subgroup was computed, and the score was further categorized as very poor (<20%), poor (20%-<40%), neutral (40%-60%), good (60%-<80%), and excellent (80% and more). A P < 0.05 was considered statistically significant.
| Results|| |
The physical characteristics of topical glaucoma medication were evaluated using five international brands and five brands manufactured in Saudi Arabia. The volume stated on the bottle was similar between international and local brands. A comparison of volume differences of each bottle is presented in [Table 1]. For most medications, the measured volume exceeded the volume stated by the manufacturer, giving a positive "difference in volume" value [Table 1]. The volume measured was less than stated on the bottle (negative volume difference) for two local brands (Xolamol and Brimo). The difference in volumes for international brands of glaucoma medication (stated on the label versus actual) was significantly greater than for local brands (P < 0.001).
The number of drops available in each bottle in local and international brands of medications is presented in [Figure 1]. The number of drops from bottles of each comparable international brand and local brand was similar (P = 0.99).
|Figure 1: Comparison of number of eye drops in a bottle for glaucoma medications|
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|Table 1: Volume differences between local and international brands of topical glaucoma medications|
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The variability in tip diameter of the bottles of different topical medications is presented in [Figure 2]. The tip diameter was variable for both local and international brands. The median tip diameter of international and local brands of glaucoma medication was similar (P = 0.3). Repeat measurements of bottle tip diameter, even for the same bottle, often differed. The highest variability was noted for Trusopt and Latanocom [Figure 2].
|Figure 2: Variability in tip diameter of different bottles of glaucoma medications|
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The cap color coding was consistent only for Alphagan and Trusopt for the international brands. Color coding was not applicable for combination drops.
There were 117 patients who reported their feedback on the use of topical medications. There were 120 patients who reported their feedback for local brands. The same patients presented feedback on both international and local brands. The demographics of the participants are compared in [Table 2]. The patient demographics were similar for local and international brands. For the patient survey, font size was graded "excellent" by 8/120 (6.7%) patients and "good" by 20/120 (16.7) patients for the local brands. For the international brands, 0/117 patients reported "excellent" font size and 24/117 (20.5%) patients reported "good" font size [Figure 3]. Similar numbers of patients graded the font size as neutral and poor for the international group. Clarity of instructions and quality of storage instructions were similar between the international and local brands.
|Figure 3: Patient's perspective regarding instruction on the international and local brands of bottles with glaucoma medications in terms of font size, clarity of instructions, and quality of storage information graded using a Likert scale. Symbols and error bars represent median and interquartile range, respectively|
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|Table 2: Demographic profile of glaucoma patients that provided feedback on bottles of glaucoma medications|
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[Table 3] presents the results of questionnaire feedback on font size, ability to squeeze the bottle, ability to open the bottle, ease of instilling a drop, and the perceived chance of mistaking the bottle with other medication bottles. The responses suggested that the local brands were more squeezable. Nearly 60% of patients graded the local brand bottles "good" or "excellent" in terms of squeezability compared with 46% for international brands. Responses for "ability to open the bottle smoothly" and "ease to get a single drop" were similar for both groups and were graded as "excellent" by 40/120 (33.3%) patients and "good" by 38/117 (31.7%) patients for local brands and by 33/117 (28.2%) patients and 40/117 (34.2%) patients for international brands.
Trusopt and Cosopt were noted to be significantly more likely to be confused with other bottles of medications. The overall score regarding ease of use in using an international and local brand of glaucoma medication was not significantly different between international and local brands (Kruskal-Wallis test: Chi-square = 0.8, P = 0.4).
| Discussion|| |
Patient compliance and the socioeconomic aspects of glaucoma therapy are affected by the physical characteristics of the medication bottle, content, drop volume, patient perceptions of the bottle, and instructions.  This comparative study evaluated some of these key issues for international brands and local brands available in Saudi Arabia and many countries in the Middle East. However, this study did not evaluate the identity, strength, purity, quality, and efficacy of the study medications. The Food and Drug Administration and other regulatory agencies in the region have indicated that a generic ophthalmic product must have the same indications for use and must meet the same batch requirements for identity, strength, purity, and quality. In addition, the generics must be manufactured to the same standards required for brand name/innovator products.  The current study included two components: a laboratory-based evaluation of the volume and bottle tip variability and patient feedback on the physical characteristics of the bottle, ease of use, and other features. These factors may be important for patient compliance with the medication regimen.
The outcomes of our study indicate that medication volume was higher than labeled for international brands and lower than labeled for local brands. Medication bottles with greater volumes than stated on the label have been previously described for international brands. ,, To our knowledge, data are unavailable in the literature for local brands from KSA. In this study, three out of five local brands had overfilled medication overfill whereas two did not. It is unclear if overfilling medication bottles is intentional to account for medication spillage during instillation or it is due to variability in the manufacturing process. Nevertheless, additional medication in the bottle is advantageous for the patient, especially when medication refills are restricted.
In the current study, the number of drops per bottle varied. For example, the Latanoprost sample had 83-86 drops per bottle whereas bottles containing other medications had between 124 and 167 drops [Figure 1]. These findings are similar to a North American study that reported variation in bottle volume between the same class of topical glaucoma drops for international brands and local Canadian brands. 
Bottle tip diameters can determine the volume of drug dispensed during instillation. In our study, the bottle tip diameter was generally similar for local and international brands of the same type of medication, except for Latanoprost-containing bottles where the tip diameter for the local brand Latano (0.57 mm) was approximately half that of the tip diameter for the international brand Xalatan (1.18 mm). In addition, the tip diameter for local brand Latanocom (0.43 mm) was much smaller than the international branded equivalent Xalacom (1.15 mm). The smaller tip diameters might have resulted from the need to puncture the tip of the bottle to create a functioning tip for both local brands. Possibly, a sharp object provided with the bottle had a small diameter and could have resulted in a smaller size and great variability in the tip diameter. The variability in tip diameter is an important factor whether a therapeutic dose is instilled or if the patient is under/over medicated. Correct dosage has important implications in the therapeutic effect of medical treatments of progressive diseases such as glaucoma. The clinical implications of smaller or larger bottle tip diameters can affect drop volume and other factors. Perhaps, a smaller bottle tip may make it more difficult for patients to squeeze the medication out of the bottle. This may be especially pertinent for the elderly who have reduced manual dexterity and finger strength. Alternately, a larger tipped bottle might cause multiple larger drops to be instilled causing wastage of medication. However, the majority of patients in the survey classified international brand bottles as being "poor" in terms of the ability to squeeze the bottle and the ease of expressing a drop. It is possible that the ability to express drops from the bottle was related to the compressibility ("squeezability") of the bottle rather than the tip diameter.
Only two of the international brands with a single medication in the container were consistent with AAO recommendations for cap color. None of the local brands followed the AAO recommendations. We noted that commercially manufactured Xalatan available in the USA follows the turquoise color recommendation by the AAO yet Xalatan from the same manufacturer does not follow the AAO recommendation in the KSA and the Middle East. The consistent bottle cap color for specific classes of glaucoma medications is useful for identifying the correct medication and hence reducing medication error by the patient.  However, the use of different colored caps may have variable benefit in patients with advanced glaucoma as the disease itself can alter contrast sensitivity and color perception. , Previous studies have shown that patients perception of bottle cap color varies considerably.  A study reported that patients reported 102 unique color descriptors to describe the colors of the 11 bottle caps.  Furthermore, the color descriptions of bottle caps frequently differed between physicians and patients. Agreement was <15% for betaxolol, brimonidine, and latanoprost. 
The survey from the current study indicated that there was general dissatisfaction (48% graded this "poor" for local brands and 38% graded this "poor" for international brands) with font size for the drug instruction pamphlet for both the international and local brands. This finding is not surprising as many glaucoma patients in the survey were elderly, had presbyopia, or had generalized vision impairment due to advanced glaucomatous damage. An increase in font size or a different type of font, contrast or visibility of the printed material may make the instructions more legible. More studies are required to determine the ideal font size and type of pamphlet instructions.
Patients found a local brand of bottles were easier to squeeze than international brands. This difference in this variable may be related to the type or thickness of the material used to manufacture the bottle. The clarity of instructions and the storage instructions were similar for local and international brands. Self-perceived difficulty in instilling eye drops is an important predictor of poor drop instillation technique.  Patients who report difficulty with instillation are less likely to use their drops correctly. This factor should be considered by the prescribing clinician.
Our study also indicated that there was a greater chance of confusing different international medication bottles than local brands. This outcome was due to the similarity of the physical structure of the international brand of bottle. This observation was particularly apparent for Trusopt and Cosopt manufactured by the same pharmaceutical company with dispensing bottles having similar designs and dimensions; however, it is unlikely that Cosopt and Trusopt would be prescribed simultaneously to a patient. Alternately, if a clinician elects to switch medications between Cosopt and Trusopt, there is a potential for confusion and medication error by the patient. We recommend that the patients be educated on the possibility of medication error.
The study has a number of limitations. First, two individuals who were not masked to the medications performed all volumetric measurements and may introduce a systematic error to the study design. The density-based values of volume may have subject to systematic error because they were calculated rather than directly measured. Our findings, however, were consistent with a previous study for some international brands.  Moreover, we grouped local and international brands to simplify analysis as bottles within each of these groups were often quite different, especially in terms of individual physical characteristics. The primary aim of this study was to evaluate differences between local and international brands; hence, this categorization was appropriate for the study. Lastly, it has been suggested that the angle at which the bottle is held may alter the effective dosage.  In this study, when determining the number of drops in each bottle, we assumed that the bottle is held vertically during instillation.
| What is New and Conclusion|| |
This is the first study of local generic equivalents of topical glaucoma medications from Saudi Arabia. In general, physical bottle characteristics of local and international brands of glaucoma medication bottles were similar except for the volume of medication in the bottles. International brands consistently contained a larger number of drops per bottle than stated on the bottle whereas two of the local brands contained less drops than stated. The bottle tip diameters varied considerably for both local and international brands. The patient survey suggested that the local brand bottles were easier to squeeze.
We thank the staff of glaucoma subspecialty, pharmacy division of King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia, for assisting us in this research project.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Weinreb RN, Khaw PT. Primary open-angle glaucoma. Lancet 2004;363:1711-20.
Heijl A, Bengtsson B, Hyman L, Leske MC; Early Manifest Glaucoma Trial Group. Natural history of open-angle glaucoma. Ophthalmology 2009;116:2271-6.
The advanced glaucoma intervention study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. The AGIS Investigators. Am J Ophthalmol 2000;130:429-40.
Leske MC, Heijl A, Hyman L, Bengtsson B, Komaroff E. Factors for progression and glaucoma treatment: The early manifest glaucoma trial. Curr Opin Ophthalmol 2004;15:102-6.
Garway-Heath DF, Crabb DP, Bunce C, Lascaratos G, Amalfitano F, Anand N, et al.
Latanoprost for open-angle glaucoma (UKGTS): A randomised, multicentre, placebo-controlled trial. Lancet 2015;385:1295-304.
US Department of Health and Human Services. Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics. 1999; v. 2015. [Last accessed on 2015 Jun 15].
Available from: http://www.sfda.gov.sa/ar/Pages/default.aspx.
Gaynes BI, Singa RM, Cao Y. Dosage variability of topical ocular hypotensive products: A densitometric assessment. J Glaucoma 2009;18:149-52.
Mammo ZN, Flanagan JG, James DF, Trope GE. Generic versus brand-name North American topical glaucoma drops. Can J Ophthalmol 2012;47:55-61.
Regnault A, Viala-Danten M, Gilet H, Berdeaux G. Scoring and psychometric properties of the eye-drop satisfaction questionnaire (EDSQ), an instrument to assess satisfaction and compliance with glaucoma treatment. BMC Ophthalmol 2010;10:1.
Fiscella R, Wilensky JT, Chiang TH, Walt JG. Efficiency of instillation methods for prostaglandin medications. J Ocul Pharmacol Ther 2006;22:477-82.
Sample PA, Weinreb RN, Boynton RM. Acquired dyschromatopsia in glaucoma. Surv Ophthalmol 1986;31:54-64.
Stamper RL, Hsu-Winges C, Sopher M. Arden contrast sensitivity testing in glaucoma. Arch Ophthalmol 1982;100:947-50.
Dave P, Villarreal G Jr., Friedman DS, Kahook MY, Ramulu PY. Ability of bottle cap color to facilitate accurate patient-physician communication regarding medication identity in patients with glaucoma. Ophthalmology 2015;122:2373-9.
Schwartz GF, Hollander DA, Williams JM. Evaluation of eye drop administration technique in patients with glaucoma or ocular hypertension. Curr Med Res Opin 2013;29:1515-22.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]