You are here

P T. 2018;43(8): 485-488, 504

Variation in Generic Drug Manufacturers’ Product Characteristics

Karl Matuszewski MS, PharmD
Joan Kapusnik-Uner PharmD
Michael Man PharmD
Robert Pardini BS
Julie Suko PharmD

INTRODUCTION

Generic drugs account for 89% of filled U.S. prescriptions, but only 26% of total drug costs.1 Savvy American consumers can achieve substantial savings on their prescriptions by insisting on generic drugs when available and by comparison shopping at several pharmacies or by using legitimate online sites/mobile apps to get the lowest price, coupons, rebates, or discounts. Ideally, these savings would translate to improved patient compliance with their medication regimens for chronic conditions because high out-of-pocket costs are frequently mentioned as a factor in noncompliance.

A study by the IMS Institute for Healthcare Informatics (now called the IQVIA Institute for Human Data Science) estimated that the 2012 avoidable cost opportunity of medication nonadherence was more than $100 billion. IMS made this estimate by studying six disease states: congestive heart failure, human immunodeficiency virus infection, osteoporosis, hypertension, diabetes, and hypercholesterolemia.2

Three studies in the last several years suggest that appearance may be an important factor in medication nonadherence.35 Given the high and increasing use of generic medications and the potential influence of pills’ physical appearance on adherence, this study was undertaken to characterize the range of appearances and costs of 16 oral solid generic medications in four major chronic disease/drug management conditions: hypertension, diabetes, heart failure, and hypercholesterolemia.

METHODS

These conditions were chosen because they are included in current Centers for Medicare and Medicaid Services medication therapy management quality measures. Six of the 16 evaluated drugs were also listed in the 2015 top 10 most dispensed generics.6

A commercial drug knowledge database (First Databank’s MedKnowledge) was used to identify these frequently prescribed oral solid medications to verify that each had at least three generic manufacturer sources in the calendar year 2016. For this paper, a manufacturer is defined as a distinct Food and Drug Administration (FDA) labeler that may or may not be the true manufacturer. Authorized generic distributors were included but repackagers were not. Generic products were defined as those approved by the FDA under an abbreviated new drug application (ANDA).

Frequently prescribed drugs were determined by choosing those ingredients/dose strengths that appeared in the 2014 IMS top 1,500 list. From this list, four drugs from each of the following chronic therapeutic classes were chosen: 1) antidiabetics (glyburide 5 mg, metformin 500 mg, acarbose 50 mg, and glipizide 10 mg); 2) 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors or statins (simvastatin 40 mg, pravastatin 40 mg, atorvastatin 40 mg, and lovastatin 20 mg); 3) beta blockers (metoprolol 100 mg, atenolol 50 mg, carvedilol 25 mg, and labetalol 100 mg); and 4) heart failure drugs (amlodipine 10 mg, losartan 50 mg, lisinopril 10 mg, and valsartan 40 mg).

The physical appearance (color, shape, scoring, and size) for each ingredient formulation was evaluated and compared. Generic product characteristics were then compared with their equivalent new drug application (NDA) product, or if information was not available, with their current FDA reference listed drug (RLD). The cost for each product was determined based on the manufacturers’ self-reported wholesale acquisition cost (WAC) effective December 31, 2016.

RESULTS

Knowledge-base queries obtained the following number of unique manufacturers per class: antidiabetics, 40; statins, 35; beta blockers, 38; and heart failure agents, 71. For all 16 drugs across all four disease states, there was an average of three colors, two shapes, 11 manufacturers, and four appearances when color and shape together were considered (Table 1). For seven of the drug formulations, at least 75% of manufacturers did not follow NDA reference drug appearance, four drugs had 50% to 74% dissimilarity, and five drugs had less than 50% dissimilarity. Individual drug formulations varied from no differences (0%) to 100% differences, with color and shape contributing to variation (Table 2). Figure 1 shows, as an example, the appearance differences of six formulations of pravastatin 40 mg.

Differences in tablet scoring were inconsequential, with only lisinopril having one scored version and 17 unscored. Differences in pill sizes with each formulation were considerable, with ranges from 0% to 88%. Average tablet size across all formulations ranged from 7 mm to 12 mm. Cost variance for each drug (Table 3) ranged from a low of 2% for labetalol 100 mg ($0.40–0.41) to more than 62,253% for lisinopril 10 mg ($0.02–12.72). Individual formulation price variation is summarized in Table 3. Looking at price comparisons within a formulation, it was not surprising that the NDA/RLD product always had the highest cost—with one exception, lovastatin 20 mg.

DISCUSSION

Given the large spread of WAC pricing reported for almost all drugs studied, it is expected that pharmacy purchasers will be incentivized to negotiate substantial discounts from large pools of generic manufacturers. This exploratory analysis of 16 commonly prescribed drugs in four chronic diseases shows there are multiple manufacturers with substantial variation in pill appearance. Only four of the 16 drugs evaluated completely followed the lead of the innovator (NDA or RLD) for pill color by all manufacturers, and only five formulations completely followed the innovator’s pill shape. Only one drug (atenolol) was identical from all seven manufacturers.

This appearance variation among common generically equivalent products presents a strong possibility that patients at some point during chronic therapy will experience a drug product substitution for prescription refills, and over time, they may fail to recognize their medication and its purpose. This may increase the likelihood of medication nonadherence and ultimately lead to adverse disease outcomes. Recognizing this potential for substantial drug appearance variation in targeted patients during the drug-dispensing process and making either educational (e.g., counseling) or dispensing interventions (e.g., including “purpose for use” on the medication label container) should reinforce the need for active adherence counseling. The issue has received attention from the FDA, which proposed to conduct a survey of pharmacists and patients in 2015 to understand their perceptions and experiences with drug appearance changes.7 To the authors’ knowledge, this survey has not yet been completed.

CONCLUSION

The FDA’s Office of Generic Drugs had a record year in 2017, approving 1,027 new generic drugs.8 Such generics, our study reveals, provide multiple sources of medications for four common chronic conditions. With substantial variation in appearance among several generically equivalent products, there is a strong possibility that a patient may experience a future drug product switch that could increase the likelihood of significant nonadherence, and ultimately result in adverse disease outcomes through discontinuation of prescribed therapy. Our data supports the need for further study of drug appearance changes and interventions as a potential factor affecting chronic disease adherence outcomes and medication therapy management.

Figure and Tables

Same Drug, Same Dose, Six Different Looks For 40-mg Dose of Pravastatin

Drug Category Pill Appearances

Diabetes Drugs Statins Beta Blockers Heart Failure Drugs
First Databank database accessed (7/22/15) Glyburide 5 mg Glipizide 10 mg Metformin 500 mg Acarbose 50 mg Group Avg Lovastatin 20 mg Simvastatin 40 mg Pravastatin 40 mg Atorvastatin 40 mg Group Avg Atenolol 50 mg Labetalol 10 mg Carvedilol 25 mg Metoprolol 100 mg Group Avg Amlodipine 10 mg Losartan 50 mg Lisinopril 10 mg Valsartan 40 mg Group Avg Row Total Overall Avg
COLOR
Beige 1 1
Blue 2 3 1 6
Brick red 6 6
Brown 1 1
Green 2 2 5 9
Light blue 1 3 6 1 11
Light brown 1 1
Light green 2 1 2 1 6
Light orange 1 1
Light pink 1 1 2
Light yellow 1 3 4
Off-white 2 2
Pink 1 4 1 1 7 14
Red 1 2 3
White 1 7 17 7 1 3 7 7 3 13 2 18 13 4 1 104
Yellow 1 1 1 14 17
Different colors, n 5 1 1 2 2.3 5 5 5 2 4.3 1 4 1 4 2.5 2 4 6 2 3.5 3.0
SHAPE
Diamond 1 1
Elliptical 2 1 3
Oblong 4 1 2 1 2 2 1 4 17
Oval 1 6 1 3 7 10 2 10 40
Rectangular (round end) 2 2
Round 4 6 15 9 7 6 4 2 7 6 5 10 19 8 14 1 123
Shield 1 1
Triangular 1 1
Different shapes, n 2 2 3 1 2 1 3 4 4 3.0 1 1 3 2 1.8 1 3 4 3 2.8 2.3
SCORED TABLET
Yes 8 7 7 6 12 20 1 61
No 17 9 7 13 9 8 13 19 17 15 127
Manufacturers, N 7 7 17 9 10 7 11 9 8 8.8 7 6 13 12 9.5 19 20 17 15 17.75 188 10.8
Overall number of different pill appearances (color + shape) 6 2 3 2 3.3 5 8 7 5 6.3 1 4 3 6 3.5 2 7 9 4 5.5 4.4
KEY:
Manufacturer with two products
New drug application reference label drug

Appearance Variation

COLOR + SHAPE Glyburide Glipizide Metformin Acarbose Lovastatin Simvastatin Pravastatin Atorvastatin Atenolol Labetalol Carvedilol Metoprolol Amlodipine Losartan Lisinopril Valsartan Total
Beige + round 1 1
Blue + oblong 2 2
Blue + round 3 1 4
Brick red + oval 4 4
Brick red + round 1 1
Brick red + shield 1 1
Brown + round 1 1
Green + oblong 1 1
Green + oval 4 4
Green + rectangular 2 2
Green + round 1 1 2
Light blue + oblong 1 1 2
Light blue + round 3 5 1 9
Light brown + round 1 1
Light green + round 2 1 2 1 6
Light orange + round 1 1
Light pink + oblong 1 1
Light pink + oval 1 1
Light yellow + oval 1 1
Light yellow + round 1 2 3
Off-white + round 2 2
Pink + oval 1 1 2
Pink + round 1 3 1 1 6 12
Red + round 1 2 3
White + diamond 1 1
White + elliptical 2 1 3
White + oblong 1 1 1 1 2 6
White + oval 1 1 3 7 6 1 19
White + round 1 6 15 7 1 1 1 7 3 5 1 18 5 3 74
White + triangular 1 1
Yellow + oblong 1 4 5
Yellow + oval 9 9
Yellow + round 1 1 1 3
TOTAL PRODUCTS 8 7 17 9 7 13 9 8 7 6 13 12 19 20 18 15 188
Unique color + shape, n 6 2 3 2 5 8 7 5 1 4 3 6 2 7 9 4
Unique color/shape: percentage of total products 75% 29% 18% 22% 71% 62% 78% 63% 14% 67% 23% 50% 11% 35% 50% 27%
Percent different than NDA/RLD 100% 100% 14% 25% 67% 75% 88% 86% 0% 100% 50% 100% 6% 74% 71% 43%
KEY: Color plus shape of NDA on RLD product
NDA = new drug application; RLD = reference listed drug

Price Variation

Number of Manufacturers Pill/Tablet Cost, U.S. Dollars* Difference, Min/Max
Mean Median Max Min
Antidiabetics
Glyburide 5 mg 7 0.45 0.29 1.66 0.20 728%
Metformin 500 mg 17 0.11 0.06 0.99 0.02 3,881%
Acarbose 50 mg 9 0.55 0.51 1.01 0.41 144%
Glipizide 10 mg 7 0.39 0.06 2.35 0.06 3,755%
Statins
Simvastatin 40 mg 11 0.73 0.12 7.61 0.04 19,413%
Pravastatin 40 mg 9 1.24 0.72 5.66 0.28 1,937%
Atorvastatin 40 mg 8 1.72 0.43 10.86 0.30 3,503%
Lovastatin 20 mg 7 0.23 0.21 0.45 0.15 192%
Beta blockers
Metoprolol 100 mg 12 0.29 0.05 2.87 0.03 8,731%
Atenolol 50 mg 7 1.86 0.03 12.72 0.03 38,098%
Carvedilol 25 mg 13 0.41 0.10 4.19 0.03 15,483%
Labetalol 100 mg 6 0.41 0.41 0.41 0.40 2%
Heart failure drugs
Amlodipine 10 mg 19 0.43 0.10 6.36 0.03 22,979%
Losartan 50 mg 20 0.32 0.19 3.50 0.06 5,566%
Lisinopril 10 mg 17 0.83 0.05 12.72 0.02 62,253%
Valsartan 40 mg 15 0.73 0.38 5.21 0.08 6,498%

*Wholesale acquisition cost

Author bio: 
At the time of writing, Drs. Matuszewski, Kapusnik-Uner, Man, and Suko were employees of First Databank in South San Francisco, California, where Mr. Pardini was a student intern.

References

  1. Association for Accessible Medicines. Generic drug access and savings in the US 2017; Available at: https://accessiblemeds.org/sites/default/files/2017-07/2017-AAM-Access-Savings-Report-2017-web2.pdf. Accessed July 5, 2018
  2. IMS Institute for Healthcare Informatics. Avoidable costs in US healthcare: the $200 billion opportunity from using medicines more responsibly June 2013; Available at: http://offers.premierinc.com/rs/381-NBB-525/images/Avoidable_Costs_in%20_US_Healthcare-IHII_AvoidableCosts_2013%5B1%5D.pdf. Accessed July 5, 2018
  3. Kesselheim AS, Misono AS, Shrank WH, et al. Variations in pill appearance of antiepileptic drugs and the risk of nonadherence. JAMA Intern Med 2013;173;(3):202–208.
  4. Kesselheim AS, Bykov K, Avorn J, et al. Burden of changes in pill appearance for patients receiving generic cardiovascular medications after myocardial infarction: cohort and nested case-control studies. Ann Intern Med 2014;161;(2):96–103.
  5. Arancon-Monge JM, de-Castro-Cuenca A, Serrano-Vázquez A, et al. Study CAMBIMED: effects of changes in medication appearance on safety of antihypertensive and hypolipidemic treatments in chronic patients older than 65 years in primary health care. BMC Public Health 2015;15:211
  6. Generic Pharmaceutical Association. Generic drug savings in the US 7th edNovember 2015; Available at: www.gphaonline.org/media/wysiwyg/GPhA2015AnnualReport.pdf. Accessed July 5, 2018
  7. Food and Drug Administration. Agency information collection activities; submission for Office of Management and Budget Review; comment request; survey of pharmacists and patients; variations in the physical characteristics of generic drug pills and patients’ perceptions; survey of pharmacists and patients. Fed Regist 2015;80;(93):27691–27694.
  8. Uhl KC. 2017 was another record-setting year for generic drugs. FDA Voice blog February 7, 2018; Available at: https://blogs.fda.gov/fdavoice/index.php/2018/02/2017-was-another-record-setting-year-for-generic-drugs. Accessed July 5, 2018