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HIV-infected man living in Zimbabwe purchased zidovudinetablets that, upon analysis, were found to contain no zidovudine [7]. In addition, 60% of tested antimalarial preparations beingsold in Cambodia were found to contain either no active in- Scott R. Penzak,1 Edward P. Acosta,2 Michele Turner,2 Jorge A. Tavel,3
gredient or inferior substitutes [8]. To this end, we assessed and Henry Masur4
drug content in comparison with label claims for 5 HIV pro- Departments of 1Pharmacy and 2Critical Care Medicine, Warren G. MagnusonClinical Center, and 3National Institute of Allergy and Infectious Diseases, tease inhibitors and the nonnucleoside reverse-transcriptase in- National Institutes of Health, Bethesda, Maryland; and 4Division of Clinical hibitor efavirenz from various international sources.
Pharmacology, University of Alabama at Birmingham Methods.
Drug products were delivered to the National Institutes of Health (NIH; Bethesda, MD), and information on Generic and brand name antiretroviral drugs are becoming
individual drug formulations was recorded (table 1). Drugs increasingly available in developing countries. We analyzed
were transported to the NIH by physicians participating in an 6 antiretroviral medications from 4 international sources for
educational program. All products were received at room tem- drug content. The active ingredient in tested drug products
perature and had been stored that way for at least several weeks.
was within 15% of the labeled amount (range, Ϫ12% to
Upon receipt, saquinavir, ritonavir, and lopinavir-ritonavir were +15%) for drugs that were properly stored.
refrigerated, according to manufacturer specifications.
The Uniformity of Dosage Units test was used to assess the Combination antiretroviral therapy has dramatically reduced dose uniformity of the different antiretroviral formulations [9].
morbidity and mortality secondary to HIV infection [1]. In the This test specifies that drug content in individual dosage units developing world, at least 6 million of the 42 million HIV- must be within 85%–115% of the label claim, unless otherwise infected patients are in urgent need of antiretroviral medica- specified in the drug’s US Pharmacopeia/National Formulary tions, yet because of the high costs, !300,000 are receiving (USP/NF) monograph. Saquinavir, the only drug product with treatment. However, generic antiretroviral medications, along a USP/NF monograph in this study, must contain 95%–105% with discounted brand name products, are quickly increasing of the label claim, according to its monograph [10]. The Uni- the availability of these drugs [2, 3].
formity of Dosage Units test also specifies that the coefficient Although generic medications offer affordable treatment for of variation among dosage units must be р6.0%. Because of many HIV-infected patients, little information is available re- the limited number of capsules/tablets available for analysis, 2– garding the integrity of these medications [4–6]. In a retro- 4 dosage units (compared with the USP-recommended 10 dos- spective study, generic nevirapine-containing antiretroviral age units) per lot number were assayed; the degree to which therapy appeared to be safe and effective in 333 HIV-infected this limits the global applicability of our data, if at all, is unclear.
patients in India [5]. We recently reported that several generic Intact capsules of efavirenz, indinavir, saquinavir, ritonavir, nevirapine formulations from 4 developing countries contained lopinavir-ritonavir, and amprenavir were weighed individually, the labeled amount of drug (ע3% of 200 mg) [6]. Large-scale and the total mass was recorded. After removal of the contents studies are necessary to assess all antiretroviral medications of each capsule, the mass of the empty capsule casing was from international sources for drug content.
recorded and subtracted from the total mass to determine the Because of the huge demand for and high cost of antiret- mass of the contents in each capsule and the percentage of roviral medications in developing countries, brand name drugs active ingredient. Contents from standard capsules (efavirenz are a likely target for counterfeiters. In an isolated report, an and indinavir products) were ground with a mortar and pestle,resulting in homogenous powders. Empty gel caps from sa- Received 13 November 2003; accepted 4 January 2004; electronically published 14 April quinavir, ritonavir, lopinavir-ritonavir, and amprenavir for- mulations were rinsed with methanol and allowed to dry before Financial support: Office of AIDS Research, National Institutes of Health, supported in part by the National Institute of Allergy and Infectious Diseases (grant UO1 AI32775 ).
weighing. Master stock solutions were then prepared by dis- Reprints or correspondence: Dr. Scott R. Penzak, Clinical Center Pharmacy Dept., Bldg. 10, solving known weights of capsule powder in precise volumes 1N 257, National Institutes of Health, Bethesda, MD 20892 (
of aqueous solvent. The exact concentration of active ingredient Clinical Infectious Diseases
2004; 38:000–000
in each of the stock solutions was calculated using the deter- 2004 by the Infectious Diseases Society of America. All rights reserved.
mined percentage of active ingredient in each capsule. The HIV/AIDS • CID 2004:38 (1 May) • 000
Antiretroviral preparations analyzed for drug content.
a Compared with the labeled amount.
b Same product.
number of capsules sampled and the number of assays per The drug content for individual dosage units was calculated as the arithmetic mean of multiple (6–9) assays. Average accuracy For quantitative analysis, standards of saquinavir, ritonavir, was determined by dividing the mean drug content by the lopinavir, amprenavir, indinavir, and efavirenz were used to labeled amount (percent error). The coefficient of variation prepare calibration and quality-control solutions. The saqui- (relative SD) was used to assess variability among the individual navir standard was provided by Roche Laboratories (Nutley, NJ), ritonavir and lopinavir standards were provided by Abbott Results.
A detailed ingredient analysis, along with specific Laboratories (North Chicago, IL), the indinavir standard was product information for each of the tested medications, is provided by Merck and Co. (Whitehouse Station, NJ), the efa- shown in Table 1. With the exception of ritonavir-containing virenz standard was provided by Bristol-Myers Squibb (Prince- products, the active ingredient in each of the products was ton, NJ), and the amprenavir standard was provided by Glaxo- within 15% of the labeled amount (range, Ϫ12% to +15%); SmithKline (Research Triangle Park, NC). Serial dilutions of the absolute value of the mean difference between measured each capsule master stock solution provided test solutions and labeled drug content was 7.7%. The median difference was within the standard curve range of the assay, which was 25– Ϫ2.0%. For efavirenz, indinavir, lopinavir, saquinavir, and am- 9000 ng/mL for all drugs except for lopinavir, for which it prenavir, expiration dates were available for 5 of the 9 lot num- was 50–9000 ng/mL. High-performance liquid chromatog- bers sampled (table 1); among these products, only amprenavir raphy/ultraviolet analysis of each test solution was performed (Ϫ7.7%, compared with the labeled amount) was analyzed after using a validated assay [11]. The intraday and interday per- its expiration date. The coefficient of variation among capsules centage error between nominal and observed concentrations in individual lots was !9.0% for amprenavir, saquinavir, lo- was !10%, and the coefficient of variation was also !10%.
Calculation of the concentrations of each test solution, fol- Ritonavir content was Ϫ19% to Ϫ16% of the labeled amount lowed by consideration of all dilutions made from capsule to in 1 lopinavir-ritonavir product and 2 ritonavir products (table assay, resulted in accurate quantification of active ingredient 1). One of the ritonavir products was analyzed ∼1 year after it had expired; expiration dates were unavailable for the other Descriptive statistics were used for data reporting. The mean ritonavir product and the lopinavir-ritonavir product. As noted drug content (table 1) was calculated as the arithmetic mean earlier, none of the ritonavir-containing products were stored of the drug amounts from each dosage unit within a given lot.
under continual refrigeration, in accordance with manufacturer 000 • CID 2004:38 (1 May) • HIV/AIDS
specifications. The coefficient of variation among capsules in been mislabeled, diluted, or substituted with less expensive in- individual lots was !10.2% for ritonavir.
In this pilot investigation, the active ingredi- Although the growth in antiretroviral availability is encour- ent(s) in several branded and generic antiretroviral medications aging, it must be accompanied by independent quality-control was quantitated. In accordance with USP standards, none of studies such as this preliminary investigation, not conducted the products, when stored according to manufacturer specifi- by the sponsoring pharmaceutical company. These investiga- cations, varied by !12% or 115% from the labeled drug amount tions, along with bioequivalence testing, are crucial to the op- [9]. Coefficients of variation ranged between 4.3% and 10.1% timal care of HIV-infected patients in developing countries.
for all of the tested samples and exceeded the USP-specifiedlimit of 6.0% in 6 of the samples. The relatively few numberof dosage units available for analysis likely contributed to this Acknowledgments
degree of variability, as did the inherent variability in the assay Drugs analyzed in this study were delivered to NIH by phy- (coefficient of variation, !10% for all drugs). Accordingly, our sicians whose travel was supported by the International Society ability to accurately assess variability with regard to USP spec- of Infectious Diseases. The cooperation of these physicians Saquinavir soft-gel capsules from 2 international sources contained 97%–99% of the labeled drug amount, which sat-isfied individual USP criteria for saquinavir capsules (95%– References
105% of the label claim), despite not having been refrigeratedin accordance with manufacturer instructions. Similarly, none 1. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodefi- of the ritonavir-containing products were stored under contin- ciency virus infection. HIV Outpatient Study Investigators. N Engl J ual refrigeration; moreover, one of the products had expired.
Med 1998; 338:853–60.
Thus, it is not surprising that ritonavir content did not meet 2. UNAIDS Fact Sheet. Access to HIV Treatment and Care. September 2003. Available at:
USP content specifications (table 1). These data reinforce the Sheets03/FS_Care_2003_en_doc.htm. Accessed 29 September 2003.
importance of storing ritonavir-containing preparations ac- 3. World Health Organization. World Health Organization says failure to cording to manufacturer specifications. This may be particu- deliver AIDS medicines is a global health emergency: global AIDStreatment emergency requires urgent response; no more business as larly true in warmer climates where the ambient temperature usual. 22 September 2003.
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In our analysis of branded and generic antiretroviral medi- 4. Gogtay JA , Manek V, Nayak VG, et al. A pharmacokinetic evaluation cations, the drug content of generic indinavir (Indivex-400; of lamivudine, stavudine, and nevirapine given as a fixed dose com-bination pill versus the same three drugs given separately in healthy Aurobindo Pharma) was comparable to that of branded prod- human volunteers [abstract PL8.4]. In: Abstracts of the Sixth Inter- ucts (Crixivan; Merck) and is consistent with USP content national Congress on Drug Therapy in HIV (Glasgow). Congress on specifications (table 1). These data are similar to those we re- HIV Infection, the Gardner Coldwell Group, part of the Thomson
Corporation. Chesire, UK, 2002:11.
cently reported for generic nevirapine formulations obtained 5. Kumarasamy N, Soloman S, Chaguturu SK, et al. The safety, tolerability from developing countries [6]. These results are a source of and effectiveness of generic antiretroviral drug regimens for HIV-in- encouragement for HIV-infected patients in developing nations fected patients in south India. AIDS 2003; 17:2267–9.
6. Penzak SR, Acosta EP, Turner M, Tavel JA, Masur H. Analysis of generic who are relying on generic medications for treatment of their nevirapine products in developing countries. JAMA 2003; 289:2648–9.
disease. However, these data describing drug content are not 7. Apoola A, Sriskandabalan PS, Wade AAH. Self medication with zi- meant to imply bioequivalence between generic and branded dovudine that was not. Lancet 2001; 357:1370.
products. In the future, bioequivalence testing will provide fur- 8. Newton PN, White NJ, Rozendaal JA, Green MD. Murder by fake drugs. BMJ 2002; 324:800–1.
ther data on the integrity of specific generic antiretroviral 9. United States Pharnmacopeia/National Formulary. Uniformity of dos- age units. Rockville, MD: United States Pharmacopeial Convention, In addition to generic antiretroviral medications, studies to 2003:2227–9.
10. United States Pharnmacopeia/National Formulary. Uniformity of dos- determine drug content among branded products from devel- age units. Rockville, MD: United States Pharmacopeial Convention, oping nations are also necessary to prevent the dissemination 2003:1665.
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HIV/AIDS • CID 2004:38 (1 May) • 000



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