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Adverse Drug Reactions and Drug-Drug Interactions: Consequences and Costs

By: AMFS Pharmocology Expert


The most recent (March 2012) alert about drug-drug interactions (DDIs) issued by the FDA warned that the combined use of commonly used drugs in the treatment of elevated cholesterol such as atorvastatin, rosuvastatin, simvastatin, or lovastatin, together with some antiviral drugs known as protease inhibitors such as tipranavir, ritonavir, and telapravir, might cause a sequence of events beginning with muscle injury, leading to rhabdomyolysis, and ultimately to permanent kidney damage. Depending on the pairing of a specific statin with a specific protease inhibitor their combined use is either cautioned against or is altogether contraindicated.

DDIs are a subset of adverse drug reactions (ADRs), accounting for about 3-5% of all ADRs, and ADRs can of course be harmful or even fatal. According to the FDA’s Center for Drug Evaluation and Research approximately two million serious ADRs occur annually in the US and are responsible for around 100,000 deaths per year. , ADRs account for 20% of the injuries occurring in hospitals, and they double the length of stay and the cost of hospitalization.3 Nearly 7% of the generalized hospital population in the US experience ADRS. In the UK ADRs were found to be responsible for 6.5% of hospital admissions, and the median length of stay per ADR-caused hospitalization was eight days. In 2000 nearly ten (10) prescriptions were filled for every person in the U.S.3 With an aging population that number is likely to increase. Thus the risk of ADRs and DDIs will also increase. The risk of hospitalization due to ADRs is four times higher in the elderly. Nearly 40% of the ADRs in elderly are likely to be serious, but many of the serious ADRs are also preventable.7

At the start of the 21st century In the US we spent about $145 billion each year on prescriptions. We now spend over $300 billion/year with prescription costs responsible for about 12% of total health care costs. ADRs cost us between $30 billion and $130 billion annually. One of the reasons for the number of ADRs may stem from the incomprehensibility of prescription literature provided to us when we get prescriptions filled. A report presented at the 28th annual meeting of the American Academy of Pain Medicine, though based on a survey of only fifty-two patients, revealed that over 80% of those patients were not able to correctly answer questions about the serious adverse effects of an antidepressant medication for which they had all been provided with three different types of information, namely a medication guide, a patient package insert, and pharmacy-generated consumer medication information.

DDIs as a subset of ADRs may pose an even more vexing problem. There may be as few as a 2-3 dozen two-drug combinations with a high probability of causing serious ADRs,8 however even these can be overlooked by prescribers or over-ridden in the pharmacy even when identified by pharmacy software. The latter can occur, because often DDI software within pharmacies will flag as serious even those potential DDIs that are likely to have no adverse consequence whatsoever.8 Thus it becomes a difficult judgement call for pharmacists to know which flagged DDIs do, in fact, pose a serious risk for patients.

The FDA, academic scientists, and scientists from the pharmaceutical industry have been developing strategies and guidelines that will identify investigational drugs early in the drug development process that are likely to have a high likelihood for causing DDIs. This may lead to newer drugs with fewer DDI liabilities. Nevertheless, there will never be such a thing as a risk-free drug, and the best way to mitigate ADRs and DDIs now and in the future requires vigilance on the part of prescribers and pharmacists, the development of smarter DDI software, the widespread implementation of electronic health records (EHRs), and better ways of educating patients about the medications they are taking.


2 Peck P. FDA adds more warnings for lipitor, crestor, and zocor. MedPage Today March 01, 2012.

4 Bachmann, K. Drug-drug interactions with an emphasis on drug metabolism and transport. In Pharmacology Principles and Practice pp 303-325, Hacker, Bachmann and Messer, Eds., Elsevier,NY, 2009.
5 Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998; 279: 1200–
6 Pirmohamed M, James S, Meakin S, Green C, Andrew K Scott AK, Walley TJ, Farrar K, Park BK, Breckenridge AM. Adverse drug reactions as cause of admission to hospital:prospective analysis of 18, 820 patients. (2004)BMJ;329:15–19
7 Beijer HJM and de Blaey CJ. Hospitalizations caused by adverse drug reactions (ADR):a meta-analysis of observational studies. Pharm World Sci 2002;24:46-54
8 Malone D, Abarca J, Hansen P, Grizzle AJ, Armstrong E, Van Bergen R, Duncan-Edgar B, Solomon SL, and Lipton R. Identification of serious drug-drug interactions:results of the partnership to prevent drug-drug interactions. J Am Pharm Assoc 2004;44:142-151.
9 Walker, E. Generic drugs’ effects on health costs unclear, GAO says. MedPage Today March 02, 2012
10 White TJ, Arakelian A, and Rho JP. Counting the costs of drug-related adverse events. Pharmacoeconomics. 1999;15:445-448.
11 Johnson K. Prescription drug information often incomprehensible to patients. Feb 28, 2012.

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