Common Drug Side Effects and Drug-Drug Interactions in Elderly Adults in Primary Care

Susan E. Merel, MD; Douglas S. Paauw, MD


J Am Geriatr Soc. 2017;65(7):1578-1585. 

In This Article

Important Drug–Drug Interactions in Older Adults in Primary Care

Older adults are at high risk of drug–drug interactions because of the prevalence of polypharmacy and age-related changes in metabolism and clearance of drugs. The prevalence of drug–drug interactions in elderly adults may be increasing over time; one study found that approximately 15% of community-dwelling older adults were at risk of a drug–drug interaction in 2010–11, compared with approximately 8% in 2005–06.[3] It is particularly important to evaluate for potential drug–drug interactions before discharging an elderly adult from the hospital and at a posthospitalization follow-up visit, because new agents are often added during hospitalization. A study of more than 2,000 elderly Italian adults at hospital discharge found that almost 70% were exposed to at least one drug–drug interaction and approximately 24% were exposed to a potentially severe interaction.[45] Here, important interactions with four agents or classes (statins, factor Xa inhibitors such as apixaban and rivaroxaban, warfarin, and calcium channel blockers) are briefly reviewed (Table 2).


Statins are often prescribed to individuals with a history of cardiac disease, diabetes mellitus, or other chronic illnesses who take multiple medications. Statin interactions are primarily pharmacokinetic, involving altered drug metabolism through cytochrome 450 or drug transporters, and increase the risk of known side effects of statins. Lipophilic statins such as simvastatin and lovastatin have a higher risk of interactions; pravastatin has the fewest drug interactions. The interaction between statins and gemfibrozil is much stronger than the interaction between statins and fenofibrate; both increase the risk of statin toxicity, as does niacin. Calcium channel blockers and amiodarone also increase the risk of statin toxicity. The American Heart Association (AHA) released consensus recommendations in 2016 regarding the management of clinically significant interactions between statins and other agents commonly used in individuals with cardiovascular disease.[46] Combinations that the AHA deemed "potentially harmful" or "should be avoided" include gemfibrozil with lovastatin and pravastatin, simvastatin and cyclosporine, or tacrolimus with lovastatin or simvastatin.[46] Noncardiac medications that interact with statins and increase the risk of statin toxicity include clarithromycin, azole antifungals, protease inhibitors, and colchicine. Nonconcurrent dosing can reduce the risk of side effects if a statin must be used with one of these agents.


Warfarin interacts with many medications and supplements, and older adults taking multiple medications are at high risk. Medications that increase the metabolism of warfarin and thus increase risk of thrombosis include antiepileptics such as phenytoin, carbamazepine and phenobarbital as well as rifampin and cholestyramine. Fluoroquinolones, TMP/SMX, and macrolides all decrease the metabolism of warfarin and increase the international normalized ratio (INR), with TMP/SMX having the strongest effect.[47] Other agents that older adults in primary care commonly take that interact with warfarin and can increase the INR include simvastatin, acetaminophen, prednisone, and omeprazole. Many clinicians are not aware of the interactions between warfarin and prednisone or acetaminophen. A small study of individuals on stable warfarin therapy who initiated short-term corticosteroid therapy with prednisone or methylprednisolone found a mean difference between pre- and postcorticosteroid INR values of 1.24 (95% CI = 0.86–1.62), with 62.5% of individuals having a supratherapeutic value and 50% requiring a modification of their anticoagulation regimen during or after corticosteroid therapy.[48] A metaanalysis of seven randomized controlled trials including 225 participants found a mean 0.62 greater INR (95% CI = 0.46–0.78) than with placebo in participants taking acetaminophen at a daily dose of approximately 1 to 4 g/d.[49] A number of herbal supplements that elderly adults may take potentiate the effects of warfarin or increase the risk of bleeding; these include omega-3 fatty acids; garlic, which inhibits platelet aggregation; gingko, which is a platelet-activating factor receptor antagonist; and saw palmetto, which inhibits cyclooxygenase and CYP2C9.[50]

Factor Xa Inhibitors

The oral factor Xa inhibitors rivaroxaban, apixaban, and edoxaban are now widely used in older adults, and evidence is emerging regarding drug interactions with these agents. As with warfarin, phenytoin, carbamazepine, phenobarbital, rifampin, and St. John's wort decrease the efficacy of factor Xa inhibitors and increase the risk of thrombosis. Agents that interact with factor Xa inhibitors to increase drug levels and increase the risk of bleeding include ketoconazole, itraconazole, clarithromycin, and ritonavir. Coadministration of rivaroxaban and ketoconazole 400 mg/d increased the area under the curve by 2.6 fold. Experts do not recommend the use of factor Xa inhibitors in individuals taking ketoconazole.[51]

Calcium Channel Blockers

Calcium channel blockers inhibit CYP3A4, which also metabolizes clopidogrel to an active metabolite. A number of studies have found a smaller antiplatelet effect of clopidogrel in individuals taking calcium channel blockers, but the clinical significance of this effect is unclear, with conflicting data on whether use of calcium channel blockers increases the risk of major adverse cardiac events in individuals with coronary stents taking clopidogrel.[52] Interactions between calcium channel blockers and statins are discussed above. Clarithromycin and erythromycin are potent inhibitors of CYP3A4, and co-prescription of these macrolides with calcium channel blockers is associated with risk of acute renal failure. The mechanism is thought to be hypotension related to high plasma calcium channel blocker concentrations. Clarithromycin and erythromycin should not be prescribed to individuals taking calcium channel blockers; azithromycin is a safe alternative.[53]