Thorough case history crucial when prescribing orals

Certain commonly used medications can cause serious adverse drug reactions when used together.

Issue: July/August 2013

Drug-drug interaction arises when the effects of one drug are altered by another drug, leading to adverse drug reactions.

A review of studies estimating the overall incidence of serious adverse drug reactions (ADRs) in a hospitalized patient population shows that more than 2 million serious ADRs and more than 100,000 deaths annually may be caused by drug-drug interactions. If the analysis is accurate, ADRs could be among the top 10 leading causes of death (www.cdc.gov/nchs/fastats/deaths.htm), ahead of Alzheimer’s disease, diabetes and kidney disease. Furthermore, the estimate for ADRs in nursing homes is even higher, with approximately 350,000 occurring annually.

This 62-year-old man presented with subconjunctival hemorrhage, which could be caused by the concomitant use of warfarin and acetaminophen.

Image: Hua LV

A few things that may account for the high incidence of ADRs include more drugs and combinations of drugs available to treat disease, the billions of prescriptions filled each year and more patients taking four or more medications. Fortunately, topical ophthalmic drugs seldom pose significant drug-drug related ADRs. However, optometrists prescribe oral medications for ocular complications, and some of these agents have the potential to interact adversely with other medications.

Warfarin and acetaminophen

Subconjunctival hemorrhage is a relatively common ocular sign that brings patients in for eye care. Various etiologies may underlie this ocular manifestation, but the anticoagulant Coumadin (warfarin, Bristol-Meyers Squibb) is high on the list of suspects. Warfarin is known to interact with numerous drugs. It is well known that nonsteroidal anti-inflammatory drugs (NSAIDs), particularly acetylsalicylic acid (ASA, aspirin), compound the effects of anticoagulants.

Clinicians know to ask about the use of baby aspirin for prevention of stroke or heart attack when the patient presents with subconjunctival hemorrhage, but less is known about the interaction of acetaminophen and anticoagulants. The alternative drug to ASA, acetaminophen, has also been reported to increase the risk of bleeding.

In a double-blind, randomized, placebo-controlled study (N = 36), the international normalized ratio (INR) in patients who were stable on warfarin therapy was found to increase significantly with moderate to high doses (2 g/d to 4 g/d) of acetaminophen for 1 to 2 weeks. Furthermore, Gebauer et al. reported that a 74-year-old patient receiving warfarin for atrial fibrillation experienced an increase in INR from 2.3 to 6.4 after acetaminophen therapy (4 g/d for 3 days).

Therefore, it is important ask about the concurrent use of acetaminophen for patients who are taking warfarin and to educate patients about potential drug-drug interaction between acetaminophen and warfarin.

Ciprofloxacin and simvastatin

Optometrists sometimes prescribe oral ciprofloxacin to treat soft tissue infection such as preseptal cellulitis and hordeolum in patients with known allergy to penicillins or cephalosporins. Many patients may be taking Zocor (simvastatin, Merck Sharp & Dohme) concurrently for hyperlipidemia. The risk of myopathy or rhabdomyolysis is augmented when the two drugs are taken simultaneously. Moreover, oral erythromycin also has been found to increase the risk of myopathy and rhabdomyolysis in patients who take simvastatin.

A tetracycline such as doxycycline is a safer option to treat soft tissue infection in these patients. One relevant note is that tetracyclines are contraindicated in children and pregnant women

Oral fluoroquinolones and antidiabetes drugs

Also use caution with oral fluoroquinolones in patients with diabetes. Diabetes is an epidemic in the U.S., hence optometrists see many patients with diabetes who are on blood glucose lowering agents. Concurrent use of fluoroquinolones and antidiabetes agents has been confirmed to cause severe hypoglycemia or hyperglycemia.

Lin et al. reported a case of persistent hypoglycemia (20 mg/dL) after a single dose of ciprofloxacin in a 68-year-old man whose blood glucose was stable with Micronase (glyburide, Pharmacia & Upjohn).

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On the contrary, an 82-year-old woman presented with symptomatic hyperglycemia (>500 mg/dL) within 48 hours of adding gatifloxacin (200 mg/d) to her usual antidiabetes agents, glipizide (10 mg/d) and metformin (1,000 mg/d).

Len V. Hua

Thus, when oral fluoroquinolones are taken concurrently with antidiabetes medications, close monitoring of blood glucose is warranted.

Tetracyclines and oral retinoids

As mentioned previously, tetracyclines are good alternatives for patients who are taking the statin class of drugs, but they are not recommended for children younger than 8 or pregnant women because they can stain teeth and adversely affect bone development in children. With respect to drug-drug interaction, tetracyclines increase the incidence of pseudotumor cerebri (benign intracranial hypertension) in patients who concurrently take oral retinoids, such as Acutane (isotretinoin, Roche), for treatment of acne.

Lee diagnosed pseudotumor cerebri in a 14-year-old boy after he took isotretinoin (40 mg/d) and tetracycline (500 mg/d) for 3 weeks. The boy was treated initially with oral acetazolamide (1,000 mg/d) and prednisone (60 mg/d), but still underwent bilateral optic nerve sheath decompression to regain visual acuity of 20/20. Nevertheless, visual field defects persisted in both eyes.

Online resources

This is by no means a comprehensive list; there will always be new drug-drug interactions discovered and reported over time. To minimize ADRs caused by drug-drug interaction, prescribers should actively consult online resources for potential interactions before releasing a prescription. One freely available online resource is www.drugs.com. Use its “drug interactions checker” feature.

The U.S. Food and Drug Administration established MedWatch in 1993 as an online resource for receiving reports of potentially serious ADRs. A report can be submitted simply by calling a toll-free number, filling out an online form or filling out a postage-paid form accessible from the website (www.fda.gov/medwatch). Moreover, MedWatch also provides up-to-date safety alerts and FDA public health advisories. It is a valuable resource to aid clinicians in judicious prescribing.

Drug-drug interaction is always a possibility when a medication is prescribed to treat an ocular problem. Thorough case history on what the patient is taking, including herbals and over-the-counter medications, and proactive consultation of online resources will assure safer prescribing to reduce serious ADRs. Additionally, by working with other health care providers and spending a bit more time to educate our patients, optometrists can play an essential role in minimizing the overall incidence of ADRs.

References:

Biggs WS. J Am Board Fam Pract. 2003;16(5):455-457.
Gebauer M, et al. Pharmacotherapy. 2003; 23(1):109-112.
Gurwitz JH, et al. Am J Med. 2000;109(2):87–94.
Kantola T, et al. Clin Pharmacol Ther. 1998;64:177-182.
Lazarou J, et al. JAMA. 1998;279:1200–1205.
Lee AG. Cutis. 1995;55:165-168.
Lin G, et al. J Toxicol Clin Toxicol. 2004;42(3):295-297.
Parra D. Pharmacotherapy. 2007;27(5):675-683.
Sawant R. Can J Clin Pharmacol. 2009; 16(1):e78-e79.

For more information:

Len V. Hua, PhD, OD, FAAO, is an associate professor at Pacific University College of Optometry. He did a residency in primary eye care at Pennsylvania College of Optometry, holds a PhD in pharmacology from the University of Toronto and conducted postdoctoral research at the National Institute of Environmental Health Sciences and the National Cancer Institute. He can be reached at 2043 College Way, Forest Grove, OR 97116; (503) 352-3059; fax: (503) 352-2929; lenvhua@pacificu.edu.

Disclosures: Hua has no relevant financial interests.