Recognizing drug interactions is a daily challenge for family physicians, and remembering all potential interactions has become virtually impossible. Most pharmacies have drug-interaction software programs with their dispensing package. However, these programs tend to “flag” all interactions, making it difficult for the pharmacist to interpret clinical significance. As a result, the pharmacist generally consults with the prescribing physician.

More than 30 medications are introduced each year, and physicians receive frequent mailings about newly discovered drug interactions. As a result, many physicians feel overwhelmed and question the safety of multiple drug regimens. This article reviews potential clinically significant drug interactions involving commonly prescribed medications (Table 1).

Warfarin

ANTIBIOTICS

Because of new clinical recommendations, the use of warfarin (Coumadin) has increased in recent years. Almost all antibiotics can potentiate the effects of warfarin by inhibiting intestinal flora that produce vitamin K. Inhibition of the hepatic metabolism of warfarin is another possible mechanism for increased bleeding.^1,2 Drugs that inhibit warfarin's metabolism include ciprofloxacin (Cipro), clarithromycin (Biaxin), erythromycin, metronidazole (Flagyl) and trimethoprim-sulfamethoxazole (Bactrim, Septra).^1,2

Clinical trials evaluating warfarin-antibiotic combinations have had mixed outcomes.² The effects of warfarin change only minimally when an interacting combination is administered to healthy volunteers. However, case reports have described potentiation of anticoagulation in patients treated with warfarin and antibiotics. The disparity between the findings of clinical trials and case reports has led investigators to conclude that multiple factors may alter the clearance of warfarin in patients with infections.¹

Unless the prothrombin International Normalized Ratio (INR) can be monitored every other day, ciprofloxacin, macrolide antibiotics, metronidazole and trimethoprim-sulfamethoxazole generally should not be prescribed to patients who are taking warfarin. Alternative antimicrobial therapy is recommended for these patients.

ACETAMINOPHEN

Some investigators advise that the hypothrombinemic response to warfarin can increase when acetaminophen is taken in a dosage of more than 2 g per day for longer than one week.^3(pp7–8) Recent information suggests that the warfarin-acetaminophen interaction may be clinically significant at even lower dosages of the pain reliever.⁴

One case-control study identified acetaminophen as a cause of 30 percent of INR values greater than 6.0 in patients taking warfarin.⁴ This response occurred with as few as seven 325-mg tablets of acetaminophen. The proposed mechanism is a reduced capacity of cytochrome P450 enzymes caused by acetaminophen and resulting in decreased metabolism of warfarin.

Because acetaminophen is the most frequently ingested medication in the United States, physicians should counsel warfarin-treated patients about the potential risks of a warfarin-acetaminophen interaction. If acetaminophen therapy is needed, the dosage should be as low as possible, and the drug should be taken for only a short period. In addition, the INR should be monitored closely.⁵

ASPIRIN

Coadministration of acetylsalicylic acid (aspirin) and warfarin increases the risk of bleeding. The mechanisms of this adverse interaction are antiplatelet effects, gastric mucosal damage and a hypothrombinemic response to warfarin (with an aspirin dosage of 2 to 4 g per day).⁶ Several studies have shown that the combination of warfarin and aspirin in a low dosage (75 to 100 mg per day) increases the incidence of minor bleeding, but not major bleeding.^7,8

Although concomitant use of warfarin and aspirin generally should be avoided, certain patients may benefit from this therapy. One study of patients at high risk for thromboembolic events (i.e., patients with mechanical heart valves or the combination of tissue valves and atrial fibrillation) demonstrated that the increased risk of bleeding with combined warfarin and aspirin therapy was outweighed by the benefit in decreased thromboembolic events.⁷ The patients in this study received aspirin in a dosage of 100 mg per day and maintained an INR of 2.5 to 3.5.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

Coadministration of nonsteroidal anti-inflammatory drugs (NSAIDs) and warfarin increases the risk of bleeding. The mechanisms of this interaction are antiplatelet effect and gastric mucosal damage, because most NSAIDs do not produce a hypothrombinemic response. When given to or withdrawn from patients maintained on warfarin, NSAIDs may actually alter anticoagulant control as a result of changes in the amount of circulating warfarin released from plasma albumin binding sites.⁶ Preliminary data suggest that the cyclooxygenase-2 inhibitors celecoxib (Celebrex) and rofecoxib (Vioxx) may be safer options in patients requiring an NSAID and warfarin, because these agents have reduced antiplatelet properties compared with traditional NSAIDs.⁹

Concomitant use of NSAIDs and warfarin should be avoided, especially in patients who are at increased risk for NSAID gastropathy (e.g., age greater than 65 years, history of peptic ulcer disease, systemic steroid therapy, heavy smoking or high NSAID dosage). One retrospective study found that the risk of hemorrhagic peptic ulcers was 13 times greater in patients older than 65 years who were taking NSAIDs and warfarin than in patients of the same age who were taking neither drug.¹⁰

If NSAID therapy is necessary, a cyclooxygenase-2 inhibitor should be used, and the INR should be closely monitored. Patients also should be informed about the risk of bleeding associated with combined warfarin and NSAID therapy.

Fluoroquinolones

Fluoroquinolone antibiotics are useful in the management of infections caused by a variety of pathogens. Several agents can substantially reduce the absorption of fluoroquinolones, thereby causing treatment failure.

Divalent cations (calcium and magnesium) and trivalent cations (aluminum and ferrous sulfate) can form insoluble complexes in the gut if they are taken concurrently with fluoroquinolones.¹¹ These cations are readily available over the counter, and patients may not report them as “medicines.” Sucralfate (Carafate), an antiulcer medication, also contains aluminum. Common products containing divalent or trivalent cations are listed in Table 2.

Studies have shown that the absorption of fluoroqinolones is reduced by 60 to 75 percent when these antibiotics are administered concomitantly with divalent or trivalent cations.¹¹ Patients should stop taking products containing these cations until fluoroquinolone therapy has been completed. If withholding therapy is not feasible, the fluoroquinolone and cation product should be administered at least two hours apart (preferably four hours apart).

Antiepileptic Drugs

Carbamazepine (Tegretol), phenobarbital and phenytoin (Dilantin) are commonly prescribed for the management of epilepsy and other disorders. These agents are eliminated through hepatic metabolism. Thus, their effects may be potentiated by drugs that inhibit cytochrome P450 hepatic metabolism, such as macrolide antibiotics, cimetidine (Tagamet) and fluconazole (Diflucan).¹²

Agents that inhibit cytochrome P450 metabolism or depend on cytochrome P450 for metabolism (substrate)¹³ are listed in Table 3. Combining a cytochrome P450 inhibitor with a substrate can potentiate the pharmacologic effects of the substrate.

Rifampin (Rifadin) is the “classic hepatic enzyme inducer.” When this agent is administered to patients who are taking an antiepileptic medication, increased hepatic metabolism may decrease the serum levels of the antiepileptic drug,¹⁴ possibly resulting in breakthrough seizures.

Specific data support interactions between the following drugs: erythromycin and carbamazepine; cimetidine and carbamazepine or phenytoin; fluconazole and phenytoin; and rifampin and phenytoin. Serum antiepileptic drug levels should be monitored in patients who receive any of these combinations.^12,14

Lithium

Lithium therapy is useful for indications ranging from bipolar disorder to migraine headaches, but several interactions must be considered. Diuretics and NSAIDs alter the sodium balance at the level of the kidney. As a result, serum lithium levels increase secondary to enhanced reabsorption.^{3(pp309,368–9)} Some NSAIDs may also alter prostaglandin effects on the kidney, thereby reducing the elimination of lithium.^3(pp368–9)

If coadministration is necessary, the dosage of lithium should be reduced by 50 percent when a diuretic or an NSAID is added. Signs or symptoms of lithium toxicity involve the central nervous system (drowsiness, confusion, hand tremor, blurred vision, vertigo and seizures), gastrointestinal tract (nausea and vomiting) and cardiovascular system (arrhythmias and widening of the QRS complex).

Oral Contraceptives

ANTIBIOTICS

Rifampin can increase the activity of hepatic enzymes involved in the metabolism of exogenous estrogens. Concomitant use of rifampin and oral contraceptive pills can lead to breakthrough bleeding and an increased risk of pregnancy. These problems are most likely to occur with formulations containing a low dosage of estrogen (less than 35 μg of ethinyl estradiol).^3(pp415–6)

The interaction between oral contraceptives and other antibiotics is controversial in that no definitive studies have demonstrated contraceptive failure from such combinations. A recent retrospective study of 356 patients who were taking an oral contraceptive and an antibiotic showed a small but insignificant increase in the risk of pregnancy.¹⁵ Other information on this subject is derived from surveys, case reports and studies of serum estradiol concentrations. One proposed mechanism is interruption of the enterohepatic circulation of estrogen as a result of reduced bacterial hydrolysis in the gastrointestinal tract. A variety of antibiotics have been implicated.^3(pp415–6)

The failure of oral contraception may be suggested by breakthrough bleeding. A reasonable recommendation is to remind patients that the baseline failure rate for oral contraceptives is approximately one pregnancy per 100 woman years (i.e., about 1 percent per year).^16,17 Because of the low frequency of oral contraceptive pill–antibiotic interactions, it is difficult to separate any antibiotic effect from the expected failure rate.

Although insufficient evidence is available to make a firm conclusion, it appears possible that oral contraception may fail while patients are taking an antibiotic. Thus, patients should be encouraged to consider using an alternative method of contraception for the duration of the cycle.^15,16

TROGLITAZONE

Troglitazone (Rezulin) has been reported to reduce the plasma concentrations of oral contraceptives by 30 percent through an unknown mechanism.¹⁷ No published studies are available, but the prescribing information suggests that this potential interaction can be managed by using an oral contraceptive pill containing a higher dosage of estrogen or by using an alternative method of contraception.

Cisapride

Potentially fatal interactions can occur with coadministration of cisapride (Propulsid) and other drugs. Cisapride has been associated with prolongation of the QT interval, torsades de pointes, syncope, cardiac arrest and sudden death.¹⁷ Some of these serious or fatal interactions have involved concomitant use of drugs that increase serum cisapride levels by inhibiting cytochrome P450 3A4, a pathway responsible for cisapride's metabolism.

The primary agents contraindicated for use with cisapride are certain macrolide antibiotics (erythromycin and clarithromycin), certain antifungal agents (fluconazole, itraconazole [Sporanox] and ketoconazole [Nizoral]), one antidepressant drug (nefazodone [Serzone]) and certain protease inhibitors (indinavir [Crixivan] and ritonavir [Norvir]).¹⁷

Most data on cisapride interactions are derived from case reports. However, current prescribing information warns against the coadministration of cisapride and any medications known to prolong the QT interval, such as class IA or III antiarrhythmic drugs, tricyclic antidepressants, erythromycin, clarithromycin and phenothiazines.¹⁷

Sildenafil

Sildenafil (Viagra) is the first oral medication labeled by the U.S. Food and Drug Administration for the treatment of erectile dysfunction. Through inhibition of phosphodiesterase type 5, sildenafil enhances the effects of nitric oxide, potentiating penile erection after sexual arousal.¹⁸ Erectile dysfunction is often associated with common chronic diseases such as hypertension, heart disease and diabetes. Therefore, patients with erectile dysfunction are often taking other medications.

Sildenafil therapy is absolutely contraindicated in patients who are taking any form of nitrates, because of the potentiation of nitrate hypotensive effects. Sildenafil is primarily metabolized in the liver by cytochrome P450 3A4. Drugs that inhibit this enzyme, including erythromycin, cimetidine, ketoconazole and itraconazole, may increase plasma sildenafil concentrations. Sildenafil therapy should be initiated in the lowest dosage (25 mg) in patients who are also taking a cytochrome P450 3A4 inhibitor.¹⁸

3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors

The benefits of lowering cholesterol levels for the primary and secondary prevention of coronary artery disease have been well established. Most evidence supports using drugs that inhibit 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase in the liver, which is the main site of cholesterol synthesis.

The HMG-CoA reductase inhibitors (statins) include atorvastatin (Lipitor), cerivastatin (Baycol), fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravachol) and simvastatin (Zocor). These drugs are metabolized through the cytochrome P450 pathway.

Concomitant use of statins and erythromycin, itraconazole, niacin or gemfibrozil (Lopid) can cause toxicity that manifests as elevated serum transaminase levels, myopathy, rhabdomyolysis and acute renal failure.¹⁹ Used alone, any statin can cause these adverse effects. However, the risk of toxicity increases when statins are coadministered with certain drugs. Because this risk may be dose-dependent, the dosage should be limited to the equivalent of 20 mg of lovastatin per day when any statin is given in combination with an interacting drug.²⁰

In many patients, HMG-CoA reductase inhibitors fail to lower triglyceride cholesterol levels to a desirable range. Although concomitant use of gemfibrozil or niacin with an HMG-CoA reductase inhibitor may appear clinically appropriate, these combinations have been associated with a 2 to 5 percent increase in the risk of myopathy.²¹ Case reports describing these interactions are questionable because gemfibrozil and niacin have independently been associated with myopathy.

Caution should be exercised when an HMG-CoA reductase inhibitor is used with gemfibrozil or niacin. If either combination is used, patients should be alert for muscle pain, tenderness or weakness. Creatine kinase levels should be measured if these symptoms occur.

Lovastatin may potentiate the effects of warfarin by displacing the drug from plasma protein binding sites or inhibiting hepatic metabolism of the drug. Although potentiation of warfarin by lovastatin has been reported in at least 10 patients, controlled trials in large numbers of patients are needed to discern the clinical importance of this effect.²² The INR should be monitored in patients who are taking lovastatin and warfarin, especially if the lovastatin dosage is changed.

Selective Serotonin Reuptake Inhibitors

Over the past 15 years, selective serotonin reuptake inhibitors (SSRIs) have become the most commonly used antidepressant drugs. These agents are generally well tolerated and have a more favorable side effect profile than tricyclic antidepressants. Nearly all SSRIs are metabolized by the cytochrome P450 system in the liver. All SSRIs except paroxetine (Paxil) have pharmacologically active metabolites.²³

The most common interactions with SSRIs result from an inhibitory effect of the SSRI on the cytochrome P450 2D6 pathway, although variability in this inhibition exists. Concurrent use of SSRIs with agents metabolized by this pathway can result in increased serum concentrations of these agents.

TRICYCLIC ANTIDEPRESSANTS

Patients already being treated with a tricyclic antidepressant may experience significant increases in plasma antidepressant concentrations (and possibly antidepressant toxicity) when fluoxetine (Prozac) is added.²⁴ This effect may also occur with other SSRIs. When concomitant use of an SSRI and a tricyclic antidepressant is required, the patient should be monitored for anticholinergic excess. Conservative dosing of the tricyclic antidepressant should also be considered.

SELEGILINE

Isolated case reports suggest that coadministration of fluoxetine and selegiline (Eldepryl) may result in mania and hypertension.²⁵ In dosages higher than 10 mg per day, selegiline may produce nonselective monoamine oxidase (MAO) inhibition. The causal mechanism has not been established. However, selegiline is thought to produce additive serotoninergic effects, because serotonin is metabolized by MAO-A. The prescribing information for selegiline recommends that the drug not be used with SSRIs.¹⁷

NONSELECTIVE MONOAMINE OXIDASE INHIBITORS

The concomitant use of fluoxetine and non-selective MAO inhibitors has resulted in the serotonin syndrome, which is characterized by anxiety, agitation, confusion, hyperreflexia, myoclonus, diaphoresis and hyperthermia. Several cases of serious or fatal reactions have occurred when tranylcypromine (Parnate) was used with fluoxetine.²⁶ Because of the long half-life of fluoxetine (two to three days) and its active metabolite norfluoxetine (half-life of seven to nine days), fluoxetine interactions theoretically can occur weeks after the drug is discontinued. It is generally accepted that all combinations of nonselective MAO inhibitors and SSRIs are contraindicated.

TRAMADOL

Tramadol (Ultram) is a centrally acting analgesic with two modes of action: weak binding to the μ-opiate receptor and inhibition of norepinephrine and serotonin reuptake. Reports of serotonin syndrome in association with tramadol and SSRI coadministration appear in the literature.²⁷ Because depression and chronic pain syndromes frequently coexist, physicians are likely to encounter situations in which this combination is used.

ST. JOHN'S WORT

At least one case report has described incoherence attributable to the combination of an SSRI and St. John's wort (extract of the Hypericum perforatum plant).²⁸ The antidepressant effect of St. John's wort is mediated through inhibition of serotonin uptake or MAO antagonism. As use of this over-the-counter product increases, more data supporting clinically significant drug interactions should become available. Given the popularity of St. John's wort, its availability and the public's propensity for self-medication, it is important to caution patients taking MAO inhibitors and SSRIs against the concomitant use of this herbal remedy.

TRIPTANS

A recent report documented six cases of serotonin syndrome in patients taking fluoxetine and sumatriptan (Imitrex).²⁹ The authors of the report suggested that this drug combination should be used with caution.

Another report found that the balance of documented clinical experience pertaining to the concomitant use of sumatriptan and SSRIs suggested that most patients tolerate the combination without adverse effect.³⁰ However, the authors of the report concluded that the combination of sumatriptan and SSRIs should be avoided until additional patient use has verified safety.

Yet another report on 14 patients discovered no significant interaction between SSRIs and sumatriptan.³¹ The authors concluded that the combination may be safe.

At least one source recommends that different triptans (e.g., naratriptan [Amerge], rizatriptan [Maxalt] and zolmitriptan [Zomig]) should not be used within 24 hours of each other because of concern about the additive vasoconstrictive effects.³²

A conservative approach would be to avoid SSRI-triptan combinations.

Sources of Information on Drug Interactions

No single method is available to enable physicians to easily avoid drug interactions in clinical practice. It can be helpful for physicians to keep files on prescribing information for new agents, maintain frequent contact with local pharmacists and have drug interaction resources readily available in the office. Several sources of information on drug interactions are described in Table 4.