Clinically Significant Drug Interactions

Am Fam Physician. 2000 Mar 15;61(6):1745-1754.

  Related Editorial

A large number of drugs are introduced every year, and new interactions between medications are increasingly reported. Consequently, it is no longer practical for physicians to rely on memory alone to avoid potential drug interactions. Multiple drug regimens carry the risk of adverse interactions. Precipitant drugs modify the object drug's absorption, distribution, metabolism, excretion or actual clinical effect. Nonsteroidal anti-inflammatory drugs, antibiotics and, in particular, rifampin are common precipitant drugs prescribed in primary care practice. Drugs with a narrow therapeutic range or low therapeutic index are more likely to be the objects for serious drug interactions. Object drugs in common use include warfarin, fluoroquinolones, antiepileptic drugs, oral contraceptives, cisapride and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Many other drugs, act as precipitants or objects, and a number of drugs act as both. Regularly updated manuals of drug interactions and CD-ROM–formatted programs are useful office references.

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).

TABLE 1

Overview of Selected Serious Drug Interactions

Interaction Potential effect Time to effect Recommendations and comments

Warfarin (Coumadin) plus ciprofloxacin (Cipro), clarithromycin (Biaxin), erythromycin, metronidazole (Flagyl) or trimethoprim-sulfamethoxazole (Bactrim, Septra)

Increased effect of warfarin

Generally within 1 week

Select alternative antibiotic.

Warfarin plus acetaminophen

Increased bleeding, increased INR

Any time

Use lowest possible acetaminophen dosage and monitor INR.

Warfarin plus acetylsalicylic acid (aspirin)

Increased bleeding, increased INR

Any time

Limit aspirin dosage to 100 mg per dayand monitor INR.

Warfarin plus NSAID

Increased bleeding, increased INR

Any time

Avoid concomitant use if possible; if coadministration is necessary, use a cyclooxygenase-2 inhibitor and monitor INR.

Fluoroquinolone plus divalent/trivalent cations or sucralfate (Carafate)

Decreased absorption of fluoroquinolone

Any time

Space administration by 2 to 4 hours.

Carbamazepine (Tegretol) plus cimetidine (Tagamet), erythromycin, clarithromycin or fluconazole (Diflucan)

Increased carbamazepine levels

Generally within 1 week

Monitor carbamazepine levels.

Phenytoin (Dilantin) plus cimetidine, erythromycin, clarithromycin or fluconazole

Increased phenytoin levels

Generally within 1 week

Monitor phenytoin levels.

Phenobarbital plus cimetidine, erythromycin, clarithromycin or fluconazole

Increased phenobarbital levels

Generally within 1 week

Clinical significance has not been established. Monitor phenobarbital levels.

Phenytoin plus rifampin (Rifadin)

Decreased phenytoin levels

Generally within 1 week

Clinical significance has not been established. Monitor phenytoin levels.

Phenobarbital plus rifampin

Decreased phenobarbital levels

Generally within 1 week

Monitor phenobarbital levels.

Carbamazepine plus rifampin

Decreased carbamazepine levels

Generally within 1 week

Clinical significance has not been established. Monitor carbamazepine levels.

Lithium plus NSAID or diuretic

Increased lithium levels

Any time

Decrease lithium dosage by 50% and monitor lithium levels.

Oral contraceptive pills plus rifampin

Decreased effectiveness of oral contraception

Any time

Avoid if possible. If combination therapy is necessary, have the patient take an oral contraceptive pill with a higher estrogen content (>35 μg of ethinyl estradiol) or recommend alternative method of contraception.

Oral contraceptive pills plus antibiotics

Decreased effectiveness of oral contraception

Any time

Avoid if possible. If combination therapy is necessary, recommend use of alternative contraceptive method during cycle.

Oral contraceptive pills plus troglitazone (Rezulin)

Decreased effectiveness of oral contraception

Any time

Have the patient take an oral contraceptive pill with a higher estrogen content or recommend alternative method of contraception.

Cisapride (Propulsid) plus erythromycin, clarithromycin, fluconazole, itraconazole (Sporanox), ketoconazole (Nizoral), nefazodone (Serzone), indinavir (Crixivan) or ritonavir (Norvir)

Prolongation of QT interval along with arrhythmias secondary to inhibited cisapride metabolism

Generally within 1 week

Avoid. Consider whether metoclopromide (Reglan) therapy is appropriate for the patient.

Cisapride plus class IA or class III antiarrhythmic agents, tricyclic antidepressants or phenothiazine

Prolongation of QT interval along with arrhythmias

Any time

Avoid. Consider whether metoclopromide therapy is appropriate for the patient.

Sildenafil (Viagra) plus nitrates

Dramatic hypotension

Soon after taking sildenafil

Absolute contraindication.

Sildenafil plus cimetidine, erythromycin, itraconazole or ketoconazole

Increased sildenafil levels

Any time

Initiate sildenafil at a 25-mg dose.

HMG-CoA reductase inhibitor plus niacin, gemfibrozil (Lopid), erythromycin or itraconazole

Possible rhabdomyolysis

Any time

Avoid if possible. If combination therapy is necessary, monitor the patient for toxicity.

Lovastatin (Mevacor) plus warfarin

Increased effect of warfarin

Any time

Monitor INR.

SSRI plus tricyclic antidepressant

Increased tricyclic antidepressant level

Any time

Monitor for anticholinergic excess and consider lower dosage of tricyclic antidepressant.

SSRI plus selegiline (Eldepryl) or nonselective monoamine oxidase inhibitor

Hypertensive crisis

Soon after initiation

Avoid.

SSRI plus tramadol (Ultram)

Increased potential for seizures; serotonin syndrome

Any time

Monitor the patient for signs and symptoms of serotonin syndrome.

SSRI plus St. John's wort

Serotonin syndrome

Any time

Avoid.

SSRI plus naratriptan (Amerge), rizatriptan (Mazalt), sumatriptan (Imitrex) or zolmitriptan (Zomig)

Serotonin syndrome

Possibly after initial dose

Avoid if possible. If combination therapy is necessary, monitor the patient for signs and symptoms of serotonin syndrome.


INR = International Normalized Ratio; NSAID = nonsteroidal anti-inflammatory drug; HMG-CoA = 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitor; SSRI = selective serotonin reuptake inhibitor.

TABLE 1   Overview of Selected Serious Drug Interactions

View Table

TABLE 1

Overview of Selected Serious Drug Interactions

Interaction Potential effect Time to effect Recommendations and comments

Warfarin (Coumadin) plus ciprofloxacin (Cipro), clarithromycin (Biaxin), erythromycin, metronidazole (Flagyl) or trimethoprim-sulfamethoxazole (Bactrim, Septra)

Increased effect of warfarin

Generally within 1 week

Select alternative antibiotic.

Warfarin plus acetaminophen

Increased bleeding, increased INR

Any time

Use lowest possible acetaminophen dosage and monitor INR.

Warfarin plus acetylsalicylic acid (aspirin)

Increased bleeding, increased INR

Any time

Limit aspirin dosage to 100 mg per dayand monitor INR.

Warfarin plus NSAID

Increased bleeding, increased INR

Any time

Avoid concomitant use if possible; if coadministration is necessary, use a cyclooxygenase-2 inhibitor and monitor INR.

Fluoroquinolone plus divalent/trivalent cations or sucralfate (Carafate)

Decreased absorption of fluoroquinolone

Any time

Space administration by 2 to 4 hours.

Carbamazepine (Tegretol) plus cimetidine (Tagamet), erythromycin, clarithromycin or fluconazole (Diflucan)

Increased carbamazepine levels

Generally within 1 week

Monitor carbamazepine levels.

Phenytoin (Dilantin) plus cimetidine, erythromycin, clarithromycin or fluconazole

Increased phenytoin levels

Generally within 1 week

Monitor phenytoin levels.

Phenobarbital plus cimetidine, erythromycin, clarithromycin or fluconazole

Increased phenobarbital levels

Generally within 1 week

Clinical significance has not been established. Monitor phenobarbital levels.

Phenytoin plus rifampin (Rifadin)

Decreased phenytoin levels

Generally within 1 week

Clinical significance has not been established. Monitor phenytoin levels.

Phenobarbital plus rifampin

Decreased phenobarbital levels

Generally within 1 week

Monitor phenobarbital levels.

Carbamazepine plus rifampin

Decreased carbamazepine levels

Generally within 1 week

Clinical significance has not been established. Monitor carbamazepine levels.

Lithium plus NSAID or diuretic

Increased lithium levels

Any time

Decrease lithium dosage by 50% and monitor lithium levels.

Oral contraceptive pills plus rifampin

Decreased effectiveness of oral contraception

Any time

Avoid if possible. If combination therapy is necessary, have the patient take an oral contraceptive pill with a higher estrogen content (>35 μg of ethinyl estradiol) or recommend alternative method of contraception.

Oral contraceptive pills plus antibiotics

Decreased effectiveness of oral contraception

Any time

Avoid if possible. If combination therapy is necessary, recommend use of alternative contraceptive method during cycle.

Oral contraceptive pills plus troglitazone (Rezulin)

Decreased effectiveness of oral contraception

Any time

Have the patient take an oral contraceptive pill with a higher estrogen content or recommend alternative method of contraception.

Cisapride (Propulsid) plus erythromycin, clarithromycin, fluconazole, itraconazole (Sporanox), ketoconazole (Nizoral), nefazodone (Serzone), indinavir (Crixivan) or ritonavir (Norvir)

Prolongation of QT interval along with arrhythmias secondary to inhibited cisapride metabolism

Generally within 1 week

Avoid. Consider whether metoclopromide (Reglan) therapy is appropriate for the patient.

Cisapride plus class IA or class III antiarrhythmic agents, tricyclic antidepressants or phenothiazine

Prolongation of QT interval along with arrhythmias

Any time

Avoid. Consider whether metoclopromide therapy is appropriate for the patient.

Sildenafil (Viagra) plus nitrates

Dramatic hypotension

Soon after taking sildenafil

Absolute contraindication.

Sildenafil plus cimetidine, erythromycin, itraconazole or ketoconazole

Increased sildenafil levels

Any time

Initiate sildenafil at a 25-mg dose.

HMG-CoA reductase inhibitor plus niacin, gemfibrozil (Lopid), erythromycin or itraconazole

Possible rhabdomyolysis

Any time

Avoid if possible. If combination therapy is necessary, monitor the patient for toxicity.

Lovastatin (Mevacor) plus warfarin

Increased effect of warfarin

Any time

Monitor INR.

SSRI plus tricyclic antidepressant

Increased tricyclic antidepressant level

Any time

Monitor for anticholinergic excess and consider lower dosage of tricyclic antidepressant.

SSRI plus selegiline (Eldepryl) or nonselective monoamine oxidase inhibitor

Hypertensive crisis

Soon after initiation

Avoid.

SSRI plus tramadol (Ultram)

Increased potential for seizures; serotonin syndrome

Any time

Monitor the patient for signs and symptoms of serotonin syndrome.

SSRI plus St. John's wort

Serotonin syndrome

Any time

Avoid.

SSRI plus naratriptan (Amerge), rizatriptan (Mazalt), sumatriptan (Imitrex) or zolmitriptan (Zomig)

Serotonin syndrome

Possibly after initial dose

Avoid if possible. If combination therapy is necessary, monitor the patient for signs and symptoms of serotonin syndrome.


INR = International Normalized Ratio; NSAID = nonsteroidal anti-inflammatory drug; HMG-CoA = 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitor; SSRI = selective serotonin reuptake inhibitor.

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.

TABLE 2

Common Products Containing Divalent or Trivalent Cations

Cations Products

Aluminum

Alu-Cap, AlternaGel, Amphojel, Basaljel

Aluminum and magnesium combinations

Gelusil, Maalox, Mylanta, Riopan

Calcium

Caltrate, Citracal, Os-Cal, PhosLo, Titralac, Tums

Iron

Feosol, Fergon, Niferex, Nu-Iron, Slow Fe

Magnesium

Almora, Citrate of Magnesia, Mag-Ox 400, Milk of Magnesia, Slow-Mag, Uro-Mag

TABLE 2   Common Products Containing Divalent or Trivalent Cations

View Table

TABLE 2

Common Products Containing Divalent or Trivalent Cations

Cations Products

Aluminum

Alu-Cap, AlternaGel, Amphojel, Basaljel

Aluminum and magnesium combinations

Gelusil, Maalox, Mylanta, Riopan

Calcium

Caltrate, Citracal, Os-Cal, PhosLo, Titralac, Tums

Iron

Feosol, Fergon, Niferex, Nu-Iron, Slow Fe

Magnesium

Almora, Citrate of Magnesia, Mag-Ox 400, Milk of Magnesia, Slow-Mag, Uro-Mag

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.

TABLE 3

Agents That Inhibit or Are Metabolized Through Cytochrome P450 Pathways*

Pathway Inhibitors Substrates

Cytochrome P450 2D6

Fluoxetine (Prozac)

Codeine

Paroxetine (Paxil)

Metoprolol (Lopressor, Toprol XL)

Sertraline (Zoloft)

Paroxetine

Perphenazine (Trilafon)

Sertraline

Venlafaxine (Effexor)

Cytochrome P450 3A4

Cimetidine (Tagamet)

Cisapride (Propulsid)

Clarithromycin (Biaxin)

Erythromycin

Erythromycin

Fluvoxamine (Luvox)

Grapefruit juice

Itraconazole (Sporanox)

Ketoconazole (Nizoral)

Lovastatin (Mevacor)

Nefazodone (Serzone)


*—Combining an agent that inhibits cytochrome P450 metabolism with a substrate of cytochrome P450 may potentiate the pharmacologic effects of the substrate through inhibition of hepatic metabolism.

TABLE 3   Agents That Inhibit or Are Metabolized Through Cytochrome P450 Pathways*

View Table

TABLE 3

Agents That Inhibit or Are Metabolized Through Cytochrome P450 Pathways*

Pathway Inhibitors Substrates

Cytochrome P450 2D6

Fluoxetine (Prozac)

Codeine

Paroxetine (Paxil)

Metoprolol (Lopressor, Toprol XL)

Sertraline (Zoloft)

Paroxetine

Perphenazine (Trilafon)

Sertraline

Venlafaxine (Effexor)

Cytochrome P450 3A4

Cimetidine (Tagamet)

Cisapride (Propulsid)

Clarithromycin (Biaxin)

Erythromycin

Erythromycin

Fluvoxamine (Luvox)

Grapefruit juice

Itraconazole (Sporanox)

Ketoconazole (Nizoral)

Lovastatin (Mevacor)

Nefazodone (Serzone)


*—Combining an agent that inhibits cytochrome P450 metabolism with a substrate of cytochrome P450 may potentiate the pharmacologic effects of the substrate through inhibition of hepatic metabolism.

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.

TABLE 4

Selected Sources of Information on Drug Interactions

Clinical Pharmacology (CD-ROM, Internet)

Complete database for drug interactions as well as clinically useful drug information; updated quarterly.

Gold Standard Multimedia

Product Ordering

320 W. Kennedy Blvd., Suite 400

Tampa, FL 33606

Telephone: 800-375-0943, 813-258-4747

Fax: 813-259-1585

E-mail: sales@gsm.com

Hansten and Horn's Drug Interactions Analysis and Management (manual)

Easy-to-use index that categorizes a drug interaction by clinical significance, along with a concise reference monograph discussing the interaction; updated quarterly.

Applied Therapeutics, Inc.

Box 5077

Vancouver, WA 98668

Telephone: 360-253-7123

Fax: 360-253-8475

Handbook of Adverse Drug Interactions (manual); Adverse Drug Interactions Program (software, Internet)

Software searches for interactions between two and up to 25 drugs.

The Medical Letter on Drugs and Therapeutics

1000 Main St.

New Rochelle, NY 10801-7537

Telephone: 800-211-2769, 914-235-0500

Fax: 914-632-1733

E-mail: custserv@themedicalletter.org

Drug Interactions Analysis and Management (loose-leaf or bound manual); Drug Interaction Facts (loose-leaf or bound manual with software)

Information about drug-drug and drug-food interactions in a quick reference format, along with descriptive monographs of drug interactions selected on the basis of their potential to alter patient outcomes; updated quarterly.

Facts and Comparisons

111 West Port Plaza, Suite 300

St. Louis, MO 63146

Telephone: 800-223-0554, 314-223-0554

Fax: 314-878-5563c

E-mail: networksales@drugfacts.com, or service@drugfacts.com

TABLE 4   Selected Sources of Information on Drug Interactions

View Table

TABLE 4

Selected Sources of Information on Drug Interactions

Clinical Pharmacology (CD-ROM, Internet)

Complete database for drug interactions as well as clinically useful drug information; updated quarterly.

Gold Standard Multimedia

Product Ordering

320 W. Kennedy Blvd., Suite 400

Tampa, FL 33606

Telephone: 800-375-0943, 813-258-4747

Fax: 813-259-1585

E-mail: sales@gsm.com

Hansten and Horn's Drug Interactions Analysis and Management (manual)

Easy-to-use index that categorizes a drug interaction by clinical significance, along with a concise reference monograph discussing the interaction; updated quarterly.

Applied Therapeutics, Inc.

Box 5077

Vancouver, WA 98668

Telephone: 360-253-7123

Fax: 360-253-8475

Handbook of Adverse Drug Interactions (manual); Adverse Drug Interactions Program (software, Internet)

Software searches for interactions between two and up to 25 drugs.

The Medical Letter on Drugs and Therapeutics

1000 Main St.

New Rochelle, NY 10801-7537

Telephone: 800-211-2769, 914-235-0500

Fax: 914-632-1733

E-mail: custserv@themedicalletter.org

Drug Interactions Analysis and Management (loose-leaf or bound manual); Drug Interaction Facts (loose-leaf or bound manual with software)

Information about drug-drug and drug-food interactions in a quick reference format, along with descriptive monographs of drug interactions selected on the basis of their potential to alter patient outcomes; updated quarterly.

Facts and Comparisons

111 West Port Plaza, Suite 300

St. Louis, MO 63146

Telephone: 800-223-0554, 314-223-0554

Fax: 314-878-5563c

E-mail: networksales@drugfacts.com, or service@drugfacts.com

The Authors

PAUL W. AMENT, PHARM.D., is assistant director of pharmacy and a faculty member in the family medicine residency program at Latrobe (Pa.) Area Hospital. He is also an instructor in family medicine at Jefferson Medical College of Thomas Jefferson University, Philadelphia. Dr. Ament earned his doctor of pharmacy degree at Duquesne University School of Pharmacy, Pittsburgh, and completed a residency in hospital pharmacy at Mercy Hospital of Pittsburgh.

JOHN G. BERTOLINO, M.D., M.S.P.H., is director of the family medicine residency program at Latrobe Area Hospital. He is also associate professor of family medicine at Jefferson Medical College, where he earned his medical degree. Dr. Bertolino completed a residency in family medicine at Latrobe Area Hospital and a fellowship in academic family medicine at the University of Missouri–Columbia School of Medicine.

JAMES L. LISZEWSKI, M.D., is an instructor in family medicine at Latrobe Area Hospital. Dr. Liszewski received his medical degree from the University of Maryland School of Medicine, Baltimore, and completed a residency in family medicine at Latrobe Area Hospital.

Address correspondence to Paul W. Ament, Pharm.D., Clinical Pharmacy Services, Latrobe Area Hospital, 121 W. 2nd Ave., Latrobe, PA 15650. Reprints are not available from the authors.

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Richard W. Sloan, M.D., R.PH., coordinator of this series, is chairman and residency program director of the Department of Family Medicine at York (Pa.) Hospital and clinical associate professor in family and community medicine at the Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pa.


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