Clinically Significant Drug Interactions

7/12/23, 12:26 PM Clinically Significant Drug Interactions | AAFP
Clinically Significant Drug Interactions

PAUL W. AMENT, PHARM.D., JOHN G. BERTOLINO, M.D., M.S.P.H., AND JAMES L. LISZEWSKI, M.D.
info Am Fam Physician. 2000;61(6):1745-1754

local_library See editorial on page 1628. (https://www.aafp.org/afp/2000/0315/p1628)
A more recent article on clinically relevant drug-drug interactions is available.
(https://www.aafp.org/afp/2019/0501/p558.html)
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
https://www.aafp.org/pubs/afp/issues/2000/0315/p1745.html 1/19
Overview of Selected Serious Drug Interactions
Time to Recommendations and

Interaction Potential effect
effect comments
Warfarin (Coumadin) plus

ciprofloxacin (Cipro),
clarithromycin (Biaxin), Generally
Increased effect of
erythromycin, metronidazole within 1 Select alternative antibiotic.
warfarin
(Flagyl) or trimethoprim- week
sulfamethoxazole (Bactrim,
Septra)
Use lowest possible

Increased bleeding,
Warfarin plus acetaminophen Any time acetaminophen dosage and
increased INR
monitor INR.
Warfarin plus acetylsalicylic Increased bleeding, Limit aspirin dosage to 100 mg

Any time
acid (aspirin) increased INR per dayand monitor INR.
Avoid concomitant use if

possible; if coadministration is
Increased bleeding,
Warfarin plus NSAID Any time necessary, use a
increased INR
cyclooxygenase-2 inhibitor and
monitor INR.
Fluoroquinolone plus Decreased

Space administration by 2 to 4
divalent/trivalent cations or absorption of Any time
hours.
sucralfate (Carafate) fluoroquinolone
Carbamazepine (Tegretol)
Generally
plus cimetidine (Tagamet), Increased
within 1 Monitor carbamazepine levels.
erythromycin, clarithromycin carbamazepine levels
week
or fluconazole (Diflucan)
Phenytoin (Dilantin) plus Generally

Increased phenytoin
cimetidine, erythromycin, within 1 Monitor phenytoin levels.
levels
clarithromycin or fluconazole week
Phenobarbital plus Generally Clinical significance has not

Increased
cimetidine, erythromycin, within 1 been established. Monitor
phenobarbital levels
clarithromycin or fluconazole week phenobarbital levels.

effect comments
Generally Clinical significance has not

Phenytoin plus rifampin Decreased phenytoin
within 1 been established. Monitor
(Rifadin) levels
week phenytoin levels.
Generally
Decreased
Phenobarbital plus rifampin within 1 Monitor phenobarbital levels.
phenobarbital levels
week
Generally Clinical significance has not

Decreased
Carbamazepine plus rifampin within 1 been established. Monitor
carbamazepine levels
week carbamazepine levels.
Lithium plus NSAID or Increased lithium Decrease lithium dosage by

Any time
diuretic levels 50% and monitor lithium levels.
Avoid if possible. If combination

therapy is necessary, have the
patient take an oral
Decreased
Oral contraceptive pills plus contraceptive pill with a higher
effectiveness of oral Any time
rifampin estrogen content (>35 μg of
contraception
ethinyl estradiol) or recommend
alternative method of
contraception.

Decreased therapy is necessary,
Oral contraceptive pills plus
effectiveness of oral Any time recommend use of alternative
antibiotics
contraception contraceptive method during
cycle.
Have the patient take an oral

Decreased contraceptive pill with a higher
Oral contraceptive pills plus
effectiveness of oral Any time estrogen content or recommend
troglitazone (Rezulin)
contraception alternative method of
contraception.
Cisapride (Propulsid) plus Prolongation of QT Generally Avoid. Consider whether

erythromycin, clarithromycin, interval along with within 1 metoclopromide (Reglan)
fluconazole, itraconazole arrhythmias week therapy is appropriate for the
(Sporanox), ketoconazole secondary to patient.
(Nizoral), nefazodone

effect comments
(Serzone), indinavir (Crixivan) inhibited cisapride
or ritonavir (Norvir) metabolism
Cisapride plus class IA or

class III antiarrhythmic Prolongation of QT Avoid. Consider whether
agents, tricyclic interval along with Any time metoclopromide therapy is
antidepressants or arrhythmias appropriate for the patient.
phenothiazine
Soon after
Sildenafil (Viagra) plus Dramatic
taking Absolute contraindication.
nitrates hypotension
sildenafil
Sildenafil plus cimetidine,

Increased sildenafil Initiate sildenafil at a 25-mg
erythromycin, itraconazole or Any time
levels dose.
ketoconazole
HMG-CoA reductase inhibitor

plus niacin, gemfibrozil Possible
Any time therapy is necessary, monitor
(Lopid), erythromycin or rhabdomyolysis
the patient for toxicity.
itraconazole
Lovastatin (Mevacor) plus Increased effect of

Any time Monitor INR.
warfarin warfarin
Monitor for anticholinergic

SSRI plus tricyclic Increased tricyclic excess and consider lower
Any time
antidepressant antidepressant level dosage of tricyclic
antidepressant.
SSRI plus selegiline (Eldepryl)

Soon after
or nonselective monoamine Hypertensive crisis Avoid.
initiation
oxidase inhibitor
Increased potential Monitor the patient for signs

SSRI plus tramadol (Ultram) for seizures; Any time and symptoms of serotonin
serotonin syndrome syndrome.
SSRI plus St. John's wort Serotonin syndrome Any time Avoid.
SSRI plus naratriptan Serotonin syndrome Possibly Avoid if possible. If combination

(Amerge), rizatriptan after initial therapy is necessary, monitor
(Mazalt), sumatriptan dose the patient for signs and

effect comments
(Imitrex) or zolmitriptan symptoms of serotonin
(Zomig) 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

Gelusil, Maalox, Mylanta, Riopan
combinations
Calcium Caltrate, Citracal, Os-Cal, PhosLo, Titralac, Tums
Iron Feosol, Fergon, Niferex, Nu-Iron, Slow Fe
Cations Products
Almora, Citrate of Magnesia, Mag-Ox 400, Milk of Magnesia,

Magnesium
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
Pathway Inhibitors Substrates
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 (mailto: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 (mailto: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 (mailto:networksales@drugfacts.com), or

service@drugfacts.com (mailto:service@drugfacts.com)
Author Information
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.
Reference(s)
1. Weibert RT, Lorentz SM, Townsend RJ, Cook CE, Klauber MR, Jagger PI. Effect of erythromycin in
patients receiving long-term warfarin therapy. Clin Pharm. 1989;8:210-4.
2. Wells PS, Holbrook AM, Crowther NR, Hirsch J. Interactions of warfarin with drugs and food. Ann
Intern Med. 1994;121:676-83.
3. Hansten PD, Horn JR. Hansten and Horn's Drug interactions analysis and management. Vancouver,
Wash.: Applied Therapeutics, 1997;7–8,309,368–9,415–6.
4. Hylek EM, Heiman H, Skates SJ, Sheehan MA, Singer DE. Acetaminophen and other risk factors for
excessive warfarin anticoagulation. JAMA. 1998;279:657-62.
5. Bell WR. Acetaminophen and warfarin: undesirable synergy [Editorial]. JAMA. 1998;279:702-3.
6. Chan TY. Adverse interactions between warfarin and nonsteroidal antiinflammatory drugs:
mechanisms, clinical significance, and avoidance. Ann Pharmacother. 1995;29:1274-83.
7. Turpie AG, Gent M, Laupacis A, Latour Y, Gunstensen J, Basile F, et al. A comparison of aspirin with
placebo in patients treated with warfarin after heart-valve replacement. N Engl J Med. 1993;329:524-9.
8. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin
and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk.
The Medical Research Council's General Practice Research Framework. Lancet. 1998;351:233-41.
9. Kaplan-Machlis B, Klostermeyer BS. The cyclooxygenase-2 inhibitors: safety and effectiveness. Ann
Pharmacother. 1999;33:979-88.
10. Shorr RI, Ray WA, Daugherty JR, Griffin MR. Concurrent use of nonsteroidal anti-inflammatory
drugs and oral anticoagulants places elderly persons at high risk for hemorrhagic peptic ulcer
disease. Arch Intern Med. 1993;153:1665-70.
11. Lomaestro BM, Bailie GR. Quinolonecation interactions: a review. Drug Intell Clin Pharm.
1991;25:1249-58.
12. Anastasio GD, Cornell KO, Menscer DM. Drug interactions: keeping it straight. Am Fam Physician.
1997;56:883-8 [Published errata in Am Fam Physician 1997;56:1728–9 and 1997;56:2192].
13. Ament PW, Paterson A. Drug interactions with the nonsedating antihistamines. Am Fam Physician.
1997;56:223-31.
14. Wagner JC. Rifampinphenytoin drug interaction. Drug Intell Clin Pharm. 1984;18:497.
15. Helms SE, Bredle DL, Zajic J, Jarjoura D, Brodell RT, Krishnarao I. Oral contraceptive failure rates
and oral antibiotics. J Am Acad Dermatol. 1997;36(5 pt 1):705-10.
16. Fleischer AB, Resnick SD. The effect of antibiotics on the efficacy of oral contraceptives. A
controversy revisited. Arch Dermatol. 1989;125:1562-4.
17. Physicians' desk reference. 53rd ed. Montvale, N.J.: Medical Economics, 1999.
18. Sildenafil: an oral drug for impotence. Med Lett Drugs Ther. 1998;40:51-2.
19. Kirk JK, Dupuis RE. Approaches to the treatment of hyperlipidemia in the solid organ transplant
recipient. Ann Pharmacother. 1995;29:879-91.
20. Kirk JK, Lightfoot SM, Conner SL. Some clinically important drug interactions. Pharm Times. July
1998:79-91.
21. Reaven P, Witzum JL. Lovastatin, nicotinic acid, and rhabdomyolysis [Letter]. Ann Intern Med.
1988;109:597-8.
22. Ahmad S. Lovastatin. Warfarin interaction. Arch Intern Med. 1990;150:2407.
23. Vanderhoff BT, Miller KE. Major depression: assessing the role of new antidepressants. Am Fam
Physician. 1997;55:249-54.
24. Preskorn SH, Beber JH, Faul JC, Hirschfeld RM. Serious adverse effects of combining fluoxetine
and tricyclic antidepressants [Letter]. Am J Psychiatry. 1990;147:532.
25. Suchowersky O, deVries JD. Interaction of fluoxetine and selegiline [Letter]. Can J Psychiatry.
1990;35:571-2.
26. Feighner JP, Boyer WF, Tyler DL, Neborsky RJ. Adverse consequences of fluoxetine-MAOI
combination therapy. J Clin Psychiatry. 1990;51:222-5.
27. Mason BJ, Blackburn KH. Possible serotonin syndrome associated with tramadol and sertraline
coadministration. Ann Pharmacother. 1997;31:175-7.
28. Gordon JB. SSRIs and St. John's wort: possible toxicity?. Am Fam Physician. 1988;57:950.
29. Joffe RT, Sokolov ST. Co-administration of fluoxetine and sumatriptan: the Canadian experience.
Acta Psychiatr Scand. 1997;95:551-2.
30. Gardner DM, Lynd LD. Sumatriptan contraindications and the serotonin syndrome. Ann
Pharmacother. 1998;32:33-8.
31. Blier P, Bergeron R. The safety of concomitant use of sumatriptan and antidepressant treatments.
J Clin Psychopharmacol. 1995;15:106-9.
32. New “triptans” and other drugs for migraine. Med Lett Drugs Ther. 1998;40:97-100.
Copyright © 2000 by the American Academy of Family Physicians.
This content is owned by the AAFP. A person viewing it online may make one printout of the material
and may use that printout only for his or her personal, non-commercial reference. This material may
not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium,
whether now known or later invented, except as authorized in writing by the AAFP. See permissions
(https://www.aafp.org/about/this-site/permissions.html) for copyright questions and/or
permission requests.

Clinically Significant Drug Interactions - AAFP

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Clinically Significant Drug Interactions - AAFP

Uploaded by

Copyright:

Available Formats

7/12/23, 12:26 PM Clinically Significant Drug Interactions | AAFP

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

Overview of Selected Serious Drug Interactions

Time to Recommendations and

Warfarin (Coumadin) plus

Use lowest possible

Warfarin plus acetylsalicylic Increased bleeding, Limit aspirin dosage to 100 mg

Avoid concomitant use if

Fluoroquinolone plus Decreased

Phenytoin (Dilantin) plus Generally

Phenobarbital plus Generally Clinical significance has not

Time to Recommendations and

Generally Clinical significance has not

Generally Clinical significance has not

Lithium plus NSAID or Increased lithium Decrease lithium dosage by

Avoid if possible. If combination

Avoid if possible. If combination

Have the patient take an oral

Cisapride (Propulsid) plus Prolongation of QT Generally Avoid. Consider whether

Time to Recommendations and

Cisapride plus class IA or

Sildenafil plus cimetidine,

HMG-CoA reductase inhibitor

Lovastatin (Mevacor) plus Increased effect of

Monitor for anticholinergic

SSRI plus selegiline (Eldepryl)

Increased potential Monitor the patient for signs

SSRI plus naratriptan Serotonin syndrome Possibly Avoid if possible. If combination

Time to Recommendations and

Recent information suggests that the warfarin-acetaminophen interaction may be clinically

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

Fluoroquinolone antibiotics are useful in the management of infections caused by a variety of

Common Products Containing Divalent or Trivalent Cations

Aluminum Alu-Cap, AlternaGel, Amphojel, Basaljel

Aluminum and magnesium

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

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

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

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

Cytochrome P450 3A4 Cimetidine (Tagamet) Cisapride (Propulsid)

Clarithromycin (Biaxin) Erythromycin

Pathway Inhibitors Substrates

If coadministration is necessary, the dosage of lithium should be reduced by 50 percent when a

The failure of oral contraception may be suggested by breakthrough bleeding. A reasonable

3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors

hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase in the liver, which is the main site of

Selective Serotonin Reuptake Inhibitors

NONSELECTIVE MONOAMINE OXIDASE INHIBITORS

ST. JOHN'S WORT

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

Sources of Information on Drug Interactions

Selected Sources of Information on Drug Interactions

Clinical Pharmacology (CD-ROM, Internet)

Gold Standard Multimedia

320 W. Kennedy Blvd., Suite 400

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

E-mail: sales@gsm.com (mailto:sales@gsm.com)

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