Drug-Drug Interaction Rules

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These drug interactions are based on a set released by the Beth-Israel Deaconess Hospital, and are used here with permission. (1) (2). Several of the interactions refer to drug classes, which are defined on the drug classes page.

Generic Drug Name or Category Interacts With Severity Text
Significant Diuretics and ACE inhibitors used together may cause hypotension. The combination of ACE inhibitors and potassium-sparing diuretics may cause significant hyperkalemia. This effect is particularly significant in patients with renal insufficiency.
ACE INHIBITORS (class) POTASSIUM (class) Critical ACE inhibitors may decrease aldosterone causing hyperkalemia. When ACE inhibitors are coadministered with potassium-containing products, the risk of hyperkalemia is increased.
ALLOPURINOL AZATHIOPRINE Critical Allopurinol inhibits the metabolism of oral azathioprine, increasing serum azathioprine levels. Concomitant use can cause marked bone marrow suppression. If these drugs must be used together, azathioprine oral doses should be reduced to 25-30% of the usual dosage and the patient should be monitored closely for toxicity. Intravenous azathioprine does not appear to be affected by allopurinol.
ALLOPURINOL THEOPHYLLINE Significant Concurrent use of allopurinol and theophylline may result in theophylline toxicity (nausea, vomiting, palpitations, seizures). This interaction is more likely to occur with daily allopurinol doses of 600 mg or more.
AMIODARONE CYCLOSPORINE Significant Reports suggest that amiodarone may interfere with the clearance of cyclosporine. The risk of cyclosporine toxicity may increase.
AMIODARONE DIGOXIN Critical Amiodarone may increase serum digoxin concentrations by up to 100%. Amiodarone may increase intestinal transit time, reduce renal clearance of digoxin, inhibit hepatic metabolism of digoxin, displace digoxin from protein-binding sites, and, in some cases, induce hypothyroidism. Empirical reduction or discontinuation of digoxin should be considered. Management also consists of monitoring clinical response or checking serum digoxin levels if toxicity is suspected.
AMIODARONE WARFARIN Critical Amiodarone may inhibit hepatic metabolism of warfarin. A 30% to 50% reduction in warfarin dosage is recommended, as is frequent monitoring of INR.
AZOLE ANTIFUNGALS (class) CYCLOSPORINE Significant Some azoles, particulary Ketoconazole and Itraconazole, may inhibit the hepatic metabolism of cyclosporine. Serum cyclosporine concentrations and nephrotoxicity may increase fourfold. Cyclosporine dosage reductions of 80% have been necessary in some patients.
AZOLE ANTIFUNGALS (class) HMG COA REDUCTASE INHIBITORS (class) Significant The use of HMG-CoA reductase inhibitors during azole therapy may increase CK, AST, ALT, and LDH serum levels.
BETA BLOCKERS (class) AMIODARONE Critical The combination of these drugs may cause severe bradycardia, cardiac

arrest, or ventricular fibrillation. Use extreme caution using these drugs

Significant The concomitant use of calcium channel blockers and beta-blockers can occasionally cause AV heart block and left-ventricular dysfunction.
RITONAVIR Significant Ritonavir may significantly increase levels of calcium channel

blockers. Be careful using this combination of drugs, and monitor for

CIMETIDINE WARFARIN Critical Cimetidine inhibits the hepatic metabolism of warfarin, and may

increase its anticoagulant effect over a one to two week period. If given together, the INR should be monitored, and the lowest possible dose of cimetidine should be used.

Another histamine-2 antagonist may be used with less risk of interaction.
CLOPIDOGREL BISULFATE NSAIDs (class) Significant The coadministration of nonsteroidal antiinflammatory drugs (NSAIDs)

and clopidogrel should be undertaken with extreme caution. The coadministration of clopidogrel with naproxen resulted in occult gastrointestinal blood loss in healthy volunteers. The mechanism may be due to additive platelet inhibition. Additionally, diclofenac, ibuprofen, naproxen, mefenamic acid, indomethacin and piroxicam are substrates for the cytochrome P450 isoenzyme 2C9 inhibited by clopidogrel. The clinical magnitude of this interaction is not known. The clinician should observe the patient for increased NSAID toxicity if these agents are co-administered with

CYCLOSPORINE MACROLIDES (class) Significant Some macrolide antibiotics may significantly increase cyclosporine

serum concentrations, possibly by inhibiting hepatic metabolism of cyclosporine, resulting in nephrotoxicity. Appropriate monitoring of cyclosporine serum concentrations

during co-administration is recommended.
CYCLOSPORINE FOSCARNET SODIUM Significant Foscarnet and cyclosporine used together may increase the risk of

nephrotoxicity and renal failure. If these agents are used concomitantly, consider close

observation of renal function and discontinue foscarnet if needed.
CYCLOSPORINE GEMFIBROZIL Significant Cyclosporine used concurrently with high doses of Gemfibrozil can cause rhabdomyolysis.
CYCLOSPORINE HMG COA REDUCTASE INHIBITORS (class) Significant Cyclosporine used concurrently with moderate to high doses of HMG CoA reductase inhibitors can cause rhabdomyolysis.
Critical Verapamil and Diltiazem may inhibit the hepatic metabolism of

cyclosporine causing increased trough and steady state levels, and the risk of nephrotoxicity. Cyclosporine levels should be monitored, and dosage should be adjusted as

DAPSONE SAQUINAVIR Critical Saquinavir may competitively inhibit the metabolism of drugs that are

substrates of the cytochrome P-450 (3A4) microsomal enzymatic pathway. Plasma levels of these drugs may be elevated. The patient should be monitored closely for toxicities and

lower dosages of these drugs may be necessary
DIGOXIN MACROLIDES (class) Critical Theoretically this interaction might occur with other macrolides.

Patients should be closely monitored for evidence of digoxin toxicity if macrolide

antibiotics and digoxin must be coadministered.
DIGOXIN ITRACONAZOLE Significant The addition of itraconazole to patients stabilized on digoxin has

resulted in two to fourfold increases in serum digoxin concentrations and digoxin toxicity. The mechanism is unknown. The onset of toxicity generally occurs within 9 to 13

days after the start of itraconazole therapy.
Critical Quinidine significantly increases serum digoxin levels in more than

90% of patients. The mechanism is related to reduced renal and biliary clearance, and reduced volume of digoxin distribution. Empiric reduction in digoxin dosing may be considered at the initiation of combination therapy. Modifications in dosage should be

DIGOXIN TETRACYCLINE Critical Tetracyclines may increase serum levels of orally administered digoxin

in about 10% of the population. The mechanism may be related to changes in intestinal flora that alter the absorption of digoxin. If these drugs must be used together, the

patient should be closely monitored for digoxin toxicity.
DIGOXIN VERAPAMIL Critical Verapamil increases digoxin levels significantly in most patients.

This important and possibly severe interaction is related to several complex mechanisms. Digoxin and verapamil have additive effects in slowing AV conduction. Verapamil also decreases the elimination of digoxin. If verapamil and digoxin are used together to control a supraventricular tachyarrhythmia, the dosage of each drug may have to be

EFAVIRENZ CLARITHROMYCIN Significant Efavirenz increases the metabolism of clarithromycin. No dosage

adjustment is recommended when these drugs are co-administered, but a rash occurs in 46% of patients administered clarithromycin and efavirenz concomitantly. Alternative therapy

such as azithromycin might be considered.
EFAVIRENZ INDINAVIR SULFATE Significant Coadministration of efavirenz and indinavir causes a decreased

indinavir level. The mechanism of this interaction is hepatic enzyme induction of CYP3A4 by efavirenz. The dosage of indinavir should be increased from 800 mg every 8 hours to

1000 mg every 8 hours when these drugs are administered concomitantly.


HEPARIN Critical Dalteparin may increase the risk of bleeding from heparin. The

mechanism is additive inhibition of thrombin and factor Xa. If these agents must be used together, extreme caution is advised, and the patient should be monitored for signs of bleeding. Other low-molecular-weight heparins (LMWHs) may interact with heparin in a

similar manner.
Significant Ketorolac is contraindicated in patients concurrently receiving

aspirin or NSAIDs because of the cumulative risks of inducing serious NSAID-related

adverse events (peptic ulcers, gastrointestinal bleeding and/or perforation).
Significant When lovastatin and some macrolide antibiotics (erythromycin) have

been used concomitantly in severely ill patients, severe myopathy and rhabdomyolysis have resulted. The mechanism appears to be inhibition of lovastatin metabolism by the macrolide. Patients should be instructed to report symptoms of muscle pain, weakness, or tenderness. If symptoms occur, creatine kinase should be measured. If creatine kinase is elevated, the drugs should be discontinued. A similar reaction may occur with other

HMG-CoA reductase inhibitors.
FENTANYL RITONAVIR Critical Ritonavir may significantly increase fentanyl plasma levels. Patients should be closely observed for toxicity if these drugs are used together.
Significant Gemfibrozil and lovastatin used together can cause severe myopathy and

rhabdomyolysis. Combined use of gemfibrozil or clofibrate with other HMG-CoA reductase inhibitors may increase the risk of this side effect as well. If this combination must be used, the patient should be instructed to report symptoms of muscular pain, weakness, or

tenderness. If creatine kinase is elevated, the drugs should be discontinued.
MEPERIDINE Critical Immediate onset of excitement, sweating, rigidity, and hypertension

can occur when monoamine oxidase inhibitors (MAOIs) are used concurrently with meperidine. Death has been reported. Similar effects have been reported with propoxyphene and fentanyl, but not with other analgesics. The combination of narcotic analgesics and MAOIs should be avoided if possible. An MAOI plus meperidine should not be used under any

Significant Monoamine oxidase inhibitors (MAOIs) stop the catalyst enzyme

catechol-O-methyltransferase (COMT) from metabolizing levodopa to 3-O-methyldopa in the

periphery, and in the brain.
Critical Severe and sometimes fatal reactions involving elevations in blood

pressure, hyperthermia, rigidity, and autonomic instability have occurred in patients taking SSRIs in combination with monoamine oxidase inhibitors (MAOIs). A minimum period

of two weeks should separate use of these drugs.
Significant Sympathomimetic amines used with monoamine oxidase inhibitors may precipitate severe hypertensive reactions
MAO INHIBITORS (class) TRICYCLIC ANTIDEPRESSANTS (class) Significant Monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants

when used together may cause hyperpyretic crises, disseminated intravascular coagulation, convulsions, and death. The mechanism is unknown. Although these agents have been used together safely in many patients, some investigators recommend that tricyclic

antidepressants not be used within two weeks of MAOIs.
MAO INHIBITORS (class) VENLAFAXINE Critical Monoamine oxidase inhibitors (MAOIs) used together with

anti-depressants may cause severe, even fatal, reactions. The reactions reported with the newer antidepressants include hyperthermia, rigidity, myoclonus, autonomic instability, and mental status changes that range from delirium to coma. In general, MAOIs and

venlafaxine or other SSRIs should be separated by 2 weeks.
Significant Narcotics and benzodiazepines used together can cause excessive

respiratory and CNS depression. The mechanism may be related in part to inhibition of hepatic oxidation of the benzodiazepine. Alprazolam has been most implicated in this interaction. Such interactions are more likely to occur in the benzodiazepine and

narcotic "naive" patient.
Significant Because nevirapine may induce the hepatic P450 cytochrome system,

reductions in plasma concentrations of protease inhibitors theoretically may occur. The manufacturer recommends that, until clinical studies provide information on dosage adjustments, protease inhibitors should not be administered concomitantly with

Significant Lovastatin and niacin used together may cause severe myopathy and

rhabdomyolysis. Although this reaction has not been reported with concomitant use of pravastatin and niacin, patients should be instructed to report symptoms of muscle pain, weakness, or tenderness. If creatine kinase is elevated, the drugs should be

Significant Aminoglycoside antibiotics may potentiate the neuromuscular blockade

caused by non-depolarizing muscle relaxants. The mechanism is presynaptic acetylcholine release and reduction of postsynaptic sensitivity to acetylcholine. These combinations

should be avoided if possible.
POLYMYXIN Significant Polymyxin B may prolong apnea and respiratory paralysis after use of

neuromuscular blocking agents. The mechanism may be related to decreased intracellular potassium or decreased ionized serum calcium. Intravenous calcium administration may be

helpful in reversing the paralysis.
Significant There may be an increased risk of CNS or respiratory depression when this combination of drugs is used.
PHENYTOIN CYCLOSPORINE Significant Phenytoin may significantly reduce cyclosporine serum concentrations.

The mechanism may be inhibition of cyclosporine absorption or induction of hepatic metabolism or both. This interaction may occur with ethotoin, fosphenytoin, and mephenytoin as well. Cyclosporine levels should be closely monitored during concomitant

PHENYTOIN RITONAVIR Significant Dilantin can accelerate the metabolism of ritonavir thus reducing its

plasma concentration. Ritonavir can raise or lower dilantin levels. Use caution if these

drugs must be used together.
Critical The combination of potassium-sparing diuretics and potassium

preparations may result in hyperkalemia. These agents should not be used together unless the patient has documented hypokalemia while taking either agent alone. If this combination is used, the patient should be given dietary counseling and monitored very

closely for hyperkalemia.
PROCAINAMIDE BETA BLOCKERS (class) Significant Some beta-blockers may decrease the clearance and increase the serum

level of procainamide. Data are available for metoprolol and propranolol

QUINIDINE AMIODARONE Critical Amiodarone can increase quinidine concentrations inducing prolongation

of the QT interval. Quinidine dose may need to be reduced by 50% if amiodarone is

QUINIDINE VERAPAMIL Critical Verapamil may increase plasma quinidine concentrations. While these

drugs can be given together safely, significant adverse side effects can occur, especially in patients with hypertrophic or dilated cardiomyopathies and in patients on higher doses of either drug. If these drugs must be given together, lower doses of quinidine are needed to achieve a given plasma concentration and clinical response. Clinical and electrocardiographic monitoring for quinidine toxicity (such as hypotension,

arrhythmias, and AV block) is recommended.
RITONAVIR MEPERIDINE Significant Ritonavir may interfere with the metabolism of meperidine. Large

increases in serum meperidine concentrations may result. The concomitant use of these

agents is contraindicated by the manufacturer and should be avoided.
RITONAVIR METRONIDAZOLE Significant Ritonavir capsules and ritonavir oral solution contain alcohol, which

may cause a reaction when this drug is used with disulfiram or metronidazole.

Simultaneous use should be avoided.
RITONAVIR SAQUINAVIR Significant The plasma concentration of saquinavir mesylate (Invirase) is

increased markedly (29-fold) by ritonavir. The safety of their concurrent use has not been established. The newer form of saquinavir (Fortovase) is more bioavailable.

Therefore, this interaction is less relevant for saquinavir (Fortovase).
RITONAVIR WARFARIN Critical Ritonavir may cause large fluctuations in the serum concentrations of

warfarin. If ritonavir and warfarin must be used together, frequent monitoring of the INR

is strongly recommended.
SULFADIAZINE PHENYTOIN Critical Some sulfonamides inhibit the hepatic metabolism of phenytoin. Serum

phenytoin levels and risk of toxicity may be increased. Data are available for sulfadiazine and sulfamethizole. Management consists of monitoring the patient for signs and symptoms of phenytoin toxicity, checking serum levels, and decreasing phenytoin

dosage as necessary.
SULFAMETHOXAZOLE WARFARIN Significant Sulfonamides increase the level of warfarin-(S) isomer by an unknown

mechanism. Hypoprothrombinemic effect is enhanced. . Frequent monitoring of the INR is

TACROLIMUS MACROLIDES (class) Critical In vitro and in vivo data suggest that erythromycin may inhibit the

hepatic metabolism of tacrolimus. Data from two case reports suggest that concomitant use of erythromycin may result in elevated serum tacrolimus concentrations. If these drugs are used concomitantly, plasma tacrolimus concentrations should be carefully monitored,

with reductions in dosage to prevent nephrotoxicity.
THEOPHYLLINE CIPROFLOXACIN Critical Ciprofloxacin can significantly reduce the clearance of theophylline

by inhibition of hepatic metabolism. The interaction can result in theophylline toxicity, and may increase the risk of seizures, especially in the elderly. The patient should be monitored for theophylline toxicity and elevated serum levels while also taking

Critical Some macrolides (erythromycin and troleandomycin) inhibit theophylline

metabolism. During coadministration, serum theophylline levels and risk of theophylline toxicity are increased. Conversely, theophylline increases the renal clearance of erythromycin and decreases erythromycin concentrations. Monitoring of theophylline levels and efficacy is recommended when erythromycin is added to or discontinued from the patient's regimen. [Dirithromycin [?on formulary]appears to increase the plasma clearance of theophylline, and plasma theophylline concentrations can be decreased by approximately 26%. The dirithromycin-theophylline interaction is unlikely to be clinically significant enough to modify treatment and outcome.] The effects of azithromycin and clarithromycin on the pharmacokinetic disposition of theophylline are not known. Azithromycin, however, does not appear to interfere with theophylline levels and may be the macrolide of choice

for patients on theophylline therapy.
TOPIRAMATE PHENYTOIN Significant Topiramate administered with phenytoin may cause a 25% increase in

phenytoin plasma concentration, particularly in patients receiving phenytoin twice a day. Additionally, the concentration of topiramate decreased by 48%. Addition or withdrawal of hydantoins during therapy with topiramate may require a dose adjustment of topiramate

and/or the hydantoin.
TOPIRAMATE VALPROATE Significant Topiramate administered with valproic acid may lead to an 11% decrease

in valproic acid plasma concentration. Additionally, the concentration of topiramate decreased by 14%. The mechanism of action may be increased metabolism of both drugs. Addition or withdrawal of valproic acid during adjunctive therapy with topiramate may

require a dose adjustment of topiramate and/or valproic acid.


Critical These drugs may increase the effect of warfarin. The mechanism is

unknown. Close monitoring of the INR is recommended if these drugs must be used

Critical Risk of bleeding is increased.
Critical Some macrolide antibiotics may inhibit the hepatic metabolism of

warfarin resulting in an enhanced anticoagulant effect. Data are available for erythromycin and clarithromycin only. Close monitoring of the INR is recommended if a

macrolide antimicrobial and warfarin must be used together.
WARFARIN METRONIDAZOLE Critical Metronidazole may inhibit the metabolism of warfarin and increase its anticoagulant effect. The INR should be monitored closely.
WARFARIN PHENYTOIN Critical Warfarin can increase phenytoin half-life and serum concentrations.

The addition of phenytoin to warfarin therapy can increase the INR. The mechanism is not known. Serum phenytoin concentrations and INR should be monitored in patients receiving

this combination.
Significant Most fluoroquinolones can inhibit the metabolism of warfarin

increasing the INR. Patients on concomitant therapy should be monitored for elevations in INR. However, one study of sixteen volunteers reported a lack of interaction between

warfarin and levofloxacin.
WARFARIN QUINIDINE Critical Quinidine can induce hypoprothrombinemia, thus raising the INR and

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