bulb.pngClinically Important, Common Drug-Drug Interactions (DDIs)

 

A clinically relevant Drug-Drug Interaction (DDI) occurs when the effectiveness or toxicity of one medication is altered by the administration of another medicine or a substance that is administered for medical purposes (to be distinguished from drug-food interactions). Adverse consequences of DDIs may result from either diminished therapeutic effect or toxicity. Among the various types of medical errors, the occurrence of adverse DDIs is one that is usually preventable. It is therefore essential that health professionals be able to evaluate the potential for DDIs and, when detected, to determine appropriate prevention or management strategies.

The potential for clinically important DDIs can often be predicted based on the drug properties, method of drug administration, and patient-specific parameters.1Consequently, adverse outcomes resulting from DDIs can be prevented by making patient- and situation-specific assessments and, if appropriate, avoiding concomitant administration by implementing alternative therapeutic strategies, or taking precautionary measures such as dosage adjustments and increased monitoring.

The table below describes potential management strategies for 16 DDIs. It is intended to serve as an educational tool and is not intended to be a guide for medical practice. The table lists the effect (e.g., pharmacokinetic, pharmacokinetic, clinical) and mechanism of the potential DDIs in addition to the propensity for related drugs to interact and options for clinical management. Click on a object-precipitant interacting drug pair to expand the table for relevant information on the interaction.

 

Amiodarone (Cordarone®) and Quinolones

Object drug
Amiodarone (Cordarone®)
Precipitant Drug

Levofloxacin (Levaquin®)

Gemifloxacin (Factive®)

Moxifloxacin (Avelox®)

Ofloxacin (Floxin®)

Ciprofloxacin (Cipro®)

Effect

Increased risk of TdP and/or QTc prolongation on ECG

Mechanism

Concomitant blockade of cardiac potassium channels

Related Drugs

·Azithromycin (Zithromax®), clarithromycin (Biaxin®), erythromycin (E-Mycin®), and telithromycin (Ketek®) also have a possible risk of TDP and/or QTc prolongation on ECG

Options

Usually Avoid

·Consider Alternatives: Alternative antimicrobials include penicillins, and cephalosporins. See www.azcert.org for QT drug lists by risk group

Carbamazepine (Tegretol®) and Macrolides

Object drug
Carbamazepine (Tegretol®)
Precipitant Drug

Clarithromycin (Biaxin®)

Erythromycin (E-Mycin®)

Telithromycin (Ketek®)

Effect

Increased carbamazepine concentrations and risk of carbamazepine toxicity

Mechanism

Inhibition of carbamazepine metabolism by CYP3A4

Related Drugs

·Azithromycin (Zithromax®) does not appear to inhibit CYP3A4

Options

Take Precautions

·Consider Alternatives: Consider alternative antimicrobials (e.g., azithromycin, quinolones, 2nd/3rd generation cephalosporins, penicillin)

·Monitor: If alternatives are not appropriate, monitor carbamazepine concentrations (e.g., within 24 hours) and consider temporary downward adjustment of the carbamazepine dosage (e.g., by 30-50%). Warn patients about symptoms of carbamazepine toxicity (e.g., nausea, vomiting, dizziness, drowsiness, headache, diplopia, confusion). Also monitor for altered carbamazepine effect when clarithromycin or erythromycin are changed in dosage or discontinued.If carbamazepine is started in the presence of one of these agents, consider conservative initial carbamazepine dosing.

Digoxin (Lanoxin®) and Macrolides

Object drug
Digoxin (Lanoxin®)
Precipitant Drug

Clarithromycin (Biaxin®)
Erythromycin (E-Mycin®)

Effect

Increased digoxin concentrations and risk of digoxin toxicity

Mechanism

Inhibition of digoxin transport by P-glycoprotein resulting in reduced renal and nonrenal elimination of digoxin

Related Drugs

Isolated reports of digoxin toxicity have been associated with azithromycin (Zithromax®) therapy

Options

Take Precautions

·Consider Alternatives: Consider alternative antimicrobials that do not inhibit P-glycoprotein (e.g., 2nd/3rd generation cephalosporins, penicillin, quinolones)

·Monitor: If alternatives are not appropriate, evaluate patients for evidence of digoxin toxicity (e.g., nausea, malaise, fatigue visual, changes, headache, arrhythmias), with downward digoxin dosage adjustments as needed. Also monitor for altered digoxin effect when clarithromycin or erythromycin are changed in dosage or discontinued. If digoxin is started in the presence of one of these agents, consider conservative initial digoxin dosing.

Digoxin (Lanoxin®) and Azole Antifungals

Object drug
Digoxin (Lanoxin®)
Precipitant Drug

Itraconazole (Sporanox®)

Ketoconazole (Nizoral®)

Posaconazole (Noxafil®)

Effect

Increased digoxin concentrations and risk of digoxin toxicity

Mechanism

Inhibition of digoxin transport by P-glycoprotein resulting in reduced renal and nonrenal elimination of digoxin

Related Drugs

·Voriconazole (Vfend®) and the non-azole antifungal, terbinafine (Lamisil®), do not appear to inhibit P-glycoprotein

·Data are lacking regarding fluconazole

Options

Take Precautions

·Consider Alternatives: Consider alternative antifungal agents (e.g., voriconazole or terbinafine)

·Monitor: If alternatives are not appropriate, monitor patients closely for evidence of digoxin toxicity (e.g., nausea, malaise, fatigue visual, changes, headache, arrhythmias), with downward digoxin dosage adjustments as necessary. Also monitor for altered digoxin effect when itraconazole, ketoconazole, or posaconazole are changed in dosage or discontinued. If digoxin is started in the presence of one of these agents, consider conservative initial digoxin dosing.

Simvastatin and Amiodarone (Cordarone®)

Object drug
Simvastatin
Precipitant Drug

Amiodarone (Cordarone®)

Effect

Increased simvastatin/ lovastatin concentrations and risk of myopathy/ rhabdomyolysis

Mechanism

Inhibition of metabolism of simvastatin/ lovastatin by CYP3A4

Related Drugs

·Atorvastatin (Lipitor®) undergoes less metabolism by CYP3A4; however cases of myopathy with CYP3A4 inhibitors have been reported

·Fluvastatin (Lescol®), rosuvastatin (Crestor®), and pravastatin (Pravachol®) arenot metabolized by CYP3A4

Options

Usually Avoid

·Consider Alternatives: Preferable statin alternatives include fluvastatin, rosuvastatin, or pravastatin. Predisposing risk factors for rhabdomyolysis include advanced age (>65 years), uncontrolled hypothyroidism, and renal impairment.

·Monitor: If alternative statins are not appropriate, monitor the patient for evidence of myopathy (muscle pain or weakness) and myoglobinuria (dark urine). The simvastatin dose should not exceed 20 mg/day in combination with amiodarone.

Statins and Azole Antifungals

Object drug
Statins
Precipitant Drug

Itraconazole (Sporanox®)

Ketoconazole (Nizoral®)

Posaconazole (Noxafil®)

Voriconazole (Vfend®)

Fluconazole (Diflucan®)

Effect

Increased simvastatin/ lovastatin concentrations and risk of myopathy/ rhabdomyolysis

Mechanism

Inhibition of simvastatin/ lovastatin metabolism by CYP3A4

Related Drugs

Antifungal Agents

·Terbinafine (Lamisil®) does not inhibit CYP3A4

·Ciclopirox nail lacquer (Penlac®) is not appreciably absorbed

Statins

·Atorvastatin (Lipitor®) undergoes less metabolism by CYP3A4 but cases of myopathy with CYP3A4 inhibitors reported

·Fluvastatin (Lescol®), rosuvastatin (Crestor®), and pravastatin (Pravachol®) arenot metabolized by CYP3A4

Options

Usually Avoid

·Consider Alternative Antifungal Agents: Terbinafine or ciclopirox nail lacquer would be relatively safer antifungal agents.

·Consider Alternative Statins: For patients requiring long-term azole antifungal therapy, preferable statin alternatives include fluvastatin, rosuvastatin, or pravastatin.

·Temporarily Hold Statin Therapy: Temporarily holding the simvastatin/lovastatin during short-term (e.g., 2-week) azole antifungal therapy is a reasonable alternative for patients with stable cardiovascular disease.

·Monitor: If alternatives are not appropriate, the patient should be monitored for evidence of myopathy (muscle pain or weakness) and myoglobinuria (dark urine).

Tamoxifen (Nolvadex®) and Antidepressants

Object drug
Tamoxifen (Nolvadex®)
Precipitant Drug

Bupropion (Wellbutrin®)

Duloxetine (Cymbalta®)

Fluoxetine (Prozac®)

Paroxetine (Paxil®)

Effect

Decreased clinical effectiveness of tamoxifen (decreased disease-free survival); people with “normal” CYP2D6 activity (extensive metabolizers) would be at risk of this interaction

Mechanism

Inhibition of activation of tamoxifen (prodrug) to its major active metabolite by CYP2D6

Related Drugs

·Citalopram (Celexa®), desvenlafaxine (Pristiq®), escitalopram (Lexapro®), and sertraline (Zoloft®), are weak inhibitors of CYP2D6

·Fluvoxamine (Luvox®) and venlafaxine (Effexor®) do not significantly inhibit CYP2D6

Options

Take Precautions

·Consider Alternatives: Preferable antidepressant alternatives are citalopram, desvenlafaxine, escitalopram, fluvoxamine, sertraline, and venlafaxine.

Warfarin (Coumadin®) and Amiodarone (Cordarone®)

Object drug
Warfarin (Coumadin®)
Precipitant Drug

Amiodarone (Cordarone®)

Effect

Increased warfarin concentrations and bleeding risk

Mechanism

Inhibition of warfarin metabolism by CYP2C9

Related Drugs

·Not applicable

Options

Take Precautions

·Monitor:  Increase the frequency of INR monitoring when amiodarone is started, stopped, or changed in dosage. The maximal effect of the interaction can take 8-12 weeks. The warfarin dosage may need to be reduced by 30%-50% during concurrent therapy. For patients stabilized on amiodarone, begin warfarin therapy with conservative doses until response is established.

Warfarin (Coumadin®) and Azole Antifungals

Object drug
Warfarin (Coumadin®)
Precipitant Drug

Fluconazole (Diflucan®)

Miconazole (Monistat®)

Voriconazole (Vfend®)

Effect

Increased warfarin concentrations and bleeding risk

Mechanism

Inhibition of warfarin metabolism by CYP2C9

Related Drugs

·Itraconazole (Sporanox®), ketoconazole (Nizoral®), posaconazole (Noxafil®), terbinafine (Lamisil®) do not appear to inhibit CYP2C9

Options

Usually Avoid

·Consider Alternatives: Itraconazole, ketoconazole, posaconazole, and terbinafine are preferable alternatives.

·Monitor: Carefully monitor for an altered warfarin response if an interacting azole antifungal is started, stopped, or changed in dosage. A change in the warfarin dosage may be necessary. For patients already receiving one of the precipitant drugs, begin warfarin therapy with conservative doses until response is established.

Warfarin (Coumadin®) and Carbamazepine (Tegretol®)

Object drug
Warfarin (Coumadin®)
Precipitant Drug

Carbamazepine (Tegretol®)

Effect

Decreased warfarin concentrations and warfarin effects

Mechanism

Induction of warfarin metabolism

Related Drugs

·Other anticonvulsant enzyme inducers that can also reduce the anticoagulant effect of warfarin include barbiturates, oxcarbazepine (Trileptal®), phenytoin (Dilantin®), and primidone (Mysoline®)

Options

Take Precautions

Monitor: If concurrent use is necessary, monitor for altered warfarin response if the inducer is started, stopped, or changed in dosage. Enzyme induction is often gradual and several weeks of more frequent monitoring is recommended. For patients already receiving carbamazepine, begin warfarin therapy with conservative doses until response is established.

Warfarin (Coumadin®) and Fibrates

Object drug
Warfarin (Coumadin®)
Precipitant Drug

Gemfibrozil (Lopid®)

Fenofibrate (Tricor®)

Effect

Increased warfarin effect and bleeding risk

Mechanism

Not established

Related Drugs

·See warfarin and statins

·An extended-release niacin product (Niaspan®) is not known to interact with warfarin

·Gemfibrozil (Lopid®) and fenofibrate (Tricor®) inhibit CYP2C9 and may increase bleeding risk

·Cholestyramine (Questran®) and colestipol (Colestid®) may reduce the effect of warfarin

Options

Usually Avoid

·Consider Alternatives: Atorvastatin and pravastatin appear to be safer alteratives. Extended-release niacin is another alternative.

·Monitor:  If alternatives are not appropriate, carefully monitor the INR if a fibrate is started, stopped, or changed in dosage and adjust the warfarin dose accordingly. If warfarin is started in a patient receiving a fibrate, conservative doses of warfarin should be used until response is established

Warfarin (Coumadin®) and NSAIDs

Object drug
Warfarin (Coumadin®)
Precipitant Drug

NSAIDs

Effect

Additive risk of bleeding

Mechanism

·Antiplatelet effects and GI erosion associated with NSAIDs and the anticoagulant effect of warfarin.

·Some individual NSAIDs may also alter the pharmacokinetics of warfarin

Related Drugs

·Opioid analgesics are not known to interact with warfarin

·Acetaminophen (Tylenol®) may alter the warfarin response but the effect is relatively small.

·Antiplatelet therapy with aspirin primarily increases the risk of minor bleeding

·Non-acetylated salicylates (e.g., salsalate [Disalcid]) may be safer than traditional NSAIDs

·COX-2 inhibitors do not affect platelet function and probably cause less GI erosion but no evidence of decreased GI bleeding risk

Options

Usually Avoid

·Consider Alternatives: A non-NSAID alternative such as acetaminophen or opioid analgesics is preferred. To be cautious, limit the acetaminophen dose to 2 g/day for no more than 7 days.  INR should be monitored closely when acetaminophen exceeds 2 g/day or chronic use >7 days occurs.

·Monitor: If any NSAID is used with warfarin, monitor carefully for evidence of bleeding, especially from the GI tract.

Warfarin (Coumadin®) and Statins

Object drug
Warfarin (Coumadin®)
Precipitant Drug

Fluvastatin (Lescol®)

Lovastatin (Mevacor®)

Rosuvastatin (Crestor®)

Simvastatin (Zocor®)

Effect

Increased warfarin concentrations and bleeding risk

Mechanism

Inhibition of warfarin metabolism by CYP2C9 is proposed

Related Drugs

·See warfarin and fibrates

·Atorvastatin (Lipitor®) and pravastatin (Pravachol®) are not known to interact with warfarin

Options

Take Precautions

·Consider Alternatives: Atorvastatin and pravastatin appear to be safer alteratives

·Monitor:  If alternatives are not appropriate, carefully monitor the INR if these agents are started, stopped, or changed in dosage and adjust the warfarin dose accordingly. If warfarin is started in a patient receiving these agents conservative doses of warfarin should be used until response is established.

Warfarin (Coumadin®) and Antibiotics

Object drug
Warfarin (Coumadin®)
Precipitant Drug

Sulfamethoxazole/trimethoprim (Bactrim®)

Metronidazole (Flagyl®)

Effect

Increased warfarin concentrations and bleeding risk

Mechanism

Inhibition of warfarin metabolism by CYP2C9

Related Drugs

·Oral penicillin, amoxicillin, ampicillin, and oral cephalosporins and penicillins havenot been shown to interact with warfarin

·Quinolones and macrolides have been reported to increase the anticoagulant effects of warfarin

Options

Usually Avoid

·Consider Alternatives: Oral penicillins and cephalosporins are preferred alternatives. Quinolones and macrolides may be relatively safer to use in combination with warfarin than sulfamethoxazole or metronidazole.

·Monitor:  When alternatives are not appropriate, carefully monitor the INR and for signs of bleeding. The warfarin dosage may need to be temporarily reduced. If warfarin is started in a patient receiving these agents conservative doses of warfarin should be used until response is established.  Also monitor for decreased anticoagulant effect after antibiotic therapy is discontinued.

·Note:Nearly all antibiotics have been reported in isolated cases to interact with warfarin; caution should be used when adding any antibiotic to a patient on warfarin therapy.

Warfarin (Coumadin®) and Thyroid Hormones

Object drug
Warfarin (Coumadin®)
Precipitant Drug

Levothyroxine (Synthroid®)

Liothyronine (Cytomel®)

Liotrix (Thyrolar®)

Thyroid USP (Armour Thyroid®)

Effect

Increased bleeding risk

Mechanism

An accelerated depletion of vitamin K-dependent clotting factors as a result of thyroid hormone administration has been proposed

Related Drugs

·Not applicable

Options

Take Precautions

·Monitor:  For patients on a therapeutic dose of warfarin, more frequent INR monitoring is required (e.g., day 4, day 7, and weekly thereafter or as clinically indicated) if thyroid hormone therapy is started. In such cases, adownward adjustment of the warfarin dosage will often be needed to avoid excessive anticoagulation and bleeding. The risk is probably minimal if warfarin therapy is started in a euthyroid patient stabilized on thyroid replacement therapy. However, conservative doses of warfarin should be used until response is established if warfarin is started in a patient receiving these agents.


info.pngNotes About the Table:


This Table is for educational purposes only and is not intended to be a solitary guide for medical decisions. It was posted on May 21, 2010 and, to the best of our knowledge, is accurate and current as of that date. However, previous or future sources of information may be relevant and the reader should consider the Table in the context of other information that they have available to them. The authors will make their best efforts to maintain the accuracy of the Table but the reader should assume that additional information may have become available after May 21, 2010 that affects the accuracy of the information in the Table. 
The DDIs in the table are arranged alphabetically by object drug (the drug whose action is altered by the interaction) and precipitant drug (the drug causing the altered action of the other drug). Drugs are listed with up to 2 common brand names. There are several brand names for some of the common drugs, such as erythromycin. It is also important to consider the active drugs that are in combination products such as Simcor®, which contains niacin and simvastatin.

The interactions were selected based on previous research,2-4 with an emphasis on cardiovascular medications (e.g., warfarin), and with consideration of more recent evidence on DDIs. References for the interactions included in the table are provided upon request. Possible options typically include using an alternative, non-interacting object or precipitant drug or increased monitoring of the patient's response. These options, listed as "avoid," "usually avoid," or "take precautions," are loosely adapted from the Operational Classification of Drug Interactions.5 Although using non-interacting alternatives is frequently preferred in order to avoid adverse drug interactions, monitoring is often a reasonable option because very few drug combinations are absolutely contraindicated. Determining the most appropriate alternative medication requires careful consideration of patient-specific risks and benefits. This table focuses specifically on DDIs although drug-disease, drug-food, and drug-herbal interactions are also important considerations.


ref.pngReferences



1. Dresser GK, Bailey DG. A basic conceptual and practical overview of interactions with highly prescribed drugs. Can J Clin Pharmacol. Winter 2002;9(4):191-198.
2. Malone DC, Abarca J, Hansten PD, et al. Identification of serious drug-drug interactions: results of the partnership to prevent drug-drug interactions. J Am Pharm Assoc (2003). Mar-Apr 2004;44(2):142-151.
3. Malone DC, Hutchins DS, Haupert H, et al. Assessment of potential drug-drug interactions with a prescription claims database. Am J Health Syst Pharm. Oct 1 2005;62(19):1983-1991.
4. Murphy JE, Malone DC, Olson BM, Grizzle AJ, Armstrong EP, Skrepnek GH. Development of computerized alerts with management strategies for 25 serious drug-drug interactions. Am J Health Syst Pharm. Jan 1 2009;66(1):38-44.
5. Hansten PD, Horn JR, Hazlet TK. ORCA: OpeRational ClassificAtion of drug interactions. J Am Pharm Assoc (Wash). Mar-Apr 2001;41(2):161-165.