Levofloxacin (Levaquin®)

Gemifloxacin (Factive®)

Moxifloxacin (Avelox®)

Ofloxacin (Floxin®)

Ciprofloxacin (Cipro®)

Increased risk of TdP and/or QTc prolongation on ECG

Concomitant blockade of cardiac potassium channels

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

Usually Avoid

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

Clarithromycin (Biaxin®)

Erythromycin (E-Mycin®)

Telithromycin (Ketek®)

Increased carbamazepine concentrations and risk of carbamazepine toxicity

Inhibition of carbamazepine metabolism by CYP3A4

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

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.

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

Increased digoxin concentrations and risk of digoxin toxicity

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

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

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.

Itraconazole (Sporanox®)

Ketoconazole (Nizoral®)

Posaconazole (Noxafil®)

Increased digoxin concentrations and risk of digoxin toxicity

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

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

·Data are lacking regarding fluconazole

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.

Amiodarone (Cordarone®)

Increased simvastatin/ lovastatin concentrations and risk of myopathy/ rhabdomyolysis

Inhibition of metabolism of simvastatin/ lovastatin by CYP3A4

·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

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.

Itraconazole (Sporanox®)

Ketoconazole (Nizoral®)

Posaconazole (Noxafil®)

Voriconazole (Vfend®)

Fluconazole (Diflucan®)

Increased simvastatin/ lovastatin concentrations and risk of myopathy/ rhabdomyolysis

Inhibition of simvastatin/ lovastatin metabolism by CYP3A4

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

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).

Bupropion (Wellbutrin®)

Duloxetine (Cymbalta®)

Fluoxetine (Prozac®)

Paroxetine (Paxil®)

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

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

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

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

Take Precautions

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

Amiodarone (Cordarone®)

Increased warfarin concentrations and bleeding risk

Inhibition of warfarin metabolism by CYP2C9

·Not applicable

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.

Fluconazole (Diflucan®)

Miconazole (Monistat®)

Voriconazole (Vfend®)

Increased warfarin concentrations and bleeding risk

Inhibition of warfarin metabolism by CYP2C9

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

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.

Carbamazepine (Tegretol®)

Decreased warfarin concentrations and warfarin effects

Induction of warfarin metabolism

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

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.

Gemfibrozil (Lopid®)

Fenofibrate (Tricor®)

Increased warfarin effect and bleeding risk

Not established

·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

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

NSAIDs

Additive risk of bleeding

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

·Some individual NSAIDs may also alter the pharmacokinetics of warfarin

·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

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.

Fluvastatin (Lescol®)

Lovastatin (Mevacor®)

Rosuvastatin (Crestor®)

Simvastatin (Zocor®)

Increased warfarin concentrations and bleeding risk

Inhibition of warfarin metabolism by CYP2C9 is proposed

·See warfarin and fibrates

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

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.

Sulfamethoxazole/trimethoprim (Bactrim®)

Metronidazole (Flagyl®)

Increased warfarin concentrations and bleeding risk

Inhibition of warfarin metabolism by CYP2C9

·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

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.

Levothyroxine (Synthroid®)

Liothyronine (Cytomel®)

Liotrix (Thyrolar®)

Thyroid USP (Armour Thyroid®)

Increased bleeding risk

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

·Not applicable

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.