Common Drug-Drug Interactions (DDIs) and alternative options

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.Consequently, 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, pharmacodynamic, clinical) and mechanism of the potential DDIs in addition to the propensity for related drugs to interact and options for clinical management.

Amiodarone and Quinolones:

Object drug
Amiodarone
Precipitant Drug
Levofloxacin, Gemifloxacin, Moxifloxacin, Ofloxacin, Ciprofloxacin
Effect
Increased risk of TdP and/or QTc prolongation on ECG
Mechanism
Concomitant blockade of cardiac potassium channels
Related Drugs
Azithromycin, clarithromycin, erythromycin and telithromycin also have a possible risk of TDP and/or QTc prolongation on ECG
Options
Usually Avoid and Consider Alternatives: Alternative antimicrobials include penicillins, and cephalosporins. See www.azcert.org for QT drug lists by risk group

Carbamazepine and Macrolides:

Object drug
Carbamazepine
Precipitant Drug
Clarithromycin, Erythromycin, Telithromycin
Effect
Increased carbamazepine concentrations and risk of carbamazepine toxicity
Mechanism
Inhibition of carbamazepine metabolism by CYP3A4
Related Drugs
Azithromycin 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 and Macrolides:

Object drug
Digoxin
Precipitant Drug
Clarithromycin, Erythromycin
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 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 and Azole Antifungals:

Object drug
Digoxin
Precipitant Drug
Itraconazole, Ketoconazole, Posaconazole
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 and the non-azole antifungal, terbinafine, 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:

Object drug
Simvastatin
Precipitant Drug
Amiodarone
Effect
Increased simvastatin/ lovastatin concentrations and risk of myopathy/ rhabdomyolysis
Mechanism
Inhibition of metabolism of simvastatin/ lovastatin by CYP3A4
Related Drugs
  • Atorvastatin undergoes less metabolism by CYP3A4; however cases of myopathy with CYP3A4 inhibitors have been reported
  • Fluvastatin, rosuvastatin, and pravastatin are not 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, Ketoconazole, Posaconazole, Voriconazole, Fluconazole
Effect
Increased simvastatin/ lovastatin concentrations and risk of myopathy/ rhabdomyolysis
Mechanism
Inhibition of simvastatin/ lovastatin metabolism by CYP3A4
Related Drugs
Antifungal Agents

  • Terbinafine does not inhibit CYP3A4
  • Ciclopirox nail lacquer is not appreciably absorbed

Statins

  • Atorvastatin undergoes less metabolism by CYP3A4 but cases of myopathy with CYP3A4 inhibitors reported
  • Fluvastatin, rosuvastatin, and pravastatin are not 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 and Antidepressants:

Object drug
Tamoxifen
Precipitant Drug
Bupropion, Duloxetine, Fluoxetin, Paroxetine
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 (pro drug) to its major active metabolite by CYP2D6
Related Drugs
  • Citalopram, desvenlafaxine, escitalopram, and sertraline, are weak inhibitors of CYP2D6
  • Fluvoxamine and venlafaxine do not significantly inhibit CYP2D6
Options
Take Precautions

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

Warfarin and Amiodarone:

Object drug
Warfarin
Precipitant Drug
Amiodarone
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 and Azole Antifungals:

Object drug
Warfarin
Precipitant Drug
Fluconazole, Miconazole, Voriconazole
Effect
Increased warfarin concentrations and bleeding risk
Mechanism
Inhibition of warfarin metabolism by CYP2C9
Related Drugs
Itraconazole, ketoconazole, posaconazole, terbinafine 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 and Carbamazepine:

Object drug
Warfarin
Precipitant Drug
Carbamazepine
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, phenytoin, and primidone
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 and Fibrates:

Object drug
Warfarin
Precipitant Drug
Gemfibrozil, Fenofibrate
Effect
Increased warfarin effect and bleeding risk
Mechanism
Not established
Related Drugs
  • See warfarin and statins
  • An extended-release niacin product is not known to interact with warfarin
  • Gemfibrozil and fenofibrate inhibit CYP2C9 and may increase bleeding risk
  • Cholestyramine and colestipol may reduce the effect of warfarin
Options
Usually Avoid

Consider Alternatives: Atorvastatin and pravastatin appear to be safer alternatives. 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 and NSAIDs:

Object drug
Warfarin
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 and Statins:

Object drug
Warfarin
Precipitant Drug
Fluvastatin, Lovastatin, Rosuvastatin, Simvastatin
Effect
Increased warfarin concentrations and bleeding risk
Mechanism
Inhibition of warfarin metabolism by CYP2C9 is proposed
Related Drugs
  • See warfarin and fibrates
  • Atorvastatin and pravastatin 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 and Antibiotics:

Object drug
Warfarin
Precipitant Drug
Sulfamethoxazole/trimethoprim, Metronidazole
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 and Thyroid Hormones:

Object drug
Warfarin
Precipitant Drug
Levothyroxine, Liothyronine, Liotrix, Thyroid USP
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, a downward 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.

References
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.

Source: CredibleMeds

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