What drug combinations should be avoided due to adverse interactions?

Drug Combinations to Avoid

The most critical drug combinations to avoid are those involving strong enzyme inducers/inhibitors with narrow therapeutic index medications, particularly oral anticoagulants with dual P-gp/CYP3A4 inhibitors, statins with gemfibrozil, macrolides with simvastatin/lovastatin, and rifampin with most hepatically metabolized drugs. 1, 2

Anticoagulant Contraindications

Direct Oral Anticoagulants (DOACs)

• Avoid all DOACs with strong P-gp inducers (rifampin, rifabutin, carbamazepine, phenobarbital, phenytoin, St. John's wort) due to decreased drug exposure and loss of efficacy 1
• Avoid apixaban and rivaroxaban with simultaneous strong CYP3A4 AND P-gp inhibitors (ketoconazole, itraconazole, ritonavir, clarithromycin) unless dose reduced by 50% for standard doses 1, 3
• Paxlovid (ritonavir-containing) with apixaban: Reduce apixaban dose by 50% if on standard dosing; avoid entirely if already on reduced dose (2.5 mg twice daily) 3
• Avoid dabigatran with strong P-gp inhibitors in renal impairment (CrCl <50 mL/min), as this combination can triple drug exposure 1

Warfarin

• Avoid amiodarone with warfarin without close INR monitoring and dose adjustment, as it inhibits CYP2C9 1

Statin Contraindications

Absolute Contraindications

• Never combine simvastatin or lovastatin with gemfibrozil - causes 6-20 fold increase in statin exposure and high rhabdomyolysis risk 1
• Never combine simvastatin, lovastatin, atorvastatin, or pitavastatin with cyclosporine - causes 6-20 fold increases in statin AUC 1
• Never combine simvastatin or lovastatin with clarithromycin or other macrolides - significantly increases rhabdomyolysis risk 1, 4, 5

Dose-Limited Combinations

• Limit rosuvastatin to 5 mg daily with cyclosporine, tacrolimus, everolimus, or sirolimus 1
• Limit pravastatin to 20 mg daily with immunosuppressants 1
• Limit fluvastatin to 40 mg daily with immunosuppressants 1
• Limit atorvastatin to ≤10 mg daily with immunosuppressants without close creatine kinase monitoring 1

Antibiotic Contraindications

Rifampin (Potent Inducer)

• Avoid rifampin with ritonavir-boosted saquinavir - causes severe hepatocellular toxicity 2
• Avoid rifampin with oral contraceptives - decreases contraceptive efficacy; use alternative contraception 1, 2
• Avoid rifampin with sofosbuvir - decreases AUC by 72%, leading to HCV treatment failure 2
• Avoid rifampin with daclatasvir - decreases AUC by 79% 2
• Avoid rifampin with most antiretrovirals (atazanavir, darunavir, fosamprenavir, indinavir, efavirenz) - causes 26-92% decreases in exposure 2

Macrolides (CYP3A4/P-gp Inhibitors)

• Avoid clarithromycin or erythromycin with cisapride - risk of fatal cardiac arrhythmias 4
• Avoid clarithromycin with ergotamine or dihydroergotamine - causes acute ergot toxicity with vasospasm and ischemia 4
• Avoid clarithromycin with lomitapide - excessive lipid-lowering drug exposure 4

Hepatitis C Direct-Acting Antiviral Contraindications

Sofosbuvir/Ledipasvir

• Avoid with amiodarone - risk of symptomatic or fatal bradycardia/asystole 1
• Avoid with potent P-gp inducers (rifampin, carbamazepine, phenobarbital, phenytoin, St. John's wort) - decreased antiviral efficacy 1

Sofosbuvir/Velpatasvir

• Avoid with potent P-gp or CYP inducers (rifampin, rifabutin, carbamazepine, phenobarbital, phenytoin, St. John's wort) - loss of antiviral efficacy 1

Opioid Contraindications

• Avoid meperidine with serotonergic/noradrenergic drugs (SSRIs, SNRIs, MAOIs) - increased toxicity risk 1
• Avoid tramadol and tapentadol with serotonergic drugs - serotonin syndrome risk 1
• Avoid codeine and tramadol with CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion) - prodrugs won't convert to active metabolites, causing inadequate analgesia 1

Cardiovascular Drug Contraindications

• Avoid colchicine with statins - competitive CYP3A4 and P-gp inhibition increases myopathy risk 1
• Avoid digoxin with ledipasvir or velpatasvir - P-gp inhibition increases digoxin levels; requires careful monitoring 1
• Avoid dabigatran with ledipasvir - P-gp inhibition significantly increases bleeding risk 1

Common Pitfalls

• Macrolide-statin combinations are frequently prescribed inappropriately - 841,864 outpatient visits involved contraindicated macrolide-statin combinations, primarily clarithromycin/erythromycin with simvastatin/lovastatin 5
• Fluoroquinolones with antiarrhythmics (amiodarone, sotalol, quinidine, procainamide) represent the second most common contraindicated combination in ambulatory care 5
• Rifampin interactions are often overlooked - it induces CYP1A2, 2B6, 2C8, 2C9, 2C19, 3A4, UGT, P-gp, and MRP2 simultaneously, affecting most hepatically metabolized drugs 2
• Patients on multiple medications have exponentially higher DDI risk - up to 80% of atrial fibrillation patients will receive a medication that interacts with their anticoagulant over their lifetime 1