High-Yield Drug Interaction Lookup Matrix

How to Use This Matrix

Type any drug into the search box (e.g. Warfarin, Statin, QT), or filter by mechanism and severity. Every entry gives the mechanism, the clinical consequence, and the next step: the three things Step 3 tests.

[!CAUTION] Severity key: Contraindicated = never combine. Major = avoid or dose-adjust with monitoring. Moderate = monitor. Severity reflects standard references and exam teaching, not a substitute for clinical judgment.

See also: High-Yield Pharmacotherapy & Adverse Reactions for antidotes, CYP450 inhibitor/inducer mnemonics (SICKFACES.COM, CRAP GPS), and HIT management.

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Mechanism: All Mechanisms (62) CYP450 Inhibition (19) CYP450 Induction (9) P-gp / Transporter (4) QT Prolongation (3) Serotonin Toxicity (4) Bleeding (3) Nephro / Ototoxicity (4) Hyperkalemia (2) Pharmacodynamic / Other (14)

Severity: All Severities (62) Contraindicated: never combine (9) Major: avoid or dose-adjust (49) Moderate: monitor (4)

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Matching: 62 interactions

Drug Pair	Severity	Mechanism	Clinical Consequence	Next Step
Diflucan Nizoral Vfend Coumadin Azole antifungals (Fluconazole, Ketoconazole, Voriconazole) + Warfarin CYP450 Inhibition	Major	Azoles inhibit CYP2C9 (and CYP3A4), blocking S-warfarin clearance.	Supratherapeutic INR with major bleeding (GI, intracranial) within days.	Preemptively reduce warfarin dose and recheck INR in 3–5 days; consider a non-azole antifungal if appropriate.
Diflucan Nizoral Sporanox Zocor Mevacor Lipitor Azole antifungals (Fluconazole, Ketoconazole, Itraconazole) + Statins (Simvastatin, Lovastatin, Atorvastatin) CYP450 Inhibition	Major	Azoles inhibit CYP3A4-mediated statin metabolism, raising statin levels many-fold.	Myopathy and rhabdomyolysis with acute renal failure.	Hold the statin during a short azole course, or switch to pravastatin or rosuvastatin (non-CYP3A4).
Diflucan Vfend Dilantin Azole antifungals (Fluconazole, Voriconazole) + Phenytoin CYP450 Inhibition	Major	Azoles inhibit CYP2C9/2C19, blocking phenytoin clearance.	Phenytoin toxicity: nystagmus, ataxia, dysarthria, altered mental status, seizures.	Monitor free phenytoin levels closely and reduce the phenytoin dose while on the azole.
Biaxin Zithromax Coumadin Macrolides (Erythromycin, Clarithromycin, NOT azithromycin) + Warfarin CYP450 Inhibition	Major	CYP3A4 inhibition plus gut-flora suppression reduces vitamin K production.	INR rise with bleeding risk within 3–5 days of starting the antibiotic.	Recheck INR in 3–5 days; prefer azithromycin when a macrolide is needed (minimal CYP3A4 effect).
Biaxin Zithromax Zocor Mevacor Lipitor Macrolides (Erythromycin, Clarithromycin, NOT azithromycin) + Statins (Simvastatin, Lovastatin, Atorvastatin) CYP450 Inhibition	Major	Potent CYP3A4 inhibition raises statin levels; simvastatin/lovastatin most affected.	Myalgias progressing to rhabdomyolysis and renal failure.	Hold the statin during the antibiotic course, or substitute azithromycin for the macrolide.
Biaxin Calan Cardizem Norvasc CCB Macrolides (Erythromycin, Clarithromycin) + Calcium channel blockers (Verapamil, Diltiazem, Amlodipine) CYP450 Inhibition	Major	CYP3A4 inhibition raises CCB levels; additive AV-nodal blockade with verapamil/diltiazem.	Hypotension, bradycardia, and heart block.	Monitor BP and heart rate; prefer azithromycin, or temporarily reduce the CCB dose.
Cipro FQ fluoroquinolone Ciprofloxacin + Theophylline CYP450 Inhibition	Major	Ciprofloxacin inhibits CYP1A2, the primary theophylline clearance pathway.	Theophylline toxicity: nausea, tachyarrhythmia, seizures (narrow therapeutic index).	Reduce theophylline dose and monitor serum levels; prefer a non-interacting antibiotic when possible.
Cipro FQ fluoroquinolone Coumadin Ciprofloxacin (and other fluoroquinolones) + Warfarin CYP450 Inhibition	Moderate	CYP1A2/3A4 inhibition plus gut-flora suppression impairs warfarin clearance and vitamin K supply.	INR elevation with bleeding risk.	Recheck INR in 3–5 days and adjust warfarin dose accordingly.
Flagyl Coumadin Metronidazole + Warfarin CYP450 Inhibition	Major	Metronidazole inhibits CYP2C9-mediated S-warfarin metabolism.	Markedly elevated INR with major bleeding risk.	Preemptively reduce warfarin dose and recheck INR in 3–5 days.
Bactrim Septra co-trimoxazole TMP SMX Coumadin Trimethoprim-Sulfamethoxazole (TMP-SMX) + Warfarin CYP450 Inhibition	Major	Sulfamethoxazole inhibits CYP2C9 and displaces warfarin from albumin, raising free drug.	Rapid INR rise with bleeding, often within 2–4 days.	Preemptively reduce warfarin dose 25–30% and recheck INR in 2–4 days.
Bactrim Septra co-trimoxazole TMP SMX Dilantin Trimethoprim-Sulfamethoxazole (TMP-SMX) + Phenytoin CYP450 Inhibition	Major	Sulfamethoxazole inhibits CYP2C9 and displaces phenytoin from albumin.	Phenytoin toxicity: nystagmus, ataxia, confusion.	Monitor free phenytoin levels and reduce dose if signs of toxicity appear.
Bactrim Septra TMP SMX Glucotrol Micronase glibenclamide SU Trimethoprim-Sulfamethoxazole (TMP-SMX) + Sulfonylureas (Glyburide, Glipizide) CYP450 Inhibition	Major	Sulfamethoxazole inhibits CYP2C9-mediated sulfonylurea clearance.	Prolonged severe hypoglycemia, especially in elderly or CKD patients.	Monitor glucose closely, counsel on hypoglycemia symptoms, and consider reducing the sulfonylurea dose.
Prilosec Nexium Protonix PPI Plavix Omeprazole / Esomeprazole + Clopidogrel CYP450 Inhibition	Major	CYP2C19 inhibition blocks conversion of clopidogrel (prodrug) to its active metabolite (FDA boxed warning).	Reduced platelet inhibition → stent thrombosis, MI, or stroke.	Switch the PPI to pantoprazole (minimal CYP2C19 effect) in patients on clopidogrel.
Pacerone Cordarone Coumadin Amiodarone + Warfarin CYP450 Inhibition	Major	Amiodarone inhibits CYP1A2, CYP2C9, and CYP3A4, markedly reducing warfarin clearance.	INR doubling with major bleeding risk within 1–2 weeks of initiation.	Reduce warfarin dose 30–50% when starting amiodarone and check INR frequently.
Dilantin Isoniazid (INH) + Phenytoin CYP450 Inhibition	Major	INH inhibits CYP2C9/2C19, blocking phenytoin metabolism.	Phenytoin toxicity: nystagmus, ataxia, lethargy.	Monitor free phenytoin levels after starting INH and reduce the phenytoin dose as needed.
Prozac Paxil Zoloft Lexapro Effexor Nolvadex SSRI SNRI Fluoxetine / Paroxetine (potent CYP2D6 inhibitors) + Tamoxifen CYP450 Inhibition	Major	CYP2D6 inhibition blocks conversion of tamoxifen to active endoxifen.	Loss of breast cancer recurrence protection.	Avoid potent CYP2D6 inhibitors with tamoxifen; prefer sertraline, escitalopram, or venlafaxine for depression/hot flashes.
Biaxin Cardizem Calan Neoral Sandimmune Prograf ciclosporin CYP3A4/P-gp inhibitors (Azoles, Clarithromycin, Diltiazem, Verapamil) + Calcineurin inhibitors (Cyclosporine, Tacrolimus) CYP450 Inhibition	Major	Dual CYP3A4 and P-gp inhibition raises calcineurin inhibitor troughs several-fold.	Acute nephrotoxicity, neurotoxicity, and opportunistic infection from over-immunosuppression.	Preemptively reduce the calcineurin inhibitor dose and monitor trough levels and creatinine closely.
Calan Cardizem Zocor Mevacor Crestor Pravachol Verapamil / Diltiazem + Statins (Simvastatin, Lovastatin) CYP450 Inhibition	Major	CYP3A4 inhibition raises statin levels (simvastatin/lovastatin most affected).	Myopathy and rhabdomyolysis.	Cap simvastatin at 10 mg daily with these CCBs, or switch to pravastatin or rosuvastatin.
BuSpar Zocor Mevacor Lipitor CCB Grapefruit juice + Statins / CCBs / Buspirone (CYP3A4 substrates) CYP450 Inhibition	Moderate	Furanocoumarins irreversibly inhibit intestinal CYP3A4, raising oral bioavailability.	Exaggerated drug effect: myopathy (statins), hypotension (CCBs).	Counsel complete avoidance of grapefruit with simvastatin, lovastatin, and affected CCBs.
Rifadin rifampicin OCP oral contraceptive birth control Rifampin + Combined oral contraceptives (OCPs) CYP450 Induction	Major	Potent CYP3A4 (and P-gp) induction accelerates estrogen/progestin clearance.	Contraceptive failure and unintended pregnancy.	Use backup contraception during rifampin and for 28 days after; prefer a copper or levonorgestrel IUD.
Rifadin rifampicin Coumadin Rifampin + Warfarin CYP450 Induction	Major	CYP2C9/3A4 induction markedly increases warfarin clearance.	Subtherapeutic INR with breakthrough thrombosis or stroke.	Increase warfarin dose (often 2–5×) with frequent INR checks; re-titrate when rifampin stops.
Rifadin rifampicin Dolophine Rifampin + Methadone CYP450 Induction	Major	CYP3A4/2B6 induction accelerates methadone clearance.	Acute opioid withdrawal in a previously stable patient.	Anticipate and increase the methadone dose; monitor with a withdrawal scale (COWS).
Rifadin rifampicin Neoral Sandimmune Prograf ciclosporin Rifampin + Transplant immunosuppressants (Cyclosporine, Tacrolimus) CYP450 Induction	Contraindicated	Potent CYP3A4/P-gp induction collapses immunosuppressant troughs.	Acute graft rejection.	Avoid the combination; if rifampin is unavoidable, massively increase immunosuppressant dosing with daily trough monitoring.
Tegretol Dilantin Luminal OCP oral contraceptive birth control Enzyme-inducing antiepileptics (Carbamazepine, Phenytoin, Phenobarbital) + Combined oral contraceptives (OCPs) CYP450 Induction	Major	CYP3A4 induction accelerates estrogen/progestin clearance.	Contraceptive failure and unintended pregnancy (plus teratogen exposure risk).	Switch to a copper or levonorgestrel IUD or depot medroxyprogesterone; counsel explicitly.
Tegretol Dilantin Luminal Coumadin DOAC NOAC Eliquis Xarelto Pradaxa Enzyme-inducing antiepileptics (Carbamazepine, Phenytoin, Phenobarbital) + Warfarin / DOACs CYP450 Induction	Major	CYP induction (plus P-gp induction for DOACs) lowers anticoagulant levels.	Breakthrough thrombosis, stroke, or PE on previously therapeutic anticoagulation.	Increase warfarin with frequent INR checks; avoid DOACs with carbamazepine/phenytoin: prefer warfarin.
Dilantin Coumadin Phenytoin + Warfarin CYP450 Induction	Major	Biphasic: transient INR rise from albumin displacement, then CYP induction predominates over days.	Net loss of anticoagulation with thrombotic risk after the first week.	Check INR frequently for 2 weeks after any change; usually requires a higher maintenance warfarin dose.
SJW Hypericum OCP oral contraceptive DOAC NOAC St. John's Wort + OCPs / Transplant drugs / DOACs / Antiretrovirals CYP450 Induction	Major	Potent CYP3A4 and P-gp induction lowers levels of many substrates.	Pregnancy, graft rejection, thrombosis, or HIV virologic failure.	Stop St. John's Wort and use backup measures; counsel that 'herbal' does not mean safe.
smoking Clozaril Zyprexa NRT nicotine Tobacco smoke (polycyclic aromatic hydrocarbons) + Clozapine / Olanzapine / Theophylline CYP450 Induction	Major	CYP1A2 induction lowers drug levels in smokers; cessation reverses induction within days.	Smoking cessation precipitates clozapine toxicity (seizures, myocarditis) or theophylline toxicity.	Reduce clozapine dose 30–50% on smoking cessation and monitor levels; nicotine replacement does NOT induce CYP1A2.
Pacerone Cordarone Lanoxin Amiodarone + Digoxin P-gp / Transporter	Major	P-gp inhibition reduces renal digoxin clearance, raising levels ~70–100%.	Digoxin toxicity: nausea, visual changes, fatal bradyarrhythmia or bidirectional VT.	Halve the digoxin dose when starting amiodarone and monitor levels, ECG, and potassium.
Calan Lanoxin Verapamil + Digoxin P-gp / Transporter	Major	P-gp inhibition raises digoxin levels ~50–70%; additive AV-nodal blockade.	Digoxin toxicity with symptomatic bradycardia or heart block.	Reduce digoxin dose, monitor levels and ECG; correct hypokalemia and hypomagnesemia.
Eliquis Xarelto Pradaxa NOAC Dual P-gp/CYP3A4 inhibitors (Amiodarone, Verapamil, Azoles, Clarithromycin) + DOACs (Apixaban, Rivaroxaban, Dabigatran) P-gp / Transporter	Major	P-gp (± CYP3A4) inhibition raises DOAC levels; effect greatest with renal impairment.	Major bleeding on a previously stable DOAC dose.	Avoid strong dual inhibitors with DOACs; dose-reduce or switch anticoagulant per renal function and label.
Rifadin Tegretol SJW Eliquis Xarelto Pradaxa NOAC Dual P-gp/CYP3A4 inducers (Rifampin, Carbamazepine, St. John's Wort) + DOACs (Apixaban, Rivaroxaban, Dabigatran) P-gp / Transporter	Contraindicated	P-gp and CYP3A4 induction markedly lowers DOAC levels.	Breakthrough stroke, VTE, or valve thrombosis.	Do not combine; use warfarin with INR monitoring instead.
Biaxin Zithromax Zofran QTc torsade Cipro Macrolides (Erythromycin, Clarithromycin, Azithromycin) + Other QT-prolonging drugs (Antipsychotics, Methadone, Fluoroquinolones, Ondansetron) QT Prolongation	Major	Additive blockade of the cardiac hERG potassium channel prolongs repolarization. Note: azithromycin spares CYP3A4 but still prolongs QT.	Marked QTc prolongation → torsades de pointes and sudden cardiac death.	Check baseline and follow-up ECG; replete K+ > 4.0 and Mg2+; stop the offending agent if QTc > 500 ms.
Dolophine buprenorphine Suboxone QTc torsade Methadone (± CYP3A4/2B6 inhibitors) + Other QT-prolonging drugs / high-dose methadone itself QT Prolongation	Major	Dose-dependent hERG blockade; CYP inhibitors raise methadone levels and QT risk.	Torsades de pointes, especially at doses > 100 mg/day or with interacting drugs.	Baseline and serial ECGs on methadone; correct K+/Mg2+; consider buprenorphine (minimal QT effect) if QTc prolongs.
Haldol Inapsine Geodon Mellaril QTc torsade Antipsychotics (IV Haloperidol, Droperidol, Ziprasidone, Thioridazine) + Other QT-prolonging drugs QT Prolongation	Major	Additive hERG blockade; IV haloperidol and droperidol carry the highest torsades risk.	Torsades de pointes, particularly with hypokalemia or bradycardia.	Continuous telemetry with IV haloperidol/droperidol; keep K+ > 4.0 and Mg2+ > 2.0; stop if QTc > 500 ms.
MAOI Nardil Parnate Eldepryl Emsam SSRI SNRI MAO inhibitors (Phenelzine, Tranylcypromine, Selegiline) + SSRIs / SNRIs Serotonin Toxicity	Contraindicated	Combined blockade of serotonin breakdown and reuptake floods synapses with serotonin.	Serotonin syndrome: clonus, hyperthermia, rigidity, autonomic instability, death.	Never combine; observe a 2-week washout (5 weeks after fluoxetine) between agents. Treat with benzodiazepines + cyproheptadine.
MAOI Demerol pethidine DXM Robitussin Ultram MAO inhibitors + Meperidine / Dextromethorphan / Tramadol Serotonin Toxicity	Contraindicated	Meperidine, dextromethorphan, and tramadol all increase synaptic serotonin, synergizing with MAOIs.	Fatal serotonin syndrome (meperidine + MAOI is a classic lethal pair).	Absolute contraindication; if an opioid is required with an MAOI, morphine is the preferred agent.
Zyvox MAOI SSRI SNRI Linezolid (weak reversible MAOI) + SSRIs / SNRIs Serotonin Toxicity	Major	Linezolid weakly inhibits MAO-A, raising synaptic serotonin in SSRI-treated patients.	Serotonin syndrome: clonus, agitation, hyperthermia.	Stop the SSRI 2 weeks before linezolid when feasible, or choose an alternative antibiotic with close monitoring.
Ultram SSRI SNRI Tramadol + SSRIs / SNRIs Serotonin Toxicity	Major	Tramadol inhibits serotonin/norepinephrine reuptake in addition to weak mu-agonism.	Serotonin syndrome plus lowered seizure threshold.	Avoid the combination in favor of non-serotonergic analgesia; counsel on agitation, clonus, and hyperthermia as red flags.
NSAID ibuprofen naproxen Advil Aleve Coumadin NSAIDs + Warfarin Bleeding	Major	Platelet COX-1 inhibition plus direct GI mucosal injury; bleeding risk rises even with a therapeutic INR.	GI hemorrhage and hemorrhagic stroke risk independent of INR.	Avoid NSAIDs on warfarin; use acetaminophen for pain (≤ 2 g/day chronically).
ASA Plavix P2Y12 Coumadin Eliquis Xarelto Pradaxa PCI Antiplatelets (Aspirin, Clopidogrel) + Warfarin / DOACs (dual or triple therapy) Bleeding	Major	Combined blockade of platelet aggregation and the coagulation cascade.	Major bleeding risk multiplies with each added agent (triple therapy highest).	Minimize triple-therapy duration post-PCI (prefer DOAC + single P2Y12 inhibitor); add a PPI for GI protection.
SSRI SNRI NSAID SSRIs / SNRIs + NSAIDs / Antiplatelets / Anticoagulants Bleeding	Moderate	Platelet serotonin depletion impairs platelet aggregation.	Increased GI and perioperative bleeding, especially combined with NSAIDs.	Add PPI prophylaxis when combining SSRIs with NSAIDs; monitor for bruising and GI blood loss.
aminoglycoside Vancocin Aminoglycosides (Gentamicin, Tobramycin) + Vancomycin (and vice versa) Nephro / Ototoxicity	Major	Additive proximal tubular injury and cochlear/vestibular hair-cell toxicity.	Acute kidney injury and irreversible ototoxicity (hearing loss, vestibular damage).	Monitor troughs, daily creatinine, and hearing; use extended-interval aminoglycoside dosing with pharmacy guidance.
Lasix Bumex aminoglycoside Loop diuretics (Furosemide, Bumetanide) + Aminoglycosides Nephro / Ototoxicity	Major	Loop diuretics alter inner-ear endolymph and potentiate aminoglycoside cochlear toxicity.	Irreversible sensorineural hearing loss, especially with renal impairment or rapid IV furosemide pushes.	Avoid the combination when possible; slow IV furosemide infusion and monitor hearing and renal function.
Zosyn pip-tazo Vancocin Maxipime cefepime Piperacillin-Tazobactam + Vancomycin (and vice versa) Nephro / Ototoxicity	Major	Synergistic acute tubular injury (mechanism incompletely defined; association well established).	Acute kidney injury within days of combined therapy.	Monitor creatinine daily; de-escalate promptly on culture results; consider cefepime instead of pip-tazo when appropriate.
NSAID ACEI ARB triple whammy kidney NSAIDs + ACE inhibitor/ARB + Diuretic ('triple whammy') + Renal perfusion Nephro / Ototoxicity	Major	NSAIDs constrict the afferent arteriole while ACE-I/ARBs dilate the efferent arteriole in a volume-depleted patient.	Acute kidney injury with hyperkalemia, especially in elderly or CHF/CKD patients.	Hold the NSAID first; monitor creatinine and potassium; rehydrate before restarting RAAS blockade.
ACEI ARB Aldactone Inspra ACE inhibitors / ARBs + Spironolactone / Eplerenone / Potassium supplements Hyperkalemia	Major	Dual blockade of aldosterone-mediated renal potassium excretion.	Severe hyperkalemia with peaked T waves and arrest risk, especially in CKD or diabetes.	Check K+ and creatinine within 1 week of starting or uptitrating; hold K+ supplements; counsel a low-potassium diet.
Bactrim TMP ACEI ARB Trimethoprim (TMP-SMX) + ACE inhibitors / ARBs / CKD patients Hyperkalemia	Major	Trimethoprim blocks the renal epithelial sodium channel (ENaC) like amiloride, impairing K+ excretion.	Hyperkalemia, particularly in elderly, CKD, or ACE-I/ARB-treated patients.	Check potassium within 3–5 days in at-risk patients; choose an alternative antibiotic when K+ is already elevated.
Viagra Cialis Levitra PDE5 NTG Isordil Imdur PDE5 inhibitors (Sildenafil, Tadalafil) + Nitrates (Nitroglycerin, Isosorbide) Pharmacodynamic / Other	Contraindicated	Synergistic cGMP-mediated vasodilation collapses preload and afterload.	Profound refractory hypotension, MI, and death.	Absolute contraindication: no PDE5 inhibitor within 24 hours of sildenafil/vardenafil or 48 hours of tadalafil after nitrates.
benzo BZD opioid narcotic Narcan Benzodiazepines + Opioids (and vice versa) Pharmacodynamic / Other	Contraindicated	Synergistic CNS and respiratory-center depression (FDA boxed warning).	Fatal respiratory depression and overdose.	Avoid co-prescribing; taper one agent, co-prescribe naloxone, and counsel on overdose signs.
Zyloprim Imuran Purinethol 6-MP Allopurinol + Azathioprine / 6-Mercaptopurine Pharmacodynamic / Other	Major	Xanthine oxidase inhibition blocks azathioprine/6-MP clearance, raising active thioguanine metabolites.	Severe pancytopenia and life-threatening infection.	Reduce azathioprine/6-MP to 25–33% of the original dose when starting allopurinol; monitor CBC frequently.
Bactrim Septra MTX Trexall leucovorin Trimethoprim-Sulfamethoxazole (TMP-SMX) + Methotrexate Pharmacodynamic / Other	Contraindicated	Dual antifolate blockade plus displacement of methotrexate from albumin.	Profound pancytopenia, mucositis, and hepatotoxicity.	Avoid the combination; if toxicity occurs, give leucovorin rescue and hold methotrexate.
NSAID ibuprofen naproxen MTX Trexall NSAIDs + Methotrexate (high-dose) Pharmacodynamic / Other	Major	NSAIDs reduce renal methotrexate clearance, prolonging exposure.	Methotrexate toxicity: pancytopenia, mucositis, AKI.	Hold NSAIDs around high-dose methotrexate; monitor CBC, creatinine, and methotrexate levels.
HCTZ hydrochlorothiazide NSAID ACEI Lithobid Eskalith Thiazide diuretics / NSAIDs / ACE inhibitors + Lithium Pharmacodynamic / Other	Major	Sodium depletion (thiazides) or reduced GFR (NSAIDs, ACE-I) increases proximal lithium reabsorption.	Lithium toxicity: coarse tremor, ataxia, confusion, polyuria, seizures.	Reduce lithium dose 25–50% when adding these agents and recheck lithium levels in 5–7 days.
doxycycline Cipro FQ Synthroid Divalent/trivalent cations (Antacids, Iron, Calcium, Magnesium, Sucralfate) + Tetracyclines / Fluoroquinolones / Levothyroxine Pharmacodynamic / Other	Moderate	Cation chelation in the gut forms insoluble complexes, blocking absorption.	Therapeutic failure: persistent infection or hypothyroidism.	Separate administration by 2–4 hours (antibiotic/thyroid drug first).
Biaxin Calan Cardizem Colcrys CYP3A4/P-gp inhibitors (Clarithromycin, Azoles, Verapamil, Diltiazem) + Colchicine Pharmacodynamic / Other	Contraindicated	Dual CYP3A4/P-gp inhibition raises colchicine levels; fatal toxicity reported (contraindicated in renal/hepatic impairment per label).	Colchicine toxicity: GI necrosis, pancytopenia, rhabdomyolysis, multiorgan failure.	Avoid the combination in CKD/hepatic disease; otherwise halve the colchicine dose with close monitoring.
EtOH ethanol Flagyl disulfiram Antabuse Alcohol + Metronidazole Pharmacodynamic / Other	Major	Disulfiram-like reaction (acetaldehyde accumulation; mechanism debated but reaction well documented).	Flushing, nausea, vomiting, tachycardia, hypotension.	Abstain from alcohol during metronidazole and for 48–72 hours after the last dose.
Depakote Depakine valproic acid divalproex Lamictal SJS Valproate + Lamotrigine Pharmacodynamic / Other	Major	Valproate inhibits UGT-mediated lamotrigine glucuronidation, doubling lamotrigine half-life.	Markedly increased Stevens-Johnson syndrome / TEN risk.	Use the low-and-slow titration (25 mg every other day initially) when adding lamotrigine to valproate.
MAOI Nardil Parnate tyramine diet Tyramine-rich foods (Aged cheese, Cured meats, Red wine, Fermented foods) + MAO inhibitors (Phenelzine, Tranylcypromine) Pharmacodynamic / Other	Contraindicated	Unmetabolized tyramine triggers massive presynaptic norepinephrine release.	Hypertensive crisis with stroke or MI risk.	Strict low-tyramine diet on MAOIs; treat crisis with phentolamine or nitroprusside.
Calan Cardizem BB beta blocker Verapamil / Diltiazem + Beta-blockers Pharmacodynamic / Other	Major	Additive SA/AV-nodal blockade plus negative inotropy.	Symptomatic bradycardia, heart block, and acute decompensated heart failure.	Avoid the combination when possible; if required, start low doses with ECG and BP monitoring.
Lopid Tricor fenofibrate Gemfibrozil (and other fibrates) + Statins Pharmacodynamic / Other	Major	Gemfibrozil inhibits statin glucuronidation (and CYP2C8), raising statin levels.	Myopathy and rhabdomyolysis; gemfibrozil carries higher risk than fenofibrate.	Avoid gemfibrozil + statin; if a fibrate is needed, prefer fenofibrate with CK monitoring.
Lasix HCTZ Lanoxin Loop / Thiazide diuretics + Digoxin Pharmacodynamic / Other	Major	Diuretic-induced hypokalemia and hypomagnesemia potentiate digoxin binding to Na+/K+-ATPase: toxicity at 'therapeutic' levels.	Fatal ventricular arrhythmia or heart block despite a normal digoxin level.	Keep K+ > 4.0 and Mg2+ > 2.0 mEq/L in all digoxin-treated patients; monitor levels and ECG.

62 curated pairs; absence here does not mean safe.