PlainMeds research
Major drug interactions
The most serious drug-drug interactions in FDA labeling. These combinations can cause dangerous effects and are generally avoided or carefully managed.
Data updated 2026-05-15
- 268
- Major interactions
- 183
- Medications involved
- 711
- Moderate (for context)
A major drug interaction is a combination of two medications that can cause serious or life-threatening effects and is generally avoided; PlainMeds documents 268 of them from FDA labeling across 183 medications.
Major interactions are the most serious class of drug-drug interaction in FDA labeling, where combining two medications can cause dangerous effects, so the pair is usually avoided or closely monitored. PlainMeds tracks 268 major interactions across 183 drugs; Theophylline appears in the most. A major rating reflects the documented risk, not certainty that harm will occur. Always confirm your own medications with a pharmacist or doctor. This is educational information, not medical advice.
According to the U.S. Food and Drug Administration (FDA), drug labels grade interactions by severity, and major is the most serious tier: the combination can cause dangerous effects and is generally avoided or closely monitored. Compiled from FDA Structured Product Labeling current to 2025, PlainMeds documents 268 major interactions across 183 medications. Theophylline appears in the most (27). A major rating reflects documented risk, not certainty of harm; fewer than 10% of all documented drug-drug interaction pairs carry it. Check a specific combination with the interaction checker, or see our methodology for how these figures are compiled.
Medications involved in the most major interactions
- Theophylline
Theophylline
27 major interactions
- Nirmatrelvir/Ritonavir
Nirmatrelvir/Ritonavir
23 major interactions
- Aliskiren
Aliskiren
22 major interactions
- Itraconazole
Itraconazole
19 major interactions
- Clarithromycin
Clarithromycin
16 major interactions
- Darunavir
Darunavir
15 major interactions
- Pimozide
Pimozide
12 major interactions
- Ranolazine
Ranolazine
12 major interactions
- Simvastatin
Simvastatin
11 major interactions
- Dronedarone 9
Dronedarone
9 major interactions
- Ezetimibe 8
Ezetimibe
8 major interactions
- Ezetimibe/Simvastatin 8
Ezetimibe/Simvastatin
8 major interactions
What this shows Theophylline and Nirmatrelvir/Ritonavir appear in the most documented major interactions, so they warrant the closest review when combined with other medicines.
Documented major interaction pairs
A sample of the 268 documented major interactions, in alphabetical order. Open any pair for the full mechanism and FDA-labeled guidance, or check a specific combination with the interaction checker.
| Combination | Why it matters |
|---|---|
| alfuzosin + ketoconazole | Ketoconazole blocks the enzyme that breaks down alfuzosin, which causes the amount of alfuzosin in your blood to rise to unsafe levels. |
| allopurinol + pegloticase | Allopurinol can hide changes in your blood levels that warn doctors of a possible severe allergic reaction to pegloticase. |
| amlodipine + simvastatin | Amlodipine makes it harder for your body to clear simvastatin, which raises the level of the cholesterol medicine in your blood. |
| amlodipine/benazepril + aliskiren | Both of these drugs target the same system that controls blood pressure, which can cause your blood pressure to drop too low. This combination also increases… |
| amlodipine/benazepril + lithium | Benazepril can make it harder for the kidneys to remove lithium from the body, causing lithium levels to rise. This increase can lead to lithium poisoning or… |
| amlodipine/benazepril + simvastatin | The amlodipine in this combination pill increases the amount of simvastatin that stays in your bloodstream. |
| amlodipine/valsartan + aliskiren | Using these two medicines together can over-block the system that regulates blood pressure and kidney health. This can lead to dangerously low blood pressure,… |
| amlodipine/valsartan + simvastatin | Amlodipine interferes with how the body processes simvastatin, leading to higher amounts of the cholesterol drug in your blood. This can increase your risk of… |
| anastrozole + tamoxifen | Tamoxifen lowers the amount of anastrozole in your blood, which may make the treatment less effective against cancer. Research also shows that taking both… |
| aprepitant + pimozide | Aprepitant stops the body from breaking down pimozide, which can cause pimozide to build up to dangerous levels in the blood. |
| atenolol + aspirin | Current medical studies do not show a clear way these two drugs interfere with each other when used for heart attacks. |
| atorvastatin + clarithromycin | Clarithromycin slows down how fast your body processes atorvastatin, which can cause the statin levels to rise too high. |
| atorvastatin + darunavir | Darunavir interferes with the enzymes that clear atorvastatin from your system, potentially leading to side effects from too much medicine. |
| atorvastatin + itraconazole | Itraconazole prevents your body from breaking down atorvastatin normally, which increases the amount of medicine in your bloodstream. |
| azilsartan + aliskiren | Both drugs block the same system that controls blood pressure, which can cause your blood pressure to drop too low and strain your kidneys. This can also lead… |
| benazepril + aliskiren | These medicines both target the same pathway for blood pressure control, which increases the risk of kidney failure and high potassium. Using them together… |
| bictegravir/emtricitabine/tenofovir + dofetilide | The HIV medicine blocks the way your body removes the heart medicine dofetilide, causing it to build up to dangerous levels. High levels of dofetilide can… |
| bictegravir/emtricitabine/tenofovir + rifampin | Rifampin speeds up how fast your body breaks down the HIV medicine, which makes the HIV medicine less effective. This can cause the HIV virus to become harder… |
| candesartan + aliskiren | Both drugs work on the same system to lower blood pressure, which can lead to severe kidney problems and high potassium levels. This double-blocking effect… |
| cidofovir + amikacin | Both of these drugs can be harmful to the kidneys. Using them together significantly increases the chance of kidney injury. |
| cidofovir + amphotericin B | Both drugs can cause damage to the kidneys. Combining them makes kidney injury much more likely. |
| cidofovir + gentamicin | These medications are both known to be toxic to the kidneys. Using them together can cause severe kidney problems. |
| cidofovir + tobramycin | Both drugs have the potential to damage your kidneys. Taking them together adds to this risk and can lead to kidney failure. |
| cidofovir + vancomycin | Both drugs can harm the kidneys. Taking them at the same time increases the risk of serious kidney damage. |
| citalopram + linezolid | Linezolid acts like a special type of medicine called an MAO inhibitor, which can cause a dangerous buildup of a brain chemical called serotonin when mixed… |
| citalopram + pimozide | Citalopram increases the amount of pimozide in your blood, which can lead to dangerous heart rhythm problems. |
| clarithromycin + colchicine | Clarithromycin blocks the enzymes and transporters that remove colchicine from your body, which can lead to toxic levels of the drug. |
| clarithromycin + cyclosporine | Clarithromycin blocks the liver enzyme that breaks down cyclosporine, which causes the drug to build up in your body. |
| clarithromycin + fluconazole | These two drugs do not significantly affect each other's levels in the body. |
| clarithromycin + fluvastatin | Clarithromycin can affect how your body handles cholesterol medications, though it does not significantly change the levels of fluvastatin. |
| clarithromycin + lurasidone | Clarithromycin stops the body from clearing lurasidone by blocking a specific enzyme, which can lead to toxic levels of the medication. |
| clarithromycin + nateglinide | Clarithromycin can increase the amount of this diabetes medicine in your blood by slowing down how your body processes it. |
| clarithromycin + pimozide | Clarithromycin prevents the breakdown of pimozide, which can cause the drug to reach dangerous levels and potentially affect your heart rhythm. |
| clarithromycin + pioglitazone | Clarithromycin can interfere with how your body handles certain diabetes drugs, which may increase the risk of your blood sugar falling too low. |
| clarithromycin + quetiapine | Clarithromycin stops your body from breaking down quetiapine, which can cause the drug to build up to toxic levels. |
| clarithromycin + repaglinide | Clarithromycin interferes with the enzyme that processes repaglinide, which can cause the medicine to stay in your system longer and drop your blood sugar too… |
| clarithromycin + rosiglitazone | Clarithromycin slows down the process your body uses to get rid of rosiglitazone, which can cause the drug to build up in your system. |
| clonazepam + felbamate | Felbamate does not change the levels of clonazepam in the body or how it is processed. |
| clonazepam + fluoxetine | Fluoxetine does not interfere with how your body breaks down or uses clonazepam. |
| clonazepam + sertraline | Sertraline does not interfere with how your body breaks down or uses clonazepam. |
How to read this list
According to the FDA, these pairs come from Structured Product Labeling current to 2025, where manufacturers document known interactions and their severity, and major interactions make up fewer than 10% of all documented drug-drug pairs. A few things matter when reading them:
- Major does not mean certain harm. It means the combination carries a documented risk serious enough that it is generally avoided or needs close monitoring. Whether it affects you depends on dose, timing, your other medicines, and your health.
- This is a sample, not the full set. The list shows a portion of the 268 documented major interactions. To check a specific combination, use the interaction checker, which searches every documented pair.
- Absence is not safety. A combination not listed here has not been cleared; it may still interact, or simply not be documented in the labels we track.
Never start, stop, or combine medications based on a list. Bring your full medication list, including over-the-counter products and supplements, to your doctor and pharmacist.
Data currency: FDA FAERS adverse-event reports through 2025, CMS NADAC acquisition-cost pricing effective December 2024, compiled and last refreshed May 2026. See our methodology for per-source dates and refresh cadence. Spot a figure that looks wrong? Report a correction.