Plaquenil Drug Interactions: What to Avoid and What to Tell Your Doctor

Plaquenil (hydroxychloroquine) has a relatively favorable drug interaction profile compared to many other disease-modifying medications, but there are several interactions that can be serious—even life-threatening. If you take Plaquenil or are about to start it, this is what you and your doctor need to know.

The Most Important Rule: Always Tell Every Provider You're on Plaquenil

Because Plaquenil affects the heart's electrical system and interacts with several common medications, every provider you see—your PCP, urgent care, ER, dentist, or specialist—needs to know you take it. This is especially critical if you need an antibiotic, a new heart medication, or any drug that affects heart rhythm.

Major Drug Interactions to Know

QT-Prolonging Medications (Most Important Risk)

Plaquenil prolongs the QT interval—a measurement of the heart's electrical cycle. When combined with other drugs that also prolong QT, the risk of life-threatening heart rhythm abnormalities (ventricular arrhythmias, torsades de pointes) increases significantly.

Common QT-prolonging drugs to discuss with your doctor include:

• Azithromycin (Z-Pak): A very commonly prescribed antibiotic. The combination of Plaquenil + azithromycin gained notoriety during COVID-19; it carries significant cardiac risk.
• Antiarrhythmic drugs: Amiodarone, sotalol, quinidine, procainamide—all can interact dangerously with hydroxychloroquine
• Antipsychotics: Haloperidol, quetiapine, ziprasidone, and others can prolong QT
• Some fluoroquinolone antibiotics: Levofloxacin, moxifloxacin

Action: Before taking any new medication, always check if it prolongs the QT interval. The free CredibleMeds database (crediblemeds.org) lists drugs by QT risk category.

Digoxin (Lanoxin)

Plaquenil increases digoxin blood levels when the two are taken together. Digoxin has a very narrow therapeutic window—meaning the difference between a therapeutic dose and a toxic dose is small. Higher digoxin levels can cause dangerous heart rhythm problems, nausea, visual changes, and in severe cases, death.

Action: If you take digoxin, your doctor must monitor your digoxin blood levels closely when starting or changing your Plaquenil dose.

Cyclosporine (Neoral, Sandimmune, Gengraf)

Hydroxychloroquine has been shown to increase cyclosporine blood levels. Cyclosporine is used to prevent organ transplant rejection and to treat some autoimmune diseases. Elevated cyclosporine levels can cause kidney toxicity, high blood pressure, and tremors.

Action: Cyclosporine levels should be monitored closely if you start or stop Plaquenil.

Methotrexate

Plaquenil and methotrexate are often prescribed together for RA (it's a common combination). However, the combination may increase the incidence of adverse effects from methotrexate. Both drugs can have effects on blood cell counts and liver function. This doesn't mean you shouldn't take them together—many patients do successfully—but it means your doctor will want to monitor your blood counts and liver function more carefully.

Antiepileptic Medications

Plaquenil may reduce the effectiveness of antiepileptic drugs (seizure medications). If you take medications like carbamazepine (Tegretol), valproate (Depakote), phenytoin (Dilantin), or others for seizure control, your neurologist needs to know you're on hydroxychloroquine. Seizure frequency should be monitored if you start Plaquenil.

Insulin and Diabetes Medications

Plaquenil can enhance the blood sugar-lowering effects of insulin and other antidiabetic medications (metformin, sulfonylureas, GLP-1 agonists, etc.). This can cause severe hypoglycemia (dangerously low blood sugar). Diabetic patients starting Plaquenil may need dose adjustments to their diabetes medications.

Rifampin (Rifampicin)

Rifampin (used for tuberculosis) significantly reduces hydroxychloroquine levels in the blood, potentially making Plaquenil ineffective for your autoimmune condition. If you need tuberculosis treatment while on Plaquenil, this interaction must be discussed with both your rheumatologist and infectious disease specialist.

Cimetidine (Tagamet)

Cimetidine, an older heartburn medication (H2 blocker), can significantly increase hydroxychloroquine blood levels by inhibiting its metabolism. Avoid concurrent use. Note: other H2 blockers (ranitidine, famotidine) and proton pump inhibitors (omeprazole, pantoprazole) do not appear to have this same interaction.

Antacids and Kaolin (Kaopectate)

Calcium-based antacids (Tums, Rolaids) and kaolin-pectin (found in some anti-diarrheal products) can reduce the absorption of hydroxychloroquine from the gut if taken at the same time. This is a minor interaction but easy to manage: simply separate your Plaquenil dose from any antacid or kaolin-containing product by at least 4 hours.

Tamoxifen

Tamoxifen (a hormone therapy used for breast cancer) combined with Plaquenil significantly increases the risk of retinal toxicity. Patients on both medications require annual ophthalmology exams from the start of combination therapy, not just after 5 years. This is one of the most important drug-related risk factors for Plaquenil eye damage.

Food and Supplement Interactions

There are no significant food interactions with Plaquenil. In fact, taking it with food is recommended to reduce GI side effects. Grapefruit juice has not been shown to interact with hydroxychloroquine. However, be cautious about herbal supplements—some immunomodulating herbs (like Thunder God Vine) may have additive effects with Plaquenil; always tell your doctor what supplements you take.

For a full overview of Plaquenil side effects, see: Plaquenil Side Effects: What to Expect and When to Call Your Doctor.