Retre-Gel Drug Interactions: What to Avoid and What to Tell Your Doctor

Retre-Gel (benzocaine topical 20%) is widely considered safe for short-term, low-dose use. However, it has 46 known drug interactions — 2 classified as major and 44 as moderate. Most of these interactions increase the risk of methemoglobinemia, the rare but serious blood disorder that the FDA has warned about since 2011. Knowing which interactions to watch for — and disclosing them to your provider — can prevent serious harm.

The Central Risk: Methemoglobinemia-Enhancing Interactions

The majority of Retre-Gel's drug interactions increase the risk of methemoglobinemia by adding to the oxidative burden on hemoglobin. When benzocaine and another methemoglobin-forming agent are used together, even a small dose of benzocaine can push hemoglobin oxidation high enough to cause symptoms.

Major Interactions (Avoid If Possible)

1. Nitrate and Nitrite Medications

This is the most important interaction to know. Using benzocaine topical with nitrate or nitrite medications significantly increases the risk of methemoglobinemia. These drugs include:

Nitroglycerin (Nitrostat, Nitro-Bid, Transderm-Nitro, Nitrolingual spray) — used for angina and acute chest pain

Isosorbide mononitrate (Imdur) — used for angina prevention

Isosorbide dinitrate (Isordil) — used for angina and heart failure

If you take any nitrate medications for heart disease, tell your dentist or doctor before they use benzocaine topical. They may choose a non-benzocaine alternative.

2. Dapsone

Dapsone is an antibiotic used for leprosy, some skin conditions (like dermatitis herpetiformis), and infection prophylaxis in immunocompromised patients. Simultaneous use of benzocaine and dapsone significantly increases the risk of methemoglobinemia. Case reports have documented serious methemoglobinemia in post-transplant patients on dapsone who received benzocaine during a procedure. Tell your provider if you take dapsone.

39,483+ patients found their medications in stock

39K+

Find Retre-Gel In Stock Today →

Moderate Interactions: 44 Known Interactions

Benzocaine has 44 moderate drug interactions. These are generally manageable with dose adjustments or monitoring, but your provider should be aware of them. The most clinically relevant categories include:

Other Topical and Injectable Anesthetics

Using multiple local anesthetics simultaneously (e.g., benzocaine topical plus lidocaine injection) may increase the total anesthetic load and the risk of methemoglobin formation. Always disclose all anesthetic exposures during dental or medical procedures.

Skip the calls, skip the stress.

Find Retre-Gel In Stock Today →

50K+

Medications
Found

99%

Success
Rate

6+

Hours saved
on average

Antimalarials and Certain Antibiotics

Certain antimalarials (chloroquine, primaquine) and sulfonamide antibiotics can independently cause methemoglobinemia. When used concurrently with benzocaine, the risk is additive. If you take any of these medications regularly, inform your dentist before any procedure involving topical benzocaine.

Prilocaine and EMLA Cream

Prilocaine — the second anesthetic in EMLA cream (lidocaine/prilocaine) — is also associated with methemoglobinemia formation. Using EMLA concurrently with benzocaine should be avoided, particularly in patients who are already at higher risk.

Disease Interactions: Conditions That Increase Risk

Benzocaine has one significant disease interaction: blood disorders that affect red blood cell function. These include:

G6PD (glucose-6-phosphate dehydrogenase) deficiency — a hereditary condition affecting red blood cell metabolism; significantly increases methemoglobinemia risk

Hemoglobin-M disease — a hereditary methemoglobin disorder

NADH-methemoglobin reductase deficiency — impairs the body's primary mechanism for clearing methemoglobin

Pyruvate kinase deficiency — affects red blood cell energy metabolism and resilience

If you have any of these conditions, benzocaine topical should be used with extreme caution or avoided entirely. Discuss alternatives with your dentist or physician before any procedure.

What to Tell Your Doctor or Dentist Before Using Retre-Gel

Always disclose the following before receiving or using Retre-Gel:

All current medications, including OTC drugs, supplements, and herbal products

Any history of allergic reactions to local anesthetics or PABA-containing products

Any known blood disorders (G6PD deficiency, hemoglobin-M disease, etc.)

Heart conditions, particularly if you take nitrate medications

Respiratory conditions (asthma, COPD, emphysema) and smoking history

Pregnancy or plans to become pregnant — benzocaine is Pregnancy Category C

For more on how side effects present, see Retre-Gel side effects. If you have contraindications to benzocaine, see alternatives to Retre-Gel.