Like oral food challenges, there are some situations where the best and most accurate way to confirm or rule out a suspected drug allergy is by performing a drug challenge. This may involve oral administration of a suspected drug allergen, such as penicillin, or a low-dose injection of a medication such as lidocaine or another local anesthetic used in dental work.

Following a drug challenge, the patient is monitored for a possible allergic reaction, usually for an hour, and of course would be treated appropriately should any concerning symptoms develop.