You cannot take 4 vicodin at once. This is too much acetaminophen for your liver to handle and you are great risk of doing long term liver damage. Can I Take Benadryl While Taking Vicodin. Can I take Benadryl while taking Vicodin, separately and not on an empty stomach? Answer. Taking benadryl while taking Vicodin could increase the chances. The only concern that I would have, as a nurse, is that the potential for being very sleepy and groggy is potentially increased. There is no, per se, interaction with the drugs, it's just with diphenhydramine (benadryl) it causes sleepiness as well as hydrocodone. Diphenhydramine is an antihistamine that reduces the effects of natural chemical histamine in the body. Histamine can produce symptoms of sneezing, itching, watery eyes, and runny nose. It's my understanding it is perfectly fine to take together, BUT, I wouldn't do it if you are driving, etc. Also, it is always best to contact your local pharmacist who can assist you with drug interactions. Yes but makes drowsy. Hydrocodone is a pain medication that will cause drowsiness. Benadryl (diphenhydramine) is an anti-histimine which also causes drowsiness and sometimes will help boost the pain controlling effect of the hydrocodone, thus potentially reducing the dose that you need. Under normal circumstances, and if taken as directed. It shouldn't be a problem. Drowsiness is a side effect of both meds, so expect to be sleepy until your body adjusts, but in the proper doses there should be no interaction. Doctors give trusted answers on uses, effects, side-effects, and cautions: Dr. Fowler on benadryl and vicodin: Either the recommended amount based on weight through the directions on the box or following your doctors recommendations if the recommended dose they made is higher. You can take these two with each other unless Pharmaceutical companies are putting harmful products on the market. Advil PM capsules consist of Ibuprofen and diphenhydramine (Benadryl). Its made. I wouldn't recommend this; benadryl is an antihistamine with the side effect that it can make you sleepy, and hydrocodone, the active ingredient in Vicodin, can also cause drowsiness.