What medication should not be taken with Phenergan? Understanding Dangerous Interactions

October 13, 2025 •

4 min read

According to the U.S. Food and Drug Administration (FDA), Phenergan is contraindicated in pediatric patients under 2 years old due to the risk of respiratory depression, a warning that highlights the severe consequences of improper use. For adults, knowing what medication should not be taken with Phenergan is critical for preventing serious complications, as its sedative and anticholinergic effects can be dangerously amplified by other drugs.

Quick Summary

Combining Phenergan with CNS depressants like alcohol and opioids, or with Monoamine Oxidase Inhibitors (MAOIs), poses a significant risk of severe side effects, including excessive sedation and respiratory depression. Always consult a healthcare provider to avoid dangerous drug interactions.

Key Points

Avoid CNS Depressants: Never combine Phenergan with alcohol, opioids, or benzodiazepines due to the high risk of severe sedation and respiratory depression.
Steer Clear of MAOIs: Monoamine Oxidase Inhibitors (MAOIs) can cause serious interactions, including extrapyramidal effects, when taken with Phenergan.
Watch for Anticholinergic Overload: Combining Phenergan with other anticholinergic drugs increases side effects like dry mouth, blurred vision, and confusion.
Be Cautious with Antipsychotics: Combining Phenergan with antipsychotic drugs heightens the risk of extreme sedation and Neuroleptic Malignant Syndrome (NMS).
Consult a Doctor Before Use: Always inform your healthcare provider about all medications and supplements you take to screen for potential interactions before starting Phenergan.
Do Not Use Epinephrine for Overdose: If hypotension occurs after a Phenergan overdose, do not use epinephrine, as Phenergan can reverse its vasopressor effect.
Avoid Sedating Herbal Supplements: Certain herbal products like valerian and passionflower can have additive sedative effects and should be avoided.

Promethazine, the active ingredient in the brand-name medication Phenergan, is a powerful antihistamine used to treat allergies, motion sickness, and nausea. While effective, it has strong sedative and anticholinergic properties that can lead to hazardous interactions with other medications. The most critical interactions involve additive effects with other Central Nervous System (CNS) depressants, which can suppress breathing and cause extreme drowsiness.

Dangerous Combinations to Avoid

Central Nervous System (CNS) Depressants

Promethazine's most significant drug interactions occur with other substances that depress the CNS. This additive effect can lead to severe drowsiness, confusion, and potentially life-threatening respiratory depression. This is why combining Phenergan with any of the following should be done with extreme caution or completely avoided, as directed by a healthcare professional.

Alcohol: Consuming alcohol while taking Phenergan significantly amplifies the sedative effects, increasing the risk of overdose, unconsciousness, and respiratory failure. The combination can cause severe dizziness, difficulty staying awake, and slow or shallow breathing.
Opioids: Pain medications like codeine, hydrocodone (Norco), and oxycodone (Percocet) are powerful CNS and respiratory depressants. Mixing them with promethazine can lead to profound sedation and respiratory depression. Historically, this dangerous combination was available in prescription cough syrups, but due to misuse risks, the FDA has issued warnings. Doses of opioids must be significantly reduced if a provider deems co-administration necessary.
Benzodiazepines and Other Sedatives: Prescription medications for anxiety and sleep, such as alprazolam (Xanax), diazepam (Valium), and lorazepam (Ativan), intensify promethazine's sedative and CNS depressant effects. The risk of oversedation and impaired mental function is high.
Other Antihistamines: Combining Phenergan, which is a sedating antihistamine, with other sedating antihistamines like diphenhydramine (Benadryl), can lead to excessive drowsiness and anticholinergic side effects.

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs are a class of antidepressants that include phenelzine (Nardil) and tranylcypromine (Parnate). Combining Phenergan with an MAOI is a serious interaction. It can lead to an increased incidence of extrapyramidal symptoms (involuntary muscle movements, tremors) and potential severe effects. A dangerous interaction could occur, and a washout period is required when switching between these medications.

Anticholinergic Medications

Promethazine itself has anticholinergic properties, which block the neurotransmitter acetylcholine. Combining it with other anticholinergic drugs, such as those used for overactive bladder (oxybutynin) or Parkinson's disease (benztropine), can have additive effects. This can worsen side effects like dry mouth, blurred vision, constipation, and confusion, particularly in older adults.

Antipsychotic Drugs

Taking Phenergan alongside antipsychotic medications like risperidone or olanzapine can increase the risk of CNS depression and severe side effects. This combination also elevates the risk of a rare but life-threatening condition called Neuroleptic Malignant Syndrome (NMS), characterized by high fever, muscle rigidity, and altered mental status.

Other Important Interactions

Epinephrine: Phenergan can reverse the vasopressor effects of epinephrine. Therefore, epinephrine should not be used to treat low blood pressure resulting from a Phenergan overdose. Other vasopressors, like norepinephrine, are the preferred treatment.
Herbal Supplements: Certain herbal remedies known for their sedative properties, including valerian root, passionflower, and evening primrose oil, should be avoided. These can enhance the CNS depressant effects of Phenergan. Evening primrose oil, in particular, may increase the risk of seizures when combined with phenothiazines like promethazine.
Seizure Medications: Promethazine can lower the seizure threshold, especially in individuals with a history of seizures. Combining it with medications that also affect the seizure threshold, such as certain narcotics or local anesthetics, requires caution.

Potential Interactions: Phenergan vs. Other Drug Classes


Drug Class	Potential Interaction	Consequences
CNS Depressants (Opioids, Alcohol, Benzos)	Additive sedative and respiratory depressant effects.	Excessive drowsiness, impaired judgment, respiratory depression, coma, and serious health consequences.
Monoamine Oxidase Inhibitors (MAOIs)	Increased risk of extrapyramidal side effects.	Involuntary movements, tremors, rigidity, and potential severe hyperthermia.
Anticholinergics	Additive anticholinergic effects.	Increased dry mouth, blurred vision, constipation, urinary retention, and confusion.
Antipsychotics	Increased sedation and risk of Neuroleptic Malignant Syndrome (NMS).	Exaggerated drowsiness, CNS depression, and severe complications like NMS.
Epinephrine	Reversal of epinephrine's vasopressor effect.	Epinephrine is ineffective for treating hypotension caused by Phenergan overdose.
Herbal Supplements (Valerian, Passionflower)	Additive sedative effects.	Enhanced drowsiness and CNS depression.

Conclusion: Prioritize Safety and Medical Consultation

Taking Phenergan with other medications is not a decision to be made lightly. The risks, particularly when combining it with CNS depressants like alcohol and opioids, can be life-threatening. The additive effects of sedation and respiratory depression are severe, and other interactions can lead to dangerous side effects such as NMS or increased anticholinergic symptoms. Always inform your healthcare provider of all prescription medications, over-the-counter drugs, and herbal supplements you are taking before starting Phenergan. A pharmacist is also an excellent resource for checking potential drug interactions. Being proactive about understanding these risks is the best way to ensure your safety and the effectiveness of your treatment.

For more detailed information on drug interactions, the FDA's labeling information is a comprehensive source(https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/07935s030lbl.pdf).

Frequently Asked Questions

No, you should never combine Phenergan with alcohol. Alcohol significantly increases the sedative and CNS depressant effects of Phenergan, leading to severe drowsiness, impaired coordination, and a dangerously high risk of respiratory depression.

No, combining Phenergan with opioids like codeine or oxycodone is extremely dangerous. The combination can cause profound sedation and respiratory depression. If you are on an opioid, your doctor must carefully manage and potentially reduce the dose if Phenergan is necessary.

Mixing Phenergan with benzodiazepines like Xanax or Valium is very risky. Both medication classes cause CNS depression, and their combined effect can lead to excessive drowsiness, mental impairment, and severe breathing problems.

Combining Phenergan with other sedating antihistamines, such as diphenhydramine (Benadryl), can cause excessive drowsiness, dizziness, and amplify anticholinergic side effects like dry mouth and constipation.

Yes, Phenergan can interact with certain antidepressants. It should not be used with Monoamine Oxidase Inhibitors (MAOIs) like phenelzine due to a risk of severe side effects. Combining it with Tricyclic Antidepressants (TCAs) can also cause increased sedation.

Yes. Herbal supplements with sedative properties, including valerian root, passionflower, and evening primrose oil, should be avoided when taking Phenergan. They can intensify the sedative effects and increase the risk of complications.

Signs of a dangerous interaction include extreme drowsiness, severe confusion, slow or shallow breathing, difficulty waking up, or involuntary muscle movements. If you experience any of these symptoms, seek immediate medical attention.