What drugs should not be co‑administered with NyQuil (acetaminophen, dextromethorphan, doxylamine, phenylephrine)?

Medications to Avoid with NyQuil

Do not take NyQuil with monoamine oxidase inhibitors (MAOIs) due to the risk of life-threatening serotonin syndrome and hypertensive crisis from the dextromethorphan component. 1, 2

Critical Drug Interactions

Absolutely Contraindicated (Do Not Combine)

• MAOIs (phenelzine, isocarboxazid, tranylcypromine, linezolid, selegiline): The dextromethorphan in NyQuil can trigger serotonin syndrome when combined with MAOIs, characterized by mental status changes, neuromuscular hyperactivity (tremors, rigidity), autonomic instability (hypertension, tachycardia, fever), and potentially fatal outcomes 1, 2

  • Wait at least 14 days after stopping an MAOI before using NyQuil 1

• Other serotonergic medications: Combining dextromethorphan with SSRIs, SNRIs, tricyclic antidepressants, or other serotonergic drugs increases serotonin syndrome risk 1

  • Examples include fluoxetine, sertraline, paroxetine, citalopram, venlafaxine, duloxetine, amitriptyline 1

• Sympathomimetic drugs: The phenylephrine in NyQuil should not be combined with other sympathomimetics (pseudoephedrine, amphetamines, midodrine) due to additive cardiovascular effects and hypertensive crisis risk, especially in patients on MAOIs 1, 3, 4

Use with Extreme Caution

• Alcohol: NyQuil already contains 10% alcohol; additional alcohol consumption increases acetaminophen hepatotoxicity risk, particularly in chronic alcohol users 5

  • Chronic alcohol use significantly increases risk of severe liver injury even at therapeutic acetaminophen doses 5

• Other acetaminophen-containing products: The acetaminophen in NyQuil (typically 325-650 mg per dose) must be counted toward the maximum daily limit of 3-4 grams to prevent hepatotoxicity 1

  • Many prescription opioid combinations (hydrocodone/acetaminophen, codeine/acetaminophen) and over-the-counter products contain acetaminophen 1, 6

• Antihypertensive medications: Phenylephrine can elevate blood pressure and counteract antihypertensive therapy 4

  • Particularly problematic with beta-blockers, calcium channel blockers, or in patients with uncontrolled hypertension 4

• Sedating medications: Doxylamine (antihistamine) in NyQuil has significant sedative effects that are additive with benzodiazepines, opioids, barbiturates, or other CNS depressants 1

• Anticoagulants and NSAIDs: Acetaminophen may increase bleeding risk when combined with warfarin, aspirin, or NSAIDs 1

Special Populations at Higher Risk

• Patients with hepatic impairment: Limit acetaminophen to ≤3 grams daily or avoid entirely in severe liver disease 1
• Patients with cardiovascular disease: Avoid due to phenylephrine's pressor effects 4
• CYP2D6 poor metabolizers (5% of European ancestry): Cannot metabolize dextromethorphan normally, leading to rapid toxic accumulation 7

Common Pitfall

The most dangerous oversight is failing to recognize that patients may be taking multiple products containing the same ingredients—particularly acetaminophen in prescription pain medications and dextromethorphan in other cough preparations—leading to unintentional overdose 1, 7, 6.