Diphenhydramine

Contraindicated in patients with known long QT syndrome or other conditions predisposing to QT prolongation. The hERG channel blockade can trigger fatal torsade de pointes in susceptible individuals.

Relative contraindication in patients with severe COPD, asthma, or obstructive sleep apnea. The sedative and anticholinergic effects can compromise respiratory function, particularly when combined with other CNS depressants.

Antihistamines including diphenhydramine can worsen restless legs syndrome symptoms. Patients presenting with sleep complaints should be screened for RLS before prescribing or recommending diphenhydramine.

Relative contraindication in hepatic impairment. The elimination half-life extends to 9–15 hours (vs. ~9 hours in healthy adults), increasing the risk of accumulation with repeated dosing and potentiating anticholinergic and CNS depressant effects.

Contraindicated during breastfeeding. Diphenhydramine is excreted in breast milk at concentrations sufficient to cause sedation in nursing infants.

Diphenhydramine is contraindicated in neonates and premature infants due to the risk of fatal respiratory depression. Immature hepatic CYP2D6 activity impairs metabolism, and the neonatal respiratory center is highly sensitive to CNS depressants.

Relative contraindication in elderly patients. High per-dose anticholinergic burden increases risk of falls, delirium, cognitive impairment, and may contribute to long-term dementia risk. The American Geriatrics Society Beers Criteria lists diphenhydramine as potentially inappropriate for older adults.

Regulatory agencies recommend against the use of antihistamine/decongestant products in children under 2 years of age due to the risk of serious adverse events including respiratory depression.

Contraindicated in narrow-angle glaucoma. The antimuscarinic mydriatic effect can trigger acute angle-closure crisis, a medical emergency requiring immediate ophthalmological intervention.

Relative contraindication in patients with benign prostatic hyperplasia or other lower urinary tract obstruction. Risk of acute urinary retention due to antimuscarinic effects on bladder function.