Can individuals, especially the elderly, young children, and those with pre-existing medical conditions like liver or kidney (renal) disease, overdose on antihistamines, such as diphenhydramine or chlorpheniramine?

Can You Overdose on Antihistamines?

Yes, antihistamine overdose is absolutely possible and can be life-threatening, particularly with first-generation antihistamines like diphenhydramine and chlorpheniramine. 1, 2, 3

Overdose Risk Profile

First-Generation Antihistamines (Diphenhydramine, Chlorpheniramine)

• Diphenhydramine was the most common antihistamine found in overdose deaths between 2019-2020, appearing in 15% of all US drug overdose deaths, with 3.6% of overdose deaths attributed to antihistamines alone. 2
• These medications cause deaths through accidental or intentional overdosing, particularly in infants, young children, teenagers, and adults. 3
• The FDA explicitly warns: "In case of accidental overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222)." 1
• Currently, there is no antidote for diphenhydramine overdose, making prevention critical. 2

Second-Generation Antihistamines (Cetirizine, Loratadine, Fexofenadine)

• The severity of poisoning from second-generation antihistamines is considerably lower than first-generation agents. 4
• Among 5,980 children exposed to second-generation antihistamines, only 9% were symptomatic, and 97% of symptoms were minor (primarily drowsiness or restlessness). 4
• Children remained asymptomatic even after ingesting doses 16 to 69 times the maximum recommended therapeutic dose, with no deaths, severe symptoms, QT prolongation, or arrhythmias observed. 4

High-Risk Populations

Elderly Patients

• First-generation antihistamines cause cognitive decline that is particularly severe in elderly populations, especially those with anticholinergic effects. 5
• Extra precautions are essential before prescribing diphenhydramine in elderly patients due to adverse renal and cognitive effects. 6
• Drivers taking first-generation antihistamines are 1.5 times more likely to be involved in fatal accidents. 7

Young Children

• Diphenhydramine should never be used to make a child sleepy, per FDA labeling. 1
• Deaths from accidental overdosing occur in infants and young children with first-generation antihistamines. 3
• Diphenhydramine is contraindicated in children under 6 years of age. 1
• Chlorpheniramine is contraindicated in children under 6 years of age. 8

Renal Impairment

• Cetirizine requires dose reduction in moderate renal impairment and should be avoided in severe renal impairment (creatinine clearance <10 mL/min) due to predominantly renal excretion. 9
• Diphenhydramine can cause acute kidney injury and has adverse effects in patients with pre-existing renal problems. 6
• Loratadine should be used with caution in severe renal impairment. 10

Hepatic Impairment

• Antihistamines require careful consideration in liver failure, though specific dosing adjustments vary by agent. 11

Maximum Safe Dosing

Diphenhydramine

• Maximum dose: 300 mg per 24 hours (6 doses of 50 mg every 4-6 hours). 1
• The FDA warns to "not take more than 6 doses in 24 hours." 1

Chlorpheniramine

• Maximum dose for adults: 24 mg per 24 hours (6 tablets of 4 mg every 4-6 hours). 8
• Maximum dose for children 6-12 years: 12 mg per 24 hours (3 half-tablets every 4-6 hours). 8

Critical Drug Interactions That Increase Overdose Risk

• Avoid combining antihistamines with alcohol, sedatives, or tranquilizers—these dramatically increase drowsiness and toxicity. 1
• Do not use with any other product containing diphenhydramine, including topical formulations. 1
• Marked drowsiness may occur even at therapeutic doses, impairing driving and machinery operation. 1

Common Pitfalls to Avoid

• Never assume over-the-counter availability means safety—first-generation antihistamines are dangerous despite being widely available without prescription. 3
• Do not use first-generation antihistamines for sleep in children; melatonin is the safer, evidence-based first-line option after behavioral interventions. 7
• Avoid first-generation antihistamines in patients prone to cardiovascular events, as those with mast cell activation syndrome are particularly vulnerable. 5
• Hydroxyzine is specifically contraindicated in early pregnancy and should never be used in this population. 10

When to Seek Emergency Care

Contact Poison Control (1-800-222-1222) or seek emergency medical help immediately if: 1

• Any amount exceeding maximum daily dosing is ingested
• Symptoms of overdose develop (excessive sedation, confusion, seizures, cardiac arrhythmias, urinary retention)
• Accidental ingestion occurs in children
• Co-ingestion with alcohol, sedatives, or other antihistamines occurs