Can a Patient on Ondansetron Also Take Benadryl or Hydroxyzine?
Yes, a patient taking ondansetron can safely take either Benadryl (diphenhydramine) or hydroxyzine, as both antihistamines are explicitly recommended in clinical guidelines as adjunctive therapies with ondansetron for managing nausea, vomiting, and opioid-related side effects. 1
Evidence Supporting Combination Use
Guideline-Based Recommendations
Multiple major oncology guidelines explicitly endorse combining ondansetron with antihistamines:
The ASCO guidelines specifically list "sedating antihistamines such as hydroxyzine or diphenhydramine" as appropriate treatments for opioid-induced pruritus, even when ondansetron is being used concurrently 1
The NCCN guidelines list both diphenhydramine and ondansetron as breakthrough treatment options that can be used together, with diphenhydramine dosed at 25-50 mg PO or IV every 4-6 hours 1
ASCO antiemetic guidelines state that "lorazepam or diphenhydramine are useful adjuncts to antiemetic drugs" including 5-HT3 antagonists like ondansetron 1
Clinical Context for Combined Use
These medications work through different mechanisms and are routinely combined:
- Ondansetron blocks serotonin 5-HT3 receptors centrally and peripherally 2
- Diphenhydramine and hydroxyzine block histamine H1 receptors and have anticholinergic effects 1
- The combination is particularly useful for managing multiple symptoms: ondansetron for nausea/vomiting, antihistamines for pruritus, anxiety, or additional antiemetic effect 1
Important Safety Considerations
QT Prolongation Risk
Both ondansetron and hydroxyzine carry warnings about QT prolongation, requiring caution when used together:
Ondansetron's FDA label warns about QT prolongation and recommends ECG monitoring in high-risk patients (electrolyte abnormalities, heart failure, bradyarrhythmias) 3
Hydroxyzine's FDA label specifically lists ondansetron as a drug that may prolong QT interval and recommends caution with concomitant use 4
Monitor patients with cardiac risk factors, electrolyte imbalances, or those taking other QT-prolonging medications 3, 4
Sedation and CNS Depression
Additive sedation is the primary practical concern:
Hydroxyzine's FDA label emphasizes that "the potentiating action of hydroxyzine must be considered when used in conjunction with central nervous system depressants" 4
Both diphenhydramine and hydroxyzine cause sedation, which may be additive with ondansetron's mild sedative effects 1
Warn patients about increased drowsiness and advise against driving or operating machinery 4
In elderly patients, start with lower doses due to increased risk of confusion and oversedation 4
Practical Dosing Recommendations
When Combining These Medications
For breakthrough nausea with ondansetron already on board:
- Add diphenhydramine 25-50 mg PO/IV every 4-6 hours as needed 1
- Alternatively, add hydroxyzine 25-50 mg PO every 6-8 hours 1
For opioid-induced pruritus in patients already receiving ondansetron:
- Use hydroxyzine or diphenhydramine if sedation is acceptable 1
- Consider non-sedating antihistamines first if excessive sedation is a concern 1
Monitoring Parameters
When using this combination, monitor for:
- Signs of excessive sedation or CNS depression 4
- Cardiac symptoms if patient has risk factors for QT prolongation 3, 4
- Anticholinergic effects (urinary retention, confusion, dry mouth) particularly in elderly patients 4
Common Pitfalls to Avoid
Do not assume these drugs cannot be combined - the evidence clearly supports their concurrent use 1
Do not use first-generation antihistamines like diphenhydramine for infusion reactions - they can worsen hypotension; use second-generation antihistamines instead in that specific context 1
Do not overlook cardiac risk factors - obtain baseline ECG in patients with known heart disease, electrolyte abnormalities, or multiple QT-prolonging medications 3, 4
Do not use standard adult doses in elderly patients - start low with hydroxyzine due to increased sensitivity 4