What are the potential interactions between Unisom (doxylamine or diphenhydramine) and Paxlovid (nirmatrelvir and ritonavir) in an elderly female patient?

Unisom and Paxlovid Interaction in Elderly Female Patients

Unisom (doxylamine or diphenhydramine) can be safely continued with Paxlovid in elderly female patients, as antihistamines are not metabolized via CYP3A4 and do not have clinically significant interactions with ritonavir, though enhanced sedation and anticholinergic effects warrant close monitoring in this vulnerable population.

Drug Interaction Assessment

Mechanism of Interaction

• Ritonavir, the boosting component of Paxlovid, is a potent CYP3A4 inhibitor that causes drug-drug interactions during active treatment and possibly for several days after completion 1
• Doxylamine and diphenhydramine (the active ingredients in Unisom formulations) are primarily metabolized through glucuronidation and other non-CYP3A4 pathways, making them low-risk for pharmacokinetic interactions with Paxlovid 2, 3
• Among the top 100 prescribed drugs in the USA, antihistamines were not identified as having expected drug-drug interactions with nirmatrelvir/ritonavir 3

Clinical Risk Profile

• The Liverpool COVID-19 Drug Interaction Tool should be used to systematically check for specific interactions, as this is explicitly recommended in guidelines 1
• Real-world evidence analysis of 100 commonly prescribed drugs found that 70 drugs, including many classes not metabolized by CYP3A4, were not expected to have DDIs with nirmatrelvir/ritonavir 3
• The 30 drugs that do cause problematic interactions include corticosteroids, narcotic analgesics, anticoagulants, statins, and sedatives/hypnotics—notably, antihistamines are absent from this high-risk list 3

Special Considerations for Elderly Female Patients

Enhanced Pharmacodynamic Effects

• Elderly patients may experience enhanced sedation and anticholinergic effects (confusion, urinary retention, dry mouth, constipation) from antihistamines, even without pharmacokinetic interactions 4, 5
• A case report documented acute encephalopathy in an elderly patient receiving Paxlovid with benzodiazepines and narcotics, highlighting the vulnerability of this population to central nervous system effects from polypharmacy 5
• In a study of 163 elderly patients (median age 82 years) treated with Paxlovid, 89% had at least one concomitant disease, and no serious adverse events were observed with appropriate monitoring 4

Monitoring Recommendations

• Monitor for signs of excessive sedation, confusion, falls, and anticholinergic toxicity during the 5-day Paxlovid treatment course 1, 5
• Consider temporarily reducing the Unisom dose or using the lowest effective dose during Paxlovid treatment to minimize additive sedative effects 2
• Dysgeusia and diarrhea occur more frequently with Paxlovid than placebo, though these adverse effects did not lead to increased drug discontinuation rates in trials 1

Alternative Management Strategies

When to Consider Pausing Unisom

• If the elderly patient experiences significant sedation, confusion, or falls risk, temporarily pausing Unisom during the 5-day Paxlovid course is a pragmatic option 2
• Pragmatic options for managing DDIs with nirmatrelvir/ritonavir are largely confined to preemptive or symptom-driven pausing of the comedication or managing additional risk through counseling 2

Paxlovid Administration Guidelines

• Treatment must be initiated within 5 days of symptom onset for optimal effectiveness, with dosing of 300 mg nirmatrelvir with 100 mg ritonavir twice daily for 5 days 1
• For patients with moderate renal impairment, the dose should be reduced to 150 mg nirmatrelvir with 100 mg ritonavir twice daily for all 5 days 1

Common Pitfalls to Avoid

• Do not confuse the lack of CYP3A4-mediated pharmacokinetic interactions with the absence of pharmacodynamic interactions—elderly patients remain at risk for enhanced sedation 5
• Avoid assuming all sleep aids are safe; benzodiazepines and Z-drugs (zolpidem, eszopiclone) have different interaction profiles and may require dose adjustment 5, 3
• Reassess renal function during treatment if clinical deterioration occurs, as COVID-19 itself can cause acute kidney injury 1
• Do not discontinue Unisom without considering alternative sleep management strategies, as poor sleep can impair immune function and recovery 2