Drug Interaction Between Restavit (Doxylamine) and Fluvoxamine
There is a clinically significant interaction between Restavit (doxylamine, a sedating antihistamine) and fluvoxamine that requires caution due to increased sedation and central nervous system depression, though this combination is not absolutely contraindicated.
Mechanism of Interaction
Fluvoxamine is a potent inhibitor of multiple cytochrome P450 enzymes, including CYP1A2, CYP2C19, CYP2C9, and CYP3A4, which substantially increases the risk of drug interactions with medications metabolized through these pathways 1, 2.
The primary concern is pharmacodynamic rather than pharmacokinetic: Both doxylamine (the active ingredient in Restavit) and fluvoxamine cause central nervous system depression and sedation, leading to additive effects when combined 1, 3.
Fluvoxamine's FDA label specifically warns about increased sedation when used concomitantly with other CNS depressants, and muscle relaxants (which share similar sedative properties) require careful monitoring for this effect 1, 3.
Clinical Significance and Risk Assessment
The interaction is classified as requiring dose adjustment, altered timing, or additional monitoring rather than absolute contraindication, based on hepatitis C treatment guidelines that categorize benzodiazepines (which share similar CNS depressant properties with antihistamines) as requiring caution but not prohibition when combined with medications 1.
Fluvoxamine has a very low overall reporting rate of drug-drug interactions (73 cases from over 8 million patients worldwide), though most reported events involve psychotropic compounds 4.
The risk is highest in specific populations: elderly patients, those with hepatic or renal dysfunction, and patients taking multiple CNS depressants are at increased risk of excessive sedation, cognitive impairment, and falls 1.
Management Recommendations
If this combination must be used:
Start doxylamine at the lowest effective dose (typically 6.25-12.5 mg rather than the standard 25 mg) and increase only if necessary while monitoring closely for excessive sedation 1, 2.
Administer doxylamine at bedtime only and avoid daytime dosing to minimize functional impairment and fall risk 1.
Monitor closely for the first 24-48 hours after starting the combination or any dose changes, watching specifically for confusion, excessive drowsiness, impaired coordination, and respiratory depression 2, 5.
Warn patients explicitly about increased sedation, impaired driving ability, and fall risk, and advise against alcohol use or other CNS depressants 3.
Consider therapeutic drug monitoring of fluvoxamine if available (therapeutic range 150-300 ng/mL) to ensure levels are not excessive 2.
Safer Alternatives to Consider
For sleep disturbance:
Non-sedating antihistamines or non-pharmacological approaches should be considered first-line to avoid the interaction entirely.
If a sedative is necessary, consider melatonin or trazodone at low doses, which have fewer interaction concerns with fluvoxamine 6.
For the SSRI component:
If the primary goal is treating depression/anxiety and sleep is secondary, consider switching from fluvoxamine to citalopram or escitalopram, which have minimal effects on CYP450 enzymes and significantly lower propensity for drug interactions 2, 7.
Sertraline is another alternative with less effect on metabolism of other medications compared to fluvoxamine 7, 6.
Critical Pitfalls to Avoid
Do not assume "over-the-counter means safe": Patients often fail to report antihistamine use, and prescribers must specifically ask about all sleep aids, allergy medications, and cold remedies 2.
Do not dismiss early sedation as "normal adjustment": Excessive sedation that impairs function requires immediate dose reduction or discontinuation 2, 7.
Do not abruptly discontinue fluvoxamine if medication changes are needed; taper slowly to avoid discontinuation syndrome with symptoms including anxiety, agitation, and flu-like symptoms 2, 3.
Do not overlook cumulative effects: The combination of even therapeutic doses can produce clinically significant impairment, particularly in activities requiring alertness 1, 3.