Melatonin and Fluvoxamine Combination: Safety and Clinical Considerations
Yes, melatonin and fluvoxamine can be taken together, but this combination results in dramatically elevated melatonin levels (12-17 fold increase) due to potent metabolic inhibition, requiring dose adjustment and clinical monitoring. 1
Mechanism of Interaction
Fluvoxamine is a potent inhibitor of CYP1A2, the primary enzyme responsible for melatonin metabolism, leading to markedly increased melatonin bioavailability. 2
- Fluvoxamine inhibits CYP1A2 with a Ki of 0.02 μM for 6-hydroxymelatonin formation and 0.05 μM for N-acetylserotonin formation 2
- Coadministration increases melatonin AUC by 17-fold and peak concentration (Cmax) by 12-fold on average 1
- The terminal elimination half-life of melatonin is not significantly affected, but bioavailability is dramatically increased 1
- This interaction is specific to fluvoxamine; other SSRIs like citalopram do not significantly affect melatonin levels 3
Clinical Implications
The elevated melatonin levels persist into morning hours, extending the duration of melatonin secretion well beyond normal physiological patterns. 4
- High melatonin levels can extend into the morning, potentially causing daytime sedation 4
- There is a direct correlation (r = 0.63; P < 0.01) between melatonin and fluvoxamine serum concentrations 1
- Patients who are CYP2D6 poor metabolizers experience more pronounced and longer-lasting effects 1
Dosing Recommendations
When combining these medications, start with significantly reduced melatonin doses (0.5-1 mg rather than standard 3-10 mg doses) due to the massive increase in bioavailability. 5, 1
- Standard melatonin doses for circadian rhythm disorders range from 3-15 mg 5
- With fluvoxamine coadministration, even 5 mg melatonin produces 12-fold higher peak concentrations 1
- Monitor for excessive sedation, morning grogginess, and daytime sleepiness 5
Safety Profile
Melatonin is generally safe with few serious adverse effects reported, even at doses up to 10 mg daily for extended periods. 5
- Common side effects at higher doses include headaches, somnolence, hypotension, hypertension, and gastrointestinal upset 5
- Melatonin has been associated with increased depressive symptoms in some cases 5
- Use caution in patients taking warfarin or those with epilepsy 5
- Recent data suggests potential impairment in glucose tolerance in healthy women 5
Monitoring Parameters
Monitor closely for signs of excessive sedation, particularly during the first few weeks of combination therapy and after any dose adjustments. 5
- Assess for morning sedation and impaired daytime functioning 4
- Evaluate sleep quality and timing of sleep onset/offset 5
- Consider checking for orthostatic hypotension, particularly in elderly patients 5
- Monitor mood, as both medications can affect depressive symptoms 5
Special Populations
Elderly patients and those with hepatic impairment require particular caution due to altered drug metabolism and increased sensitivity to sedative effects. 5
- Long-term pediatric studies (mean ~4 years) with melatonin doses up to 10 mg showed no serious adverse events 5
- No significant effects on pubertal development were detected in children/adolescents using melatonin (mean dose ~3 mg) for approximately 3 years 5
- CYP2D6 poor metabolizers experience more pronounced interactions 1
Product Quality Considerations
Use U.S. Pharmacopeial Convention Verified melatonin products to ensure reliable dosing, as melatonin is a dietary supplement with variable quality control. 5
- Melatonin supplements are not subject to FDA medication scrutiny in the United States 5
- Concerns exist about purity and reliability of stated doses across formulations 5
- The U.S. Pharmacopeia Verification Mark indicates verified content 5
Contraindications to Fluvoxamine
Do not use fluvoxamine in combination with monoamine oxidase inhibitors, and exercise caution in patients at high risk for glaucoma. 5
- Contraindicated with MAOIs 5
- Risk of acute angle-closure glaucoma in susceptible patients 5
- Risk of suicidal behavior/ideation in people younger than 24 years 5
- Contraindicated in patients with unmanaged hypertension when combined with certain other medications 5
Alternative Considerations
If excessive sedation occurs with the combination, consider using melatonin alone at standard doses or switching to an alternative SSRI that does not inhibit CYP1A2. 3, 2