Can you take doxepin and ramelteon (Rozerem) together?

Combining Doxepin and Ramelteon for Insomnia Treatment

Yes, doxepin and ramelteon can be safely taken together, and this combination is specifically mentioned as a potential treatment strategy in clinical guidelines for insomnia. 1

Rationale for Combination Therapy

• Clinical guidelines explicitly list "Combined BzRA or ramelteon and sedating antidepressant" as a recommended treatment option for patients with primary insomnia when initial treatments are unsuccessful 1
• Doxepin (a sedating antidepressant) and ramelteon (a melatonin receptor agonist) target different aspects of insomnia:
  • Ramelteon is primarily effective for sleep onset insomnia (difficulty falling asleep) 1, 2
  • Doxepin is primarily effective for sleep maintenance insomnia (difficulty staying asleep) 1, 3

Pharmacological Considerations

• Ramelteon is metabolized primarily by CYP1A2 with minor involvement of CYP2C and CYP3A4 enzymes 4
• When co-administered with doxepin, ramelteon exposure may increase:
  • Studies show doxepin 10mg daily administration resulted in approximately 66% increase in overall exposure to ramelteon and 69% increase in maximum exposure 4
  • Patients should be monitored closely when these medications are used together 4

Dosing Recommendations

• Ramelteon: Recommended dose is 8mg taken 30 minutes before bedtime 1, 2
• Doxepin: Low doses (3mg and 6mg) are FDA-approved for insomnia and show efficacy with minimal side effects 1, 3
• Start with the lowest effective doses of both medications to minimize potential side effects 1

Efficacy Considerations

• Ramelteon:

  • Reduces latency to persistent sleep by 10-19 minutes compared to placebo 5, 6
  • Most effective for sleep onset difficulties 1, 2
  • Lacks abuse potential and does not cause next-day residual effects 7

• Doxepin:

  • Low-dose doxepin (3-6mg) improves sleep maintenance and duration 1, 3
  • Small to medium effect size for sleep maintenance parameters 3
  • Limited evidence for sleep initiation benefits 3

Monitoring and Safety

• Monitor for increased sedation due to the potential additive effects of both medications 1, 4
• Neither medication is classified as a controlled substance, reducing concerns about abuse potential 2, 7
• Follow patients regularly, especially during the initial treatment period, to assess effectiveness and side effects 1
• Common side effects to monitor:
  • Ramelteon: headache (7%), dizziness (5%), somnolence (5%) 5
  • Doxepin: headache and somnolence 3

Important Considerations

• Behavioral treatments (CBT-I) should be used alongside pharmacotherapy whenever possible 1
• Employ the lowest effective maintenance dosage and consider tapering when conditions allow 1
• Avoid alcohol when using these medications as it may have additive effects on sedation and psychomotor performance 4

Contraindications

• Ramelteon should not be used with fluvoxamine (strong CYP1A2 inhibitor) 4
• Use caution when combining with other strong CYP enzyme inhibitors 4
• Consider potential drug interactions with other medications the patient may be taking 1, 4