Which of the following medications interact with BelSomra (suvorexant), a sleep aid: indomethacin, meloxicam, fish oil, Prolia (denosumab), pramipexole, atorvastatin, or gabapentin, in a patient with potential complex medical history and multiple comorbidities?

Drug Interactions with Belsomra (Suvorexant)

Among the medications listed, atorvastatin is the only one with a clinically significant interaction with Belsomra (suvorexant), requiring dose adjustments and monitoring, while the others have no documented significant interactions.

Atorvastatin: Clinically Significant Interaction

Atorvastatin requires careful management when combined with suvorexant due to shared CYP3A4 metabolism.

• Suvorexant is predominantly metabolized by CYP3A4 and demonstrates reversible inhibition of CYP3A4 with an IC50 of approximately 4-5 μM 1
• Atorvastatin is also a CYP3A4 substrate, creating potential for competitive inhibition when combined with suvorexant 2
• The American Heart Association recommends limiting atorvastatin to ≤10 mg daily when combined with moderate CYP3A4 inhibitors to minimize risk of muscle toxicity 3, 4

Monitoring Requirements for Atorvastatin + Suvorexant

• Obtain baseline creatine phosphokinase (CPK) levels before initiating combination therapy 3
• Monitor for muscle pain, tenderness, or weakness at each visit 4
• Check CPK levels immediately if any muscle symptoms develop 3
• Consider CPK monitoring every 3-6 months in asymptomatic patients on combination therapy 4

Alternative Statin Options

• Pravastatin ≤20 mg daily may be considered as a safer alternative, as it has less CYP3A4 dependence 4
• Fluvastatin ≤40 mg daily may also be considered with similar safety profile 4
• Pitavastatin represents another alternative with less reliance on CYP3A4 metabolism 3

Medications Without Significant Interactions

Indomethacin and Meloxicam: No Interaction

• No documented pharmacokinetic or pharmacodynamic interactions exist between NSAIDs and suvorexant 1
• Suvorexant does not inhibit or induce enzymes relevant to NSAID metabolism 1
• The combination of meloxicam and gabapentin shows additive effects in neuropathic pain models, but this is unrelated to suvorexant interactions 5

Fish Oil: No Interaction

• Omega-3 fatty acids do not interact with CYP3A4 pathways 1
• No documented interactions between fish oil supplements and suvorexant exist in the literature 1

Prolia (Denosumab): No Interaction

• Denosumab is a monoclonal antibody that does not undergo hepatic metabolism 2
• No CYP-mediated or transporter-mediated interactions occur with suvorexant 1
• Denosumab's mechanism of action (RANKL inhibition) is independent of pathways affected by suvorexant 2

Pramipexole: No Interaction

• Pramipexole is primarily renally eliminated without significant hepatic metabolism 1
• No documented interactions with CYP3A4 substrates like suvorexant exist 1

Gabapentin: No Interaction

• Gabapentin is not metabolized and is eliminated unchanged in urine 5
• No hepatic enzyme interactions occur with suvorexant 1
• Gabapentin does not affect CYP3A4 activity 5

Key Clinical Considerations

The primary concern in this medication list is the atorvastatin-suvorexant combination, which requires proactive dose limitation and monitoring.

• Suvorexant demonstrates weak time-dependent inhibition of CYP3A4 (KI = 12 μM, kinact = 0.14 min⁻¹), but at clinical doses, plasma concentrations remain low enough that significant drug interactions via CYP inhibition are not anticipated for most medications 1
• The exception is with other CYP3A4 substrates with narrow therapeutic indices, such as statins, where even modest increases in exposure can lead to muscle toxicity 2
• Advanced age increases the risk of muscle toxicity with statin combinations, making monitoring even more critical in elderly patients 3