Retatrutide and Flexeril (Cyclobenzaprine) Combination Safety
There is no evidence of clinically significant drug-drug interactions between retatrutide and cyclobenzaprine (Flexeril), and these medications can be used together safely based on their distinct pharmacological profiles and lack of overlapping metabolic pathways.
Pharmacological Basis for Safety
The combination appears safe because these medications operate through completely different mechanisms without shared metabolic pathways:
- Retatrutide is a triple-hormone receptor agonist (GLP-1, GIP, and glucagon receptors) used for obesity and type 2 diabetes management 1, 2
- Cyclobenzaprine is a centrally-acting muscle relaxant with anticholinergic properties, metabolized primarily through CYP3A4, CYP1A2, and CYP2D6
Key Considerations
No Overlapping Toxicities
- Retatrutide's primary adverse effects are gastrointestinal (nausea, diarrhea, vomiting) and dose-dependent increases in heart rate 2, 3
- Cyclobenzaprine causes sedation, dry mouth, and dizziness through its anticholinergic and CNS depressant effects
- These distinct toxicity profiles suggest no additive or synergistic adverse effects when combined
Metabolic Pathway Analysis
- Retatrutide is a peptide administered subcutaneously and does not undergo significant hepatic CYP metabolism 2
- Cyclobenzaprine undergoes hepatic metabolism via CYP enzymes
- No pharmacokinetic interaction is expected as they do not compete for the same metabolic pathways
Monitoring Recommendations
While the combination is safe, monitor for:
- Gastrointestinal symptoms from retatrutide (nausea, diarrhea, vomiting), which occur in a dose-dependent manner and are typically mild-to-moderate 2, 3
- Heart rate changes with retatrutide, which can increase by up to 6.7 beats/min and peak at 24 weeks 4, 2
- Sedation from cyclobenzaprine, particularly if the patient is on other CNS depressants
Clinical Pitfalls to Avoid
- Do not confuse the lack of interaction data with contraindication—absence of evidence is not evidence of harm when pharmacological mechanisms are distinct
- Be aware that retatrutide causes substantial weight loss (8.7-24.2% at 48 weeks depending on dose) 2, which may affect overall medication dosing requirements for other conditions
- Cyclobenzaprine should still be limited to short-term use (2-3 weeks) as per standard practice, regardless of retatrutide co-administration