Rhofade may come with a heart valve damage risk

A recently published paper that seeks to compare the actions of oxymetazoline (Rhofade) and brimonidine (Mirvaso) has raised a possible safety issue with the action of oxymetazoline.

The paper states the safety issue as;

As the 5-HT_2B receptor is potentially involved in drug-induced valvulopathy, the benefit/risk ratio (of Rhofade ed.) should be carefully considered, especially in patients with cardiovascular disease or other comorbidities.

What is Valvulopathy?

Valvulopathy is the term to describe any disease to do with the valves of the heart. As you can imagine, this sort of risk is not to be glossed over lightly.

The 5-HT_2B receptor was observed to be activavted when exposed to oxymetazoline, but not brimonidine. This receptor is thought to possibly be involved with drug-induced valvulopathy.

Negligible activity was observed with brimonidine at the 5-HT_2B receptor, whereas oxymetazoline had significant 5-HT_2B receptor agonist activity and caused proliferation of mitral VICs in vitro.

Why didn’t Allegan tell us this?

We know from the prescribing information associated with Rhofade that (at least) the following conditions require supervision from your doctor;

severe or uncontrolled cardiovascular disease
orthostatic hypotension
uncontrolled hypertension/hypotension
cerebal or coronary insufficiency

And indeed Allergan has highlighted that Rhofade may affect cardiovascular disease, but no explicit mention of valvulopathy.

Once-Daily Treatment Reduces Persistent Facial Erythema (Redness) Associated With Rosacea Through 12 Hours
Potential Impacts on Cardiovascular Disease
Alpha-adrenergic agonists may impact blood pressure. RHOFADE should be used with caution in patients with severe or unstable or uncontrolled cardiovascular disease, orthostatic hypotension, and/or uncontrolled hypertension/hypotension. Advise patients with cardiovascular disease, orthostatic hypotension, and/or uncontrolled hypertension/hypotension to seek immediate medical care if their condition worsens.

Your doctor is your friend

The phenomenon of `diagnose and treat yourself’ has blossomed since the availability of Dr. Google. This study further confirms the importance of having the support of your doctor to try prescription treatments, even apparently simple topicals.

It is not all bad news

It remains unclear what concentrations are safe and admittedly systemic concentrations from topical treatment may be very low since mean maximum observed systemic concentrations reported for oxymetazoline cream were subnanomolar (0.4 nM)

As is usual for a lot of research, more investigation is required to determine the actual disease risk. Just how much system absorption of topical Rhofade might cause a safety issue – that is not known. Indeed the systemic absorption of Rhofade may be so low as to render this risk negligible.

Article Extracts

In Vitro Safety Pharmacology Profiling of Topical α-Adrenergic Agonist Treatments for Erythema of Rosacea
Piwnica, D., Pathak, A., Schäfer, G. et al. Drugs R D (2018). https://doi.org/10.1007/s40268-018-0227-y
Objectives
The objective of this in vitro safety pharmacology study was to compare the potential safety profiles of brimonidine and oxymetazoline.
Methods
Brimonidine and oxymetazoline underwent pharmacological profiling with a standard panel of 151 assays, including α-adrenergic receptors and 5-hydroxytryptamine (5-HT) receptors. A valvular interstitial cell (VIC) proliferation assay was performed with oxymetazoline hydrochloride.
Results
Brimonidine was highly selective for the α₂ adrenergic receptors, specifically α_2A, whereas oxymetazoline was found to be much less selective and was highly active against a wide range of targets. Negligible activity was observed with brimonidine at the 5-HT_2B receptor, whereas oxymetazoline had significant 5-HT_2B receptor agonist activity and caused proliferation of mitral VICs in vitro.
Conclusion
As the 5-HT_2B receptor is potentially involved in drug-induced valvulopathy, the benefit/risk ratio should be carefully considered, especially in patients with cardiovascular disease or other comorbidities.