What's in the atropine bottle? Q&A With Professor Mark Bullimore

Our Q&A format is designed to explore a particular clinical topic, intervention, product or research paper with an expert. In this interview we asked some key atropine questions of Professor Mark Bullimore, arguably one of the world's thought leaders in myopia; being co-author of landmark papers in the field such as Myopia Control: Why Each Diopter Matters, Efficacy in Myopia Control and The Risks and Benefits of Myopia Control. Professor Bullimore's latest publication explores the characteristics of compounded low-concentration atropine, which is currently the primary method by which eye care practitioners are able to prescribe this treatment for access by their patients. Is what's on the label found in the bottle? What other impacts could there be? Read on to learn more about the present and future of atropine treatment for childhood myopia.

Prof. Bullimore: With spectacles and contact lens, there are a variety of designs with varying levels of myopia control efficacy. Considering spectacles, progressive addition lenses have limited efficacy slowing progression by 0.25 D over three years.¹ This applies to all myopes, including esophores.² Flat top bifocals have a mixed history with some clinical trials showing meaningful efficacy,³ while others show modest or no slowing.⁴ The new generation of designs incorporating peripheral lenslets appear to have robust efficacy.^{5, 6}

Studies have shown that the efficacy of atropine in slowing myopia progression and axial elongation is primarily dependent on its concentration. Higher concentrations of atropine have been shown to be highly effective in slowing myopia progression but result in potentially debilitating mydriasis and cycloplegia.⁷ Lower concentrations offer meaningful slowing of progression and are well tolerated.⁸ The choice of concentration is best determined by the eyecare practitioner's assessment of the individual patient.

Prof. Bullimore: In the United States (US), low-concentration atropine can only be obtained through compounding pharmacies and is not FDA-approved to treat myopia. US Food and Drug Administration (FDA)-approved drugs undergo rigorous testing, and manufacturers are required to follow current good manufacturing practices in order to consistently produce high quality products.⁹ Compounding pharmacies are generally held under the authority of state boards of pharmacy.^{9, 10}

We surveyed 26 pharmacies across 19 US states.¹¹  There were a wide variety of formulation methods, which may affect atropine stability and potency. This includes the source of the active pharmaceutical ingredient, the liquid, the excipients and the preservatives. Similarly, there are a wide variety of storage and beyond-use recommendations. Unlike FDA-approved products, compounded medications are not routinely analyzed.  Some pharmacies may employ analytical methods if batches of drug are being compounded, but it is highly unlikely that any assessment of stability is made.

Prof. Bullimore: Efficacy is influenced by the stability of the formulation. Atropine is relatively unstable as it is susceptible to hydrolysis, and the rate of degradation is influenced by pH and the ingredients used in formulation.^{12, 13} The degradation products, tropic acid and apoatropine, do not have anticholinergic activity and thus reduce efficacy. Lower concentrations of atropine degrade more rapidly.

Our recent analysis of compounded atropine¹⁴ found that the concentration relative to the prescribed concentration was as low as 70% and a quarter of all samples were under the 90% minimum target concentration. There was a significant correlation between higher pH and higher tropic acid concentration. In other words, the more neutral the pH, the greater the degradation. Of course, a lower pH may sting slightly, potentially influencing acceptance.

Prof. Bullimore: Sterility is a key feature. This can be achieved by preservatives, but this may be a cause for concern, given that a child will likely use the drops for several years. The long-term effects of chemicals such as BAK on a child's cornea are unknown. High levels of BAK could cause irritation and can be toxic to the ocular surface.¹⁵ Allergic reactions are known to occur with chronic use of BAK-preserved ophthalmic medications.^{15, 16} An attractive alternative is a preservative-free single dose.

Prof. Bullimore: The book on atropine for myopia control is still in early draft form. We know that 1% works best, but that it is unacceptable to most children. The chronic pupil dilation presents its own challenges for long-term retinal health. We have some early, quality data on delaying onset with low concentration atropine, but only on Chinese children. Indeed, the bulk of the published research in the field is on East Asians. Atropine does not correct myopia, so optical therapies have something of an advantage. We need to know how best to combine atropine with the optical therapies that work well. Finally, an atropine-eluting soft contact lens may be an attractive option. In the meantime, practitioners need to ask themselves and their compounding pharmacies, "what's in the bottle?"¹⁴

• Clinical Article: Compounded Atropine For Myopia Control - Safe And Effective Prescribing

• Case Study: Compounded Topical Atropine - Is Every Bottle The Same?

• Case Study: Atropine Eye Drops And Ocular Allergy - What's The Cause?

• Science Summary: The LAMP Study Data Over Three Years: 0.05% Atropine Leads And Minimally Rebounds