Compounded atropine for myopia control: safe and effective prescribing

Most medications are commercially manufactured, or mass produced, where that drug has been approved by a country's regulatory body (such as the FDA in the United States). These drugs have had their efficacy, side effects and outcomes studied and extensively documented, and their manufacturing processes are regulated and continuously reviewed.¹ There are specific standards under GMP (Good Manufacturing Practices) to which all approved pharmaceutical manufacturers must adhere. Compliance with these standards comes at considerable expense, due to the acquisition and maintenance of the manufacturing and laboratory equipment.

Pharmaceutical compounding, by contrast, is the creation of a pharmaceutical preparation by a licensed pharmacist to meet the unique needs of an individual patient when a commercially available drug does not meet those needs.¹ Licensed pharmacists learn to perform compounding as part of their training and education. Examples of compounding could include making a powder into a cream, or in the case of atropine changing the commercially manufactured 1% atropine to lower concentrations desired for myopia control.

Simple compounding is the development of compounded medications using basic equipment that produces a non-sterile product using standard procedures and facilities.²

Complex compounding includes medications which must be produced in a sterile environment, and/or the compounded products themselves may not have much published literature detailing stability of efficacy. All compounded eye drops fit the definition of complex compounding as they must be sterile. Other examples of complex compounding include medications that may cause health and safety hazards such as hormones and cytotoxins, medications for parenteral administration (eg. intravenous or intramuscular), or that have very low concentrations/micro-doses of the active ingredient. It requires specialized skills, competencies and equipment compared to simple compounding.²

The answer to this may vary by country, based on the level of regulation, training and oversight. It would be fair to say that the majority of compounding pharmacies are high-quality and rigorous, providing crucial services for patients needing unique medications.

There have been reports, however, of some facilities exhibiting inappropriate sterilization techniques and compounding practices, and improper medication storage. The FDA in the United States has published reports on such, with serious incidents involving compounded medications for intravenous injection sadly resulting in fatalities. Isolated incidents in the UK and Australia indicate high-level risk factors such as parenteral (non-oral) use and/or in vulnerable patients, which have resulted in increased regulatory oversight and professional awareness.^1,3

The formulation of atropine could influence its efficacy. With few commercially manufactured preparations of low-concentration atropine available, many research studies use compounded versions. These are either diluted from commercially available 1% atropine or prepared from raw materials such as by dissolving atropine from a powder. While both methods could produce an accurate product, dilution alters the concentration of preservatives and other constituents which can influence the final product's stability, efficacy, comfort and consistency.⁴

Clinical studies on atropine don't always describe how the test medication was formulated or if any verification of accuracy or stability was performed. Some studies have utilized diluted preparations from 1% atropine,5 some don't describe the process6,7 and some, such as the Low-Concentration Atropine for Myopia Progression (LAMP) Study8 describe extra verification steps to ensure concentration, stability and sterility.

The fact that atropine is compounded may explain the variability in outcomes seen in some atropine studies, particularly in studies of 0.01% atropine. Atropine at low concentrations can be quite unstable.⁹ Variability in compounding could also be why some studies report minimal side effects with 0.01%, while other studies report problems with photophobia and accommodation.^10,11

Compounded topical atropine is typically produced in multi-dose bottles requiring preservatives. The commonly used preservative benzalkonium chloride, or BAK, is a known ocular surface irritant. Sensitivity to BAK can worsen over time and cause surface toxicity similar to allergy^12,13

The most common side effect of low-concentration atropine is allergic conjunctivitis,10 and this seems independent of concentration - even occurring in the placebo group.8 This points to the value of considering preservatives to ensure tolerance to long-term treatment, and seeking non-preserved formulations of topical atropine wherever possible.

As eye care practitioners, we are not chemistry experts and cannot hope to grasp the full scope of the field of complex medication compounding. Where available, a commercially manufactured drug is always the first choice to ensure verification of safety, efficacy, comfort and stability; but properly produced compounded medications can also be safe, effective and fulfil an important role for patients.^1,3

1. Do you have experience and equipment specifically for complex / sterile compounding of ocular medications?
   Most countries appear to require ophthalmic medications to be compounded under sterile conditions, although any additional qualifications required may vary.
2. Will you compound the medication by dilution of the commercial 1% product, or from raw materials?
   While either could result in an accurate product, this question could be followed with discussion on the pharmacist's preference and why. 
3. Will preservatives be used, and if so, which chemical?
   Keep in mind that BAK is a known ocular irritant,¹² so avoiding this for daily use in children is ideal. Preservative free is best - some multidose bottles can facilitate this, but may not be available for compounded medications or in your country.
   
4. What is the shelf-life of the compounded medication? Is there anything specific about the preparation or the bottle that influences this?
   This could lead to important information about medication safety for your patient and knowledge on packaging (bottle) technology and innovations.
   

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