Survey results from the United States on variations in compounding low dose atropine

Paper title: Compounding of Low-Concentration Atropine for Myopia Control

Authors: Kathryn Richdale (1), Erin S. Tomiyama (1), Gary D. Novack (2), and Mark A. Bullimore (1)

1. University of Houston, College of Optometry, Houston, Texas, USA.
2. PharmaLogic Development, Inc, San Rafael, CA; and Department of Ophthalmology & Vision Sciences, School of Medicine, University of California, Davis, California, USA.

Date: Dec 2022

Reference:  Richdale K, Tomiyama ES, Novack GD, Bullimore MA. Compounding of Low-Concentration Atropine for Myopia Control. Eye Contact Lens. 2022 Dec 1;48(12):489-492. [Link to abstract]

Atropine sulphate is commonly used in the United States for myopia control. An international survey of the prescribing habits of paediatric ophthalmologists¹ reported that 0.01% concentration atropine was the most prescribed concentration used for slowing myopia progression.

Although the Food and Drug Administration (FDA) in the United States approves 1% atropine for purposes other than myopia control, there is no current approval for concentrations under 1% when used to slow myopia progression. As a result, low concentration atropine is often used 'off-label' and a compounding pharmacy is used to supply this.

While using medications off-label is not uncommon, the FDA does not regulate compounded medicines. When compounding low dose atropine, pharmacies may use either powdered atropine or 1% atropine ophthalmic solution as the active ingredient and a range of diluting liquids and preservatives, meaning there may be differences in product quality, safety and efficacy.

This study investigated the approach for compounding, labelling and cost of low dose atropine from U.S compounding pharmacies.

A sample of compounding pharmacies were identified across 19 states in the U.S via social media, internet searches, conference meetings and optometric colleges. They were asked to provide information on:

• whether their compounding pharmacy was accredited by a national body
• the size of their standard low-concentration atropine bottle
• the cost, storage instructions and expiry period for each bottle
• if powdered atropine or commercially available solution was used for compounding
• the dilution solution used
• if a preservative-free option was available
• their standard shipping method

Of the 28 pharmacies approached, 26 agreed to provide information with 21 supplying answers to all questions asked.

• Nearly half of the responding pharmacies (46%) were accredited by a national body. Only one was not accredited with the Pharmacy Compounding Accreditation Board (PCAB).
• The most common bottle size was 5mL (approximately 100 drops, equating to a month's supply). 42% of pharmacies charged between $76-$100 for 10mL (median cost of $95)
• 62% of pharmacies advised that room temperature storage would suffice and 38% recommended refrigeration
• The expiry/beyond-use date was a mean of 65 days and 27% of pharmacies advised 180 days (6mths). Two pharmacies stated that the bottle needed to used within 28 or 30 days after opening
• For compounding preparation, 12 (50%) pharmacies used 1% commercially available atropine solution, 38% used powdered atropine, 2 used both and only 1 pharmacy used a proprietary approach.
• For dilution, 42% used artificial tears solution, 23% used saline and 27% used more than one ingredient. Proprietary dilution was used by 2 pharmacies.
• A preservative-free option was only available from 7 out of the 26 pharmacies.

1. This study found differences in the active ingredient and diluting agents used, storage advice and beyond-use dates from compounding pharmacies who produce low-dose atropine. This could impact safety and efficacy for myopia control.
2. Commercially available 1% atropine uses benzalkonium chloride (BAK) as a preservative. When combined with a non-preserved fluid, the BAK is further diluted. The non-standardised use of preservatives may affect sterility with the potential for infection.
3. The US FDA is closely monitoring the public health issue of variable quality at compounding pharmacies in the USA. Regulation of compounding in other parts of the world could vary. Eye care practitioners should be aware of the impact of potential variability in compounded formulations, and consider all treatment options before commencing compounded atropine treatment for myopia control.

The results from this survey revealed that a lack of standardised formulations for compounding low dose atropine, labelling and testing could lead to variations in safety and efficacy. Further research is needed to investigate the impact that this may have on the use of low-concentration atropine for myopia control, and comparisons between compounded and commercially formulated preparations, the latter of which are stringently tested and monitored for quality.

This study was conducted in the United States and as such, the results cannot be extrapolated to other countries where low dose atropine also needs to be compounded. Repeating the survey would show if the potential issues highlighted here hold true in other countries.

Title: Compounding of Low-Concentration Atropine for Myopia Control

Authors: Kathryn Richdale, Erin S. Tomiyama, Gary D. Novack, and Mark A. Bullimore

Purpose: Low-concentration atropine is commonly prescribed to slow myopia progression in children but is not Food and Drug Administration-approved for that indication and is only available in the United States from compounding pharmacies. The purpose of this study was to ascertain its reported compounding and labeling in the United States.

Methods: US compounding pharmacies were identified through a survey of eye doctors, social media, conferences, and web search. Twenty-eight pharmacies were identified and contacted through telephone and asked a standard set of questions about their methods to compound and label low-concentration atropine.

Results: Twenty-six pharmacies across 19 states provided responses, with 21 answering all nine items (81%) and a mean of 8.7 of nine responses. The most frequently reported bottle size was 5 mL (interquartile range [IQR]: 3.5-10). For storage, 10 pharmacies (38%) recommended refrigeration and 16 (62%) stated room temperature was sufficient. The median beyond-use date provided was 65 days (IQR: 45-158). For preparation, 12 pharmacies (50%) used commercially available 1% solution, 9 (38%) used powdered atropine, 2 (8%) used both, and 1 (4%) stated their approach was proprietary. For the added excipients, 11 (42%) used artificial tears only, 6 (23%) added 0.9% saline only, 7 (27%) used more than one ingredient, and 2 (8%) were proprietary. Only two pharmacies mentioned adding boric acid and two mentioned "pH-adjusted" saline.

Conclusions: There were a wide variety of formulation methods in the United States, which may affect atropine stability and potency. Similarly, there are a wide variety of storage and beyond-use recommendations. Further research is needed to assess how these variations may affect the efficacy and safety of low-concentration atropine and of myopia control.

[Link to abstract]