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Compounded topical atropine: is every bottle the same?

 Posted on March 8th 2022 by Connie Gan

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How consistent is compounded topical atropine from bottle-to-bottle? What clinical results could indicate variability?

Low-concentration atropine is not commercially available in most countries at present. Hence, prescriptions for low-concentration atropine drops need to be compounded for each individual patient. Can the efficacy of compounded atropine drops differ from one compounded batch to the next? Here is a case from PC where a similar concentration of low-concentration atropine elicited variable side effects over time.

PC An interesting case to ponder on the effects of atropine and whether one bottle of compounded atropine is the same as another. I’ve been managing an 8yo girl with a strong family of myopia (mum -11.00, dad -6.00). She started on 0.02% atropine with glasses at -2.00, then MiSight, then OrthoK, and continued to show progression on all treatments. Axial elongation in the past 9 months had been around 0.5mm/year while using OrthoK and 0.02% atropine. Still too much for my liking. I noticed her pupils weren’t particularly large considering the 0.02% atropine, about 4.3mm on average. I questioned her compliance with the eye drops and she indicated she used them nightly 30 minutes before her OrthoK lenses. Is she simply a poor responder to atropine? Should I try a higher dosage? Or is this the best control we can achieve for her? I decided to try a different compounding chemist and issued her with 0.025% atropine. At today’s review, 2 months after her last, there was no axial length progression! None! Her pupils were also more dilated, at 6mm. Assuming compliance to be the same, that’s a significantly different ocular response to (almost) the same dosage of atropine. Does the therapeutic effect of atropine vary with the way it is compounded? Her sisters, with only mild progression on the same treatment strategy, also showed less progression in these 2 months. While I need longer term data to verify the effect is sustained and not due to measurement error, so far it’s encouraging.

Compounded atropine: is it the same from bottle-to-bottle?

BR I’ve come across information that talks about the stability of atropine? Could it be the initial dose was not stable so inconsistent & by the time it’s instilled it’s actually much weaker than initially prescribed?GO We (disclosure financial interest as patent holder) have measured this quite extensively. You are correct on both fronts - measured concentrations "right out of the box" from different or either the same compounder have had significant differences. There are compounders who are much more reliable than others. Also, as you previously stated stability is an issue so you need to make sure the drops were compounded for your patient and not an old batch…GO …Atropine is most stable at pH in the 3.5-4 range (not useful for an eye drop). Higher concentrations self buffer but lower concentrations do not (not enough tropic acid). Depending on what you consider reasonable purity/potency numbers, non-pH adjusted/non buffered (compounded) dilute atropine has a few months of useful stability. Not reasonable unless you compound as needed.

A second batch of low-concentration atropine, changing from 0.02% to 0.025%, led to an increase in pupil size of almost 2mm. It would not be expected to see such a change with a 0.005% increase in concentration, especially considering that both 0.025% and 0.05% had similar impact on pupil size in the LAMP Study.1

The stability of compounded atropine may play a role in this case. The preparation method, other components used, preservatives, pH, and temperature can affect its stability and shelf-life.2 You can read more about this in Compounded Atropine For Myopia Control: Safe And Effective Prescribing.

Is the observed axial growth normal?

DS Why do you feel that the earlier axial length growth was excessive? Could the cessation of axial progression be developmental and independent of both the atropine and orthokeratology treatment in this case?...PC 0.5mm/year of axial length growth is still 1D/year. I verified that refractive change with an OK washout. I think that’s excessive. Sure, she might progress at 2D/year without intervention, but I believe in doing as much as possible within the limitations of our tools. Do you think cessation of axial progression occurs naturally at age 8? Not in my experience… RN I agree with DS, you need to look at the difference in axial length change compared to the norm for that age and race. Because from memory I thought ~0.35mm change per year is normal in children. 0.5mm still high, but in the grand scheme of things, it could have easily been 1mm per year without treatment.

In the CLEERE and SCORM studies, the 'normal' axial elongation of 8-year-old emmetropic children is 0.16mm/year and 0.22mm/year respectively.3,4 For progressing myopes, the COMET study showed that axial elongation was 0.3mm/year in children of the same age.5 This patient's 0.5mm/year axial elongation, while undergoing various myopia control treatments, exceeds the average rate of progression in an untreated (single vision corrected) myope. Therefore it was reasonable of PC to consider this an unsatisfactory myopia control outcome and seek to alter treatment.

As highlighted by other commenters, it is impossible to know what this child's axial length progression could have been without myopia control treatment - whether it could have been much faster or similar. The average 'untreated' axial elongation of 0.3mm/year for an age-matched child is just that - an average. Children can fall above or below that average, but for those notably exceeding the average it is worth considering the most effective treatment.

Currently, there is no clear 'best' treatment, with the best in each category of "orthokeratology, soft multifocal contact lenses, spectacles and atropine showing similar effect with some caveats."6 With potentially different mechanisms of action, it could make sense to try different treatments to test for better efficacy, but there is no evidence base to support this. There is emerging evidence for combining atropine and orthokeratology which, in the short-term, appears to have greater efficacy to control axial elongation by an additional 0.09mm/year compared to orthokeratology alone.7

This patient appears to be on the most effective treatment possible, being orthokeratology combined with atropine. There is only one retrospective study on combining 0.025% atropine with orthokeratology,8 while most other studies have employed 0.01% in the combination.7 Read more about this in Combination Atropine Treatments: When More Is More.

Why not a higher concentration?

SN Is there a reason why you don’t use 0.05% ?PC In cases where I’ve tried 0.05% I found many kids don’t tolerate it well, then the parents get worried about the side effects. I use it sometimes when I’ve exhausted other options.SN ...I usually let parents know to buy their kids sunnies if on treatment and that seems to settle down the glare. Maybe that will help your little patients? I’ve been using 0.05% and have been able to stabilise the Rx over a year . Now I have AXL machine I’ll check to see how all this correlatesPC Kids on OK/MFSCL plus atropine generally don’t need as much as 0.05%. In this case if this didn’t work I would have gone to 0.05%. I have a few on 0.05% with MF photochromatic glasses when CL isn’t an option.

The comments suggest a higher concentration of atropine as the originally prescribed 0.02% compounded atropine did not have the intended myopia control effect. This is a reasonable suggestion, given that 0.05% atropine has been shown to have better efficacy than 0.025% when compared directly in the LAMP Study for up to 3 years, with a similar side effect profile.1

In this case, PC's prescription of a new batch of compounded 0.025% atropine produced the desired myopia control effect: in the short-term, appearing to be much more effective than the prior treatment of 0.02%. Since the small change in concentration is unlikely to have generated this contrasting clinical outcome, the question of consistency of the compounded medication(s) is fairly raised.

Take home messages:

  1. When a patient does not respond as expected to low-concentration atropine in a compounded formulation, question compliance first, as PC has done here. If compliance is good, consider that compounding can potentially introduce variability from bottle-to-bottle. To learn more about this and questions to ask your compounding pharmacist, read this clinical article: Compounded Atropine For Myopia Control: Safe And Effective Prescribing. 
  2. Monitoring axial length growth can allow one to properly gauge treatment outcomes. Where a child's outcomes on myopia control treatment appear to be similar to the 'untreated' (single vision corrected) for their age, this could reasonably be considered an unsatisfactory result, leading to a change in treatment strategy.

Learn more about topical atropine for myopia control

Check out these clinical cases

Meet the Authors:

About Connie Gan

Connie is a clinical optometrist from Kedah, Malaysia, who provides comprehensive vision care for children and runs the myopia management service in her clinical practice.

Read Connie's work in many of the case studies published on MyopiaProfile.com. Connie also manages our Myopia Profile and My Kids Vision Instagram and My Kids Vision Facebook platforms.

About Kimberley Ngu

Kimberley is a clinical optometrist from Perth, Australia, with experience in patient education programs, having practiced in both Australia and Singapore.

Read Kimberley's work in many of the case studies published on MyopiaProfile.com. Kimberley also manages our Myopia Profile and My Kids Vision Instagram and My Kids Vision Facebook platforms.

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