Feature, Report

Myopia indication for low dose atropine

Low dose atropine for myopia management has largely been sourced off-label by Australian eyecare professionals, but the country will now gain access to its first approved product from this month.

Prof Frank Martin.

Atropine’s rise to becoming a key myopia management tool – and the ensuing debate around optimal concentrations – is one that Sydney paediatric ophthalmologist Professor Frank Martin has watched with intrigue over the decades.

Its early use can be traced back to the 1970s when prominent Canadian ophthalmologist Dr Howard Gimbel published a paper in which 279 children received 1% atropine over three years and reported a 66% reduction in myopia progression compared with 572 controls.

“It was effective in slowing myopia progression, but it wasn’t well tolerated because the participants couldn’t accommodate and had problems with glare due to their dilated pupils,” says Martin, whose various roles include visiting ophthalmologist at The Sydney Children’s Hospitals Network at Westmead and Randwick, Sydney Eye Hospital and his private practice at Sydney Ophthalmic Specialists.

“But researchers started looking at it again, and it was the ATOM [Atropine for the Treatment of Myopia] studies out of the Singapore National Eye Centre that started looking at different strengths of atropine and found that 0.01% – which was essentially being used as a placebo – turned out to be effective. That really helped kickstart the use of low dose atropine for myopia control.”

The ATOM studies began with the first published study in 2006 (ATOM 1), which focused on 1% atropine. Although it was effective in controlling myopia progression, it resulted in visual side effects from cycloplegia and mydriasis. This spurred the same research group to publish the ATOM 2 studies where they compared three lower doses: 0.5%, 0.1%, and 0.01%. While the higher concentrations had better refractive and axial length control, 0.01% retained comparable efficacy and had fewer side effects.

It has been widely reported that the 0.01% strength in this study was intended as a non-active control as it was assumed to have minimal effect. But a 2014 ATOM 2 follow-up showed the higher doses (0.5% and 0.1%) had greater rebound effects than 0.01% when participants treated for two years stopped for 12 months (three years in total).

The researchers extended the study to five years. Only those whose myopia progressed by ≥-0.50 D in at least one eye during the washout period recommenced treatment, with all receiving 0.01% concentration for another two years, regardless of their previous regimen. Ultimately, by year five, it was those in the 0.01% group that had the lowest overall progression of myopia. This was primarily due to fewer children in the 0.01% group progressing after treatment was stopped, and the rate of progression in the washout year in those who needed retreatment was also less in the 0.01% group. Atropine 0.01% also caused minimal pupil dilation (0.8 mm), minimal loss of accommodation (2-3 D), and no near visual loss compared with higher doses.

On the back of such illuminating studies, Martin says a greater number of Australian eyecare professionals have prescribed low dose atropine, which has largely been sourced off-label through compounding pharmacists. This is because, unlike some markets, Australia doesn’t have an atropine product specifically approved for myopia control.

That is set to change this month when EIKANCE 0.01% eye drops – an ophthalmic solution containing 100 micrograms of atropine sulfate in 1 mL (0.01%) – is listed on the Australian Register of Therapeutic Goods.

It becomes the first atropine product in Australia with a myopia control indication. Specifically, it is indicated as a treatment to slow the progression of myopia in children aged from four to 14 years. It may be initiated in children when myopia progresses ≥-1.0 D per year.

The product is being produced and distributed by Sydney-based Aspen Pharmacare Australia, which produces ATROPT 1% – another eye drop containing atropine that eyecare professionals use to dilate the pupil and paralyse accommodation.

It has taken several years to secure the myopia indication for EIKANCE, which now joins an expanding suite of orthokeratology (OrthoK), soft contact lenses and defocus spectacle lens products that have a myopia control indication in Australia.

EIKANCE is a preservative-free eye drop and will be available in packs containing 30 sterile, single dose ampoules.

According to the product information, treatment should be supervised by a paediatric ophthalmologist, and the eye drop should be administered as one drop to each eye at night. The maximum benefit of treatment may not be achieved with less than a two-year continued administration period.

Martin says having access to an approved atropine product for myopia control will provide more certainty and better accessibility for patients.

In recent months, community pharmacies in NSW have also been reprimanded by the Pharmacy Council of NSW after preparing a low dose atropine dilution from commercially available eye drops, affecting the stability of the final product. The drops were also being compounded in a non-sterile environment, with one patient complaining to the Australian Health Practitioner Regulation Agency.

“Parents are becoming more aware of how progressive myopia isn’t good for a child’s eye. This product is meeting a growing need and I think it will help atropine gain wider acceptance,” Martin, who has been prescribing atropine off-label for around six years, says.

“It’s going to be valuable because we have had to ask for atropine to be compounded. Myself and my colleagues have all had experiences where the incorrect strength has been given, so having a product that is going to be under strict pharmaceutical control and readily available will make a big difference.”

A timely addition to the myopia toolkit 

The looming myopia public health crisis is no secret to Australian eyecare professionals. By 2050, it is estimated more than half the world’s population will have myopia and 10% or almost one billion will have high myopia. Thirty-six per cent of Australians were predicted to be myopic by now and by 2050, that number is set to increase to 55%.

Although Australia doesn’t compare to countries like Singapore, Hong Kong, South Korea, Taiwan and urban China where more than 90% of adolescents entering university are myopic, Martin says myopia is progressing at an unacceptable rate (≥-0.50 D per year) among many Australian youngsters.

In his own clinic, he has seen the exacerbating effects of COVID-19 lockdowns on myopic patients brought about by increased screen time for school and recreation.

This has been backed by several recent studies, including a Chinese study published in JAMA Ophthalmology that found myopia prevalence was three times higher in six-year-olds during the COVID-19 pandemic, giving rise to the term ‘quarantine myopia’.

Martin says studies have shown that myopic children are developing a higher degree of disease than their myopic parents, indicating the environmental factors at play. Children over -6.0 D are considered to have high grade myopia, with the stress of the enlarged eye leaving them susceptible to more serious issues such as glaucoma, retinal tears and detachment and macular degeneration.

Whilst eyecare professionals can’t stop myopia, he says they can play a role in delaying the onset. A key part of this is advising parents their children need to spend at least two hours outdoors accumulatively each day and limit screen time.

“The longer we can delay the onset, the better it is going to be because if myopia starts in a child who is five years old who is -3.0 D, for example, once you extrapolate that out, they could increase to around -6.0 to -7.0 D in 10 years’ time when their myopia progression slows or stops,” he says.

“We’re fortunate now that we have atropine and other interventions we know work once the onset of myopia occurs.”

Increased uptake 

With Australia gaining access to a range of approved myopia therapies in recent years, Martin expects there to be greater uptake of these interventions.

A 2016 survey of Australian optometrists found their most common approach to myopia management were single-vision distance spectacles, with more than 50% of respondents indicating they would ‘always’ or ‘mostly’ prescribe this modality.

This is despite the same survey finding that, relative to a single‐vision distance full‐correction, practitioners considered OrthoK (85%), low‐ dose atropine (54.4%) and soft defocus contact lenses (40.6%) as the three most effective modalities.

The researchers concluded that: “Australian optometrists appear aware of emerging evidence, but are not routinely adopting measures that have not yet received regulatory approval for modulating childhood myopia progression.”

Martin says a lot has changed in the last five years since that survey, including more evidence relating to efficacy of low-dose atropine, OrthoK lenses, peripheral defocus contact lenses and spectacle lenses slowing the progression of myopia.

“There have also been papers on the effect of combining treatments. Low-dose atropine eye drops are often used in conjunction with multifocal or peripheral defocus spectacle lenses. Myopia is an important topic at almost every conference for ophthalmologists and optometrists today,” he says.

“I expect having a product with regulatory approval to significantly improve uptake. Parents at times are reluctant to use a compounded product. They view it as not a mainline pharmaceutical.”

While research suggests 0.01% atropine is nearly as effective as higher concentrations in reducing the progressive increase in myopic refractive error, without the unpleasant side effects and significant rebound, others have suggested it may have a limited effect on axial elongation – the root cause of pathology later in life – compared to higher concentrations.

The 2018 Low-Concentration Atropine for Myopia Progression (LAMP) study led by Dr Jason Yam from The Chinese University of Hong Kong, compared the rate of myopia progression in 438 children with myopia aged four to 12 years treated with 0.05%, 0.025% or 0.01% atropine or placebo drops over 12 months of treatment.

As expected, the change in axial length was larger in the placebo group (0.41 ± 0.22 mm) than in the 0.05% (0.20 ± 0.25 mm), 0.025% (0.29 ± 0.20 mm) and 0.01% (0.36 ± 0.29 mm) groups. The difference between the placebo and 0.01% group was not considered significant. However, for all other pair wise comparisons between active treatment groups the difference was statistically significant.

In a follow-up study in 2019, compared with the first year, the second- year efficacy of 0.05% and 0.025% atropine remained similar but improved mildly in the 0.01% atropine group.

While the LAMP study points to the use of 0.05% atropine to effectively control both spherical equivalent and axial length elongation, Martin says 0.01% may be beneficial as a frontline treatment that practitioners may choose early on in the treatment plan with patients, or later combine with optical-based interventions.

In the case of EIKANCE 0.01%, he believes the fact it is preservative- free will be particularly beneficial for patients, many whom may be prescribed low-dose atropine for several years.

“The decision to also package the eye drop in 30 single-use ampoules also helps bring an improved safety profile,” he says.

“Practically, it’s also useful for families when they’re travelling or if children live between two homes because the cost and hassle of losing an ampoule is a lot less than an entire multidose bottle.”

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