There is no one reason why there are shortages in medicine supply. Medicine supply chains are complex and subject to global and local external and internal factors. There can be increases in demand for medication, changes in the companies who produce and supply the medication, changes to pricing and reimbursement at a national or local level and issues in manufacturing of the products.
The supply of ADHD medication has been subject to many of these challenges, and we are closely monitoring the situation in the UK and beyond. A product of current interest is Atomoxetine - a selective norepinephrine reuptake inhibitor used to treat ADHD in children and adults.
Along with other ADHD medications, there has been a steady increase in Atomoxetine prescribed in primary care (40% over 4 years), and secondary care doubling over the last few years. Whilst demand has soared in the UK, it is still believed that ADHD is under diagnosed, and the increasing demand for medicines to treat ADHD is expected to continue. In February, ADHD UK estimated about 150,000 people were experiencing issues with their education.
Eli Lilly, the originator of Atomoxetine (brand name Strattera), has been discontinuing all strengths of the product since 2022 and has now exited most major markets including the UK. Post the patent loss in 2017 there was a plethora of generic companies who began supplying the product across the world. Generic medicines and brand-name medicines share the same active ingredient, but other characteristics that do not affect the performance, safety, or effectiveness of the generic medicine, may be different.
In the UK, at least eight generic pharmaceutical companies hold marketing authorisations for Atomoxetine. This should provide adequate supply for patients - however, several of these are not actively marketing the product, and many of the remaining companies have reported out of stocks or limited supplies over the past few months.
Manufacturing issues not only impact product entering the supply chain, but can also impact product already in the market if product is recalled by the manufacturer. The UK has seen three MHRA recalls of Atomoxetine in quick succession, affecting all dosages and multiple batches, due to out of specification results. As a result, of the remaining suppliers only one is reporting availability of all strengths of product in the UK.
The global nature of supply chains means these issues have not been limited to the UK. Multiple EU and North and South American markets are reporting manufacturing issues and supply interruptions with the domestic supplies. The manufacturing issues are believed to relate to out of specification results for an impurity in the API (active pharmaceutical ingredient).
Manufacturer of Atomoxetine is known to produce small amounts of a nitrosamine impurity. Nitrosamines may increase the risk of cancer if people are exposed to them above acceptable levels and over long periods of time. Nitrosamines are common in water and foods, including cured and grilled meats, dairy products and vegetables. Everyone is exposed to some level of nitrosamines.
Every medication has the potential to do harm (an adverse drug reaction) as well as good. When considering approving a medication, the possible harms are weighed against the expected benefits. Use of a medication is not justified unless the expected benefits outweigh the possible harms. Regulatory agencies around the world have set internationally-recognized acceptable daily intake limits for nitrosamines in medicines and medicines must adhere to these limits. If medicines contain levels of nitrosamines above the acceptable daily intake limits, these medicines are recalled by the manufacturer.
As a result of these supply constraints, the reimbursement price of Atomoxetine has fluctuated widely since loss of exclusivity, reflecting the changes in availability of the product over the period. The 100mg product has seen a low of £19.54 in 2023 to the current high of £72.96 - which is more than the branded product price in 2017 (£70.79). Other Atomoxetine doses have seen similar swings over the same period.
When prices fluctuate widely, pharmacies play Russian Roulette deciding when and what to buy. Pharmacies are reimbursed for products when they are dispensed not when they are purchased. In addition, widely available generic products are reimbursed at the rate of the drug tariff, not the purchased price. This disconnect can result in both losses and gains for individual pharmacies. A pharmacy buying at a low point (~ £18/pack), will have benefited hugely if the product was dispensed at the high point (~£72/pack) and vice versa. These commercial challenges can lead to further supply constraints at a local pharmacy level where ultimately, they impact patients.
Atomoxetine is just one in a long list of medicines facing supply interruptions in the UK, and the problems impacting its supply chain are not unique. As with Atomoxetine, many of the underlying issues are the result of economic factors and the misaligned incentives that favour price over security of supply. Whilst there is much anecdotal evidence about the impact upon patients and the healthcare system, a comprehensive data driven assessment on the overall impact upon medical, social, and economic of impact shortages remains lacking. Perhaps this is the first step in addressing this persistent problem.