Reduced prescription tacrolimus use: a cross-sectional analysis of England's national prescription statistics during the COVID-19 pandemic, by region.

To the editor:

Many UK transplant centers currently provide restricted access due to coronavirus disease 2019 (COVID-19). Full-year total organ transplants numbered 3997 in 2019–2020 versus 4183 in the previous year, a fall of 4.45% (Table 1 ; Supplementary Transplant Waiting List).

Table 1

Organ donation and transplantation activity data for England

Organ transplantsa	2015/2016	2016/2017	2017/2018	2018/2019	2019/2020	% variation
DD transplants by organ
Kidney	1721	1876	2035	2070	1967	0.95
Pancreas	15	15	16	16	13	0.81
Kidney/pancreasb	141	141	146	139	132	0.95
Pancreas islets	12	16	11	13	11	0.85
Heart	167	163	170	158	151	0.96
Lung(s)	154	150	168	138	130	0.94
Heart/lung	6	2	9	2	5	2.5
Liver/lobe	679	763	809	787	766	0.97
Intestinal	13	14	21	19	19	1
Other (multi-organ)	23	15	24	11	16	1.45
Total DD transplants	2931	3155	3409	3353	3210	0.96
LD transplants by organ type
Kidney	848	800	834	810	769	0.95
Liver	32	26	28	20	18	0.9
Intestinal	0	0	1	0	0
Total LD transplants	880	826	863	830	787	0.95
Total organ transplants	3811	3981	4272	4183	3997	0.96

DD, deceased donor; LD, living donor.

All data are as recorded on April 8, 2020 and are subject to change as the UK Transplant Registry is updated.

Source: NHS Blood and Transplant. Organ donation and transplantation activity data: England. Published April 8, 2020. Available at: https://nhsbtdbe.blob.core.windows.net/umbraco-assets-corp/18651/nhsbt-england-summary-report-mar-20.pdf. Accessed May 25, 2020.

Transplant waiting list and transplants based on English, Channel Island, and Isle of Man postcode of residence of patient.

Includes kidney and pancreas islets.

Calcineurin inhibitors such as tacrolimus prevent transplant rejection in kidney or liver recipients, and withdrawal or tapering should be gradual to prevent transplant failure. Oral tacrolimus should be prescribed and dispensed by brand to minimize inadvertent switching, which is associated with toxicity and graft rejection. Tacrolimus modified-release (MR) capsules are indicated once daily in adults. Patients taking high doses—of 1 mg, 3 mg, and 5 mg—are vulnerable to harm (e.g., acute rejection of organ or graft) from abrupt withdrawal and are at increased risk of infections, including COVID-19, as they are immunosuppressed. Minimal prescription volume variation is expected, as long-term community care can be pre-planned during lockdown in England.

The publicly available English Prescribing Dataset (EPD) provides prescription data, which were used. This dataset excludes prescriptions in prisons and hospitals, private prescriptions, and items prescribed but not dispensed nor reimbursed. To represent vulnerable patients, we focused on the high-dose MR formulations, but ignored ointments, as these are used predominantly for cutaneous conditions.

We compared nonpandemic versus pandemic data (March 2019 vs. 2020) of Advagraf MR capsules (1 mg, 3 mg, and 5 mg; Advagraf [tacrolimus], Astellas Pharma Europe B.V., Leiden, Netherlands) and tacrolimus MR capsules (1 mg and 3 mg). We found a fall in all high-dose MR formulations (Table 2 ) being prescribed in the pandemic.

Table 2

Volume and prices for Advagraf ([tacrolimus], Astellas Pharma Europe B.V., Leiden, Netherlands) modified release (MR) formulations of 1 mg, 3 mg, and 5 mg

Strength (British National Formulary code)	Volume and prices of Advagraf MR capsules	Volume and prices of tacrolimus MR capsules
1 mg (0802020T0BCABAN; 0802020T0AAANAN)	Quantities were lower by 200 capsules, or £266.55.	Quantities were lower by 150 capsules, or £199.55.
3 mg (0802020T0BCADAT; 0802020T0AAATAT)	Quantities were lower by 50 capsules, or £200.33.	Quantities were lower by 50 capsules, or £199.54.
5 mg (0802020T0BCACAP)	Quantities were lower by 850 capsules, or £4219.61.	—

The Supplementary All Tacrolimus Formulations includes details of all oral-dose tacrolimus formulations in March 2019 versus 2020, showing a fall in all tacrolimus quantities, except Prograf 1 mg (Prograf [tacrolimus], Astellas Pharma Ltd., Surrey, UK) and 500 mcg capsules and Adoport 0.5 mg capsules (Adoport [tacrolimus], Sandoz Ltd., Surrey, UK). Detailed total quantity analysis shows that Advagraf 5 mg MR fell to 900 in March 2020, compared to 1750 in 2019 (–49%). Similarly, Prograf 5 mg fell to 250, from 350 (–29%); Adoport 5 mg fell to 300, from 400 (–25%); tacrolimus 1 mg fell to 250, from 1700 (–85%); and Modigraf 0.2 mg sachets fell to 350, from 724 (–52%).

Regional variation was also noted with 370 prescriptions issued in 2019 versus 351 prescriptions issued in 2020, a 5% fall (Figure 1 ). For medicines with 1000+ doses in the north, the increases were dramatic in 2020: Prograf 1 mg (n = 1900 vs. 11,250; 592%); Adoport 1 mg (n = 1650 vs. 5200; 315%); Prograf 500 mcg (n = 550 vs. 2750; 500%); Adoport 0.5 mg (n = 450 vs. 2200; 489%); Advagraf 1 mg MR (n = 150 vs. 1000; 667%).

Figure 1

Fall in the number of prescriptions issued (for all oral solid dosage forms of tacrolimus) in 2020 versus 2019.

We postulate some explanations: first, there are differences in prescribing policy by clinical commissioning groups, such that people entering lockdown were allowed prescriptions (of up to 6 months) by some primary care organizations but not others. Second, COVID-19 affected London and South East England approximately 10 days before the rest of the UK. Many surgeries were closed once an initial COVID-19 case was diagnosed, and the administrative push toward online care may have affected prescription issuance. Third, sudden, and unexpected demands led to falls in medicine availability, as already stretched (by Brexit) supply chains became even more stretched. Thus, there are many factors that may have affected prescriptions.

However, for these reasons, there is a risk that vulnerable groups like transplant patients will be disproportionately affected. Our concern is especially for those patients who do not have their medicines, who now cannot get the medicines from local or hospital pharmacies, and/or those patients who are unable to re-establish prescription issuance from their normal doctor(s). There is a risk that health inequalities along geographic and ethnic lines (40% of London residents are from ethnic minorities) may be further exacerbated. In these times, incomplete implementation of the Falsified Medicines Directive (Directive 2011/62/EU) in Europe and the UK leaves us collectively vulnerable to falsified medicines entering the supply chain in response to medicine shortages.

Low prescription issuance of these important medicines during lockdown may have dire clinical implication for patients and may mean that organ transplants and donations that were so far successful have been put at risk. This study represents a fraction of the cost invested in these patients, organs, and procedures. Serious effort must be made immediately to identify these patients at the surgery level and safeguard their health.