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Medicines Q&As
Q&A 390.2
Can oseltamivir be used in adult patients on renal replacement
therapies?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 13th September 2013
Background
Oseltamivir phosphate is a pro-drug which is extensively converted to the active metabolite
oseltamivir carboxylate (OC). OC is a selective inhibitor of influenza virus neuraminidase enzymes,
which are glycoproteins found on the virion surface. Viral neuraminidase enzyme activity is important
both for viral entry into uninfected cells and for the release of recently formed virus particles from
infected cells, and for the further spread of infectious virus in the body (1).
The normal adult dose of oseltamivir for the treatment of influenza is 75mg twice daily for 5 days (1,
2). The normal adult dose of oseltamivir for post-exposure prophylaxis of influenza is 75mg once daily
for 10 days (1, 2). For prevention during an influenza epidemic in the community, the normal adult
dose is 75mg once daily for up to six weeks (1, 2).
Answer
Oseltamivir is readily absorbed from the gastrointestinal tract after oral administration of oseltamivir
phosphate. At least 75% of an oral dose reaches the systemic circulation as OC. Exposure to the prodrug is less than 5% relative to the active metabolite (1).
Absorbed oseltamivir is primarily (>90 %) eliminated by conversion to OC (1). OC is eliminated
entirely (>99%) in the urine (1, 3). Renal clearance (18.8 L/h) exceeds glomerular filtration rate (7.5
L/h) indicating that tubular secretion occurs in addition to glomerular filtration (1,3). Peak plasma
concentrations of OC decline with a half-life of 6 to 10 hours in most subjects (1). The half-life of
oseltamivir is prolonged in patients with end stage renal failure (4,5). Renal clearance of OC
decreases linearly with creatinine clearance (CrCl) (6).
Oseltamivir is generally well-tolerated, but gastrointestinal side effects and dizziness may appear with
increasing doses, particularly in patients with renal failure (7). However, oseltamivir has a wide safety
margin so one source suggests that there appears to be little risk associated with higher-than-usual
concentrations in renal failure (5). However, another source reporting a possible case of oseltamivirinduced angioedema in a patient with chronic renal failure, suggests that it is important to
appropriately dose patients with compromised renal function as supratherapeutic dosing increases
the risk of drug-related adverse events (8).
In Japan, it was recommended that acute renal failure be added as a clinically significant adverse
reaction to product literature for oseltamivir. This was based on reports associating oseltamivir use
with acute renal failure. It is recommended that patients be carefully observed upon onset of renal
failure and appropriate measures taken immediately if any abnormalities occur (9). Renal failure is not
listed as an adverse effect of oseltamivir in UK product literature (1).
Where there is any concern about renal function, zanamivir may be the preferred option (10).
Renal Replacement Therapies
Oseltamivir is licensed for patients undergoing haemodialysis (HD) or peritoneal dialysis (PD) (1).
There are few data available regarding the use of oseltamivir in patients receiving other forms of renal
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
replacement therapy (RRT) and reference sources provide conflicting advice. Therefore there is no
definitive dose guidance available for these patients.
An open label, multiple-dose study of 30mg oseltamivir over 6.5 weeks in 24 patients with end stage
renal disease (ESRD) was undertaken (11). At the outset 12 patients were on maintenance
haemodialysis (HD) three times a week and 12 on continuous ambulatory peritoneal dialysis (CAPD)
with 4 exchanges per 24h. HD patients received 9 doses, given one hour after completion of alternate
HD sessions. CAPD patients received 6 doses, given once weekly immediately after a dialysate
exchange. The pharmacokinetics and tolerability of oseltamivir were studied in these patients. The
primary parameters were peak plasma concentration (Cmax) and the AUC for oseltamivir and OC.
Peak concentrations of OC were substantially delayed in HD patients following single and repeated
dosing when compared with patients with normal renal function. Cmax was approximately four times
higher in ESRD patients after a single 30mg dose of oseltamivir than in patients with normal renal
function after a single 75mg dose. The AUC for OC in patients with ESRD after repeated 30mg doses
was approximately three times higher than in patients with normal renal function receiving repeated
doses of 75mg twice daily.
HD contributed substantially to the total body clearance, and CAPD constituted 32.6% of the total body
clearance of OC. This study showed that a dose of 30mg oseltamivir in ESRD patients provides an
exposure to OC that has been shown to be clinically effective in other patient groups. Oseltamivir was
generally well-tolerated in this study, although GI events including nausea and vomiting were
experienced in 50% of the patients on HD and CAPD. Efficacy was not assessed, since patients were
not infected with or exposed to influenza, therefore the study findings warrant further research in a
clinical scenario (11).
Haemodialysis
For patients undergoing HD, reference sources provide conflicting dosing advice. However, following
the licensing of oseltamivir for use in this population the manufacturer has made definitive dosing
recommendations.
 For the treatment of influenza, a dose of 30mg after each HD session is recommended (1).
 For prevention of influenza, a dose of 30mg after every second HD session is recommended
(1).
Since HD enhances plasma clearance of oseltamivir, doses should be administered after a dialysis
session (12).
Other (unlicensed) doses have been used for patients on HD. However, these should be considered
with caution as recommendations may precede the licensed manufacturer’s guidance.
 It has been suggested that oseltamivir should be given at a dose of 30mg three times a week,
post dialysis for both treatment and prophylaxis for low-flux HD (13).
 Whilst the Renal Drug Handbook quotes the manufacturers recommended dosages, the
authors also suggest that anecdotally a dose of 75mg after each dialysis session has been
used in patients on HD without any problems (4). This dose was used in a case reported in
2010. An anuric patient with H1N1 influenza on HD was given 75mg oseltamivir after each
dialysis during a 10 day course of treatment. No adverse effects were noted. The patient
eventually recovered. Peak and trough concentrations of oseltamivir carboxylate were similar
to those seen in healthy volunteers taking 150mg twice daily (14). This dose was also used in
a case reported in 2011. The patient recovered but experienced mild gastrointestinal
complaints which were manageable (15).
 An alternative regimen for prophylaxis of influenza was studied in 286 HD patients. In this
study a dose of 75mg every 5 days was found to be tolerable and effective (16).
Intermittent Haemodiafiltration (HDF) / High Flux Haemodialysis
The Renal Drug Handbook and the Renal Association offer empirical dosing advice:
 It has been suggested that oseltamivir should be given at a dose of 75mg three times a week,
post dialysis for both treatment and prophylaxis (4,13).
There is one published report of using oseltamivir 75mg daily for 5 days in one patient who was
undergoing high-flux haemodialysis. No safety or side effect information was described for this case
(17).
Available through NICE Evidence Search at www.evidence.nhs.uk
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Peritoneal Dialysis
Oseltamivir is licensed for use in the PD population and therefore the manufacturer has made
definitive dosing recommendations. The manufacturer notes that their dose guidance for PD patients
is based upon data in CAPD patients. The clearance of oseltamivir carboxylate is expected to be
higher when automated peritoneal dialysis (APD) mode is used. Treatment mode can be switched
from APD to CAPD if considered necessary by a nephrologist (1).
 For treatment of influenza the recommended dose is a single 30mg dose (1,13).
 For prevention of influenza the recommended dose is 30mg once weekly (2 doses) (1,13).
The dose of oseltamivir should be administered immediately after a CAPD dialysate exchange (11).
The pharmacokinetic study (described above) demonstrated that for ongoing prophylaxis, oseltamivir
may be administered weekly over a 6-week period (11). An alternative regimen for prophylaxis of
influenza was studied in 45 CAPD patients. In this study a dose of 75mg every 5 days was found to
be tolerable and effective (16).
Continuous renal replacement therapies (CRRT)
The use of oseltamivir in patients undergoing CRRT is unlicensed. There is no definitive dose
guidance available and reference sources provide conflicting advice. Additional dosing
recommendations have also been made specifically for patients in critical care (see later).
 The Renal Drug Handbook states that in CAV/VVHD there is unknown dialysability and
suggests that the dose used should be that recommended for GFR 10-30mL/min. This source
therefore suggests that the treatment dose used should be 30mg once daily. For prophylaxis
the dose should be 30mg on alternate days (4). However, this source does discuss that in
practice higher doses have been used for GFR 10-30mL/min. Please see Q&A 389.2 for
further details.
 Dosage reduction recommendations for patients with reduced CrCl cannot be directly applied
to anuric patients receiving haemofiltration, because of the absence of tubular secretion in
these patients (18).
 Drug Prescribing in Renal Failure suggests that no dosage reduction is required in patients
undergoing CRRT (5).
An in vitro study of the elimination of OC by haemofiltration showed that the sieving coefficient (SC) of
OC is close to 1, suggesting that the clearance of OC can be estimated from the UF rate (18).
However, this is an in vitro study, and there may be other factors that affect the SC or adsorption in
vivo. The authors suggest that an appropriate dose in anuric patients on CVVH can be calculated
from:
Cp x I x CL where Cp=desired plasma conc (mg/mL), I=dosage interval (min),
_________ CL=clearance (mL/min) and f=bioavailability
f
However, the authors recommend that this dose recommendation is an estimate which requires
confirmation in clinical studies (18).
There is a published report of 3 patients who received 150mg oseltamivir twice daily via nasogastric
tubes whilst on CVVH (19). The mean SCs were calculated in two patients as 1.055 and 1.1. Trough
OC concentrations varied markedly but were higher than previously reported in healthy volunteers
(19). Only one patient had renal failure. The virus was cleared in two patients but two patients died,
suggesting antiviral efficacy but poor clinical efficacy. The surviving patient experienced severe
headache and vomiting, which resolved upon cessation of oseltamivir, suggesting that OC levels were
high and not well tolerated (19). Health care professionals should be aware that supratherapeutic
levels should be expected when high-dose oseltamivir is given to patients receiving CRRT (20).
Five patients on CRRT were included in a study of 41 patients assessing the absorption and
pharmacokinetics of oseltamivir in critically ill patients. The average plasma concentrations in the 5
CRRT patients, with the dose normalised to 75mg twice daily, was approximately five times higher in
the dialysis group than in the primary study group (2000 v. 404 micrograms/L). The median trough
concentration of OC was approximately four times higher in the dialysis group compared to the
Available through NICE Evidence Search at www.evidence.nhs.uk
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primary study group (1170 v. 282micrograms/L). The median AUC for OC (dose normalised to 75mg
twice daily) was also much higher in CRRT patients than in those with relatively normal renal function
(28023 v. 4854). The authors propose that to achieve an exposure to the carboxylate metabolite in
the dialysis population that is relatively equivalent to the exposure in patients with normal renal
function receiving 75mg twice daily, either 30mg daily or 75mg every 48hours should suffice. This
study was unable to assess penetration of oseltamivir into lung tissue. Adverse effects were not
reported, however seven patients died, including two patients with renal failure (21).
There is a published report of 1 patient who underwent both veno-venous extracorporeal membrane
oxygenation (ECMO) and continuous veno-venous haemodiafiltration (CVVHDF), and received
150mg oseltamivir twice daily. High plasma levels of OC (Cmax 3900ng/mL) and long half-life (15h)
were observed suggesting accumulation. The authors concluded that it is probably unnecessary to
increase oseltamivir doses in patients with acute renal failure (22,23). Seven patients on ECMO
received oseltamivir 75mg (n=2) or 150mg twice daily via nasogastric tube. Three patients received
CVVHDF in addition to ECMO, because of renal failure, and these three patients received oseltamivir
150mg twice daily. Patients on both ECMO and CVVHDF had higher mean Cmax/D (Cmax divided by
daily dose) (13.9 v. 5.3) and higher AUC/D (AUC divided by daily dose)(0.143 v. 0.044), than patients
on ECMO alone.
Half-lives were considerably prolonged in the ECMO + CVVHDF group compared with the ECMO
group (1352 v. 9.2 h). The authors conclude that plasma concentrations of OC seem to be mainly
dependent on renal elimination and CVVHDF had little impact on OC concentrations. Patients with
renal failure or acute kidney injury on CVVHDF should receive the lower dose of oseltamivir (i.e.
75mg twice daily). Daily doses should be adapted based on repeated monitoring of OC plasma levels
on the basis of concentrations found in healthy volunteers (100-200 ng/mL for trough plasma levels
(24).
Twelve patients receiving continuous venovenous haemodialysis (CVVHD) were given oseltamivir
150mg twice daily nasogastrically or nasoenterically. Four patients were also on ECMO. Considerable
variability was seen in OC pharmacokinetic parameters. The lowest and highest Cmax (maximum
plasma concentration) differed by 18-fold. The median Cmax and AUC0-12 for OC were 2000 and
21,500 ng/mL respectively. The median half-life in patients receiving CVVHD only (n=8), was 22.3
hours. The median AUC0-12 for OC was substantially greater than would be expected in non-critically
ill patients receiving the same dose, even though OC freely crossed the CVVHD membrane and
clearance by CVVHD represented an important route of elimination. The authors conclude that a
reduced dosage of 75mg daily as advised for patients with a reduced CrCl of 10-30mL/min seems
reasonable for critically ill patients requiring CVVHD at the rates used in this study. Centres using
CRRT at higher effluent rates may require more aggressive dosing (25).
Results obtained with one type of CRRT cannot be directly extrapolated to another. For example,
CVVHDF removes solutes by a combination of diffusive and convective mechanisms whereas CVVH
involves convection only. Also studies vary in design, using different haemofilters; blood, dialysate
and ultrafiltration rates; and calculated drug clearance by various methods. For these reasons advice
on drug dosage in CRRT from the literature should be applied cautiously to individual patients.
(24,26).
Critical Care Setting
It has been noted that many critical care units are now prescribing double the usual dose of
oseltamivir for treatment (13).
 For patients on CAVH / CVVH / CAVHD / CVVHD oseltamivir 75mg twice daily for 5 days has
been suggested (13).
 Alternatively, for patients on CVVH a treatment dose of oseltamivir 75mg once or twice daily
has been recommended. For prophylaxis in patients on CVVH, oseltamivir 75mg every
second day has been recommended (27).
It has been noted that these doses have been associated with an increase in adverse effects (28).
Summary
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
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Oseltamivir carboxylate (OC) (the active metabolite of oseltamivir phosphate) is excreted entirely in
the urine through glomerular filtration and tubular secretion.
Oseltamivir is generally well-tolerated, but gastrointestinal side effects and dizziness may appear
with increasing doses, particularly in patients with renal failure.
Renal clearance of OC decreases linearly with creatinine clearance (CrCl).
Oseltamivir is licensed in dialysis patients who are receiving HD or CAPD. It is not licensed for
patients receiving other forms of RRT. In these patients zanamivir is the preferred option for both
prophylaxis and treatment. Please see Q&A 270.2 for more information about the use of zanamivir
in patients with RI or on RRT.
Oseltamivir carboxylate is removed through dialysis.
The manufacturers have made definitive dosing recommendations for HD and CAPD patients.
However other reference sources provide conflicting advice.
o The manufacturer’s recommended doses for patients undergoing HD are 30mg oseltamivir
after each dialysis session for treatment, and 30mg oseltamivir after every second HD
session for prophylaxis of influenza. Alternative doses have also been suggested (see
above).
For patients undergoing CAPD, the most commonly suggested dose is 30mg (repeated every
week where necessary) for treatment or prophylaxis of influenza
There is no definitive dosing guidance available for patients on other forms of RRT and reference
sources provide conflicting advice.
o There is very little published data documenting the use of oseltamivir in patients on HDF or
high flux haemodialysis. A dose of 75mg three times a week post dialysis has been
empirically suggested.
o For patients on CRRT both dose reduction (dose as for CrCl 10-30mL/min) and normal
adult dose have been suggested. Dose recommendations based on results of published
studies depend on the type of CRRT and system factors e.g. filter type; results obtained
with one type of CRRT e.g. CVVH cannot be directly extrapolated to another e.g.
CVVHDF.
o The absence of tubular secretion in anuric patients should also be considered.
o The sieving coefficient has been reported to be close to 1.
For patients in the critical care setting, many units are reported to be prescribing double the usual
dose (see above).
The decision to prescribe oseltamivir, and which dose to use, for a patient on RRT lies with the
physician and should be based on an appropriate assessment of the likely risk versus benefit ratio.
If oseltamivir is prescribed in this situation (and particularly where such prescription is outside of
the product license) the patient must be monitored closely for efficacy, adverse effects and signs of
toxicity.
Limitations
There are very few data available for patients undergoing renal replacement therapies receiving
oseltamivir. Some reference sources precede dosing guidance recommended by the manufacturers
therefore conflicting dose information should be interpreted with caution. Paediatric patients are
outside of the scope of this document. The information in this Q&A relates only to oral oseltamivir, it is
not applicable to the use of intravenous oseltamivir.
References
1) Roche Products Limited. Summary of Product Characteristics for Tamiflu 30mg and 45mg
capsules. Date of revision of text 15/11/12. Accessed via: www.emc.medicines.org.uk on
20/08/13.
2) Khanderia S (managing editor). British National Formulary. Accessed online via:
http://www.medicinescomplete.com/mc/bnf/current/ on 16/08/13.
3)
DRUGDEX Drug Evaluations: Oseltamivir. Accessed via
www.micromedexsolutions.com on 13/08/13.
4) Ashley, C. Currie, A. editors. Renal Drug Handbook 3rd Edition. Oxford, Radcliffe Medical Press
Ltd; 2009. Updated monograph for oseltamivir received by personal communication 24/04/12 and
28/08/13.
5) Aronoff GR, Bennett WM, Berns JS, et al. Drug Prescribing in Renal Failure; Dosing Guidelines
for Adults and Children 5th edition (2007).
Available through NICE Evidence Search at www.evidence.nhs.uk
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6) American Society of Health-System Pharmacists. AHFS Drug Information. August 2013 update.
Accessed online via: www.medicinescomplete.com on 28/08/13.
7) Karie S, Launay-Vacher V, Janus Nicolas et al. Pharmacokinetics and dosage adjustment of
oseltamivir and zanamivir in patients with renal failure. Nephrol Dial Transplant 2006; 21; 3606-8.
8) Callen EC, Kesler TL, Peace JF et al. Possible oseltamivir-induced angioedema in a patient with
chronic renal failure. Hosp Pharm 2011; 46(8): 591-595.
9) WHO pharmaceuticals newsletter. 2003. no 5. Accessed online at:
http://apps.who.int/medicinedocs/pdf/s4948e/s4948e.pdf on 11/11/11 and 28/08/13.
10) Clinical Knowledge Summaries (CKS) (2011) Influenza - seasonal. . Accessed online via:
http://cks.nice.org.uk/influenza-seasonal#!scenariorecommendation:1 on 28/08/13.
11) Robson R, Buttimore A, Lynn K et al. The pharmacokinetics and tolerability of oseltamivir
suspension in patients on haemodialysis and continuous ambulatory peritoneal dialysis. Nephrol
Dial Transplant 2006; 21; 2556-2562.
12) Bailie GR, Mason NA, Renal Pharmacy Consultants. Dialysis of Drugs 2013. Accessed via:
http://renalpharmacyconsultants.com/assets/2013dodbooklet.pdf on 16/08/13.
13) Renal Association Clinical Affairs Board / JSC Renal Medicine. Briefing and guidance for adult
renal units in the UK during an influenza pandemic, updated 3rd August 2009. Accessed via:
www.renal.org/pages/media/download_gallery/RenalFluPlanrev070709.pdf on 01/12/11.
14) Dolley-Hitze T, Verdier M, Tribut O et al. Oseltamivir dose adjustment in an H1N1 patient requiring
haemodialysis. Intensive Care Med 2010; 36:1618.
15) Kute VB, Shah PR, Goplani KR et al. Successful treatment of critically ill chronic kidney disease
patient with multi-organ dysfunction associated with H1N1 infection. Indian J Nephrol 2011; 21:
59-61.
16) Choo D, Hossain M, Liew P et al. Side effects of oseltamivir in end-stage renal failure patients.
Nephrol Dial Transplant 2011; 26: 2339-44.
17) Wiebe C, Reslerova M, Komenda P et al. Atypical presentation of H1N1 influenza in a dialysis
patient. Lancet 2009; 374: 1300.
18) Gruber PC, Tian Q, Gomersall CD et al. An in vitro study of the elimination of oseltamivir
carboxylate by haemofiltration. Int J Antimicrob Agents 2007; 30; 93-100.
19) Taylor WRJ, Thinh BN, Anh GT et al. Oseltamivir is adequately absorbed following nasogastric
administration to adult patients with severe H5N1 influenza. PLoS ONE 2008; 3 (10); e3410
20) Eschenauer GA, Lam SW. Supratherapeutic oseltamivir levels during continuous dialysis: and
expected risk. Intensive Care Med 2011; 37: 371.
21) Ariano RE, Sitar DS, Zelenitsky SA et al. Enteric absorption and pharmacokinetics of oseltamivir
in critically ill patients with pandemic (H1N1) influenza. CMAJ 2010; 182(4): 357-63.
22) Roullet-Renoleau F, Lemaitre F, Zahr N et al. Pharmacokinetics of oseltamivir carboxylate in a
patient treated by extracorporeal membrane oxygenation. Int J Clin Pharm 2011; 33; 287 (CCR7).
23) Lemaitre F, Luyt C, Roullet-Renoleau F et al. Oseltamivir carboxylate in a patient treated by
Haemodiafiltration and extracorporeal membrane oxygenation. Intensive Care Med 2010; 36:
1273-4.
24) Lemaitre F, Luyt C, Roullet-Renoleau F et al. Impact of extracorporeal membrane oxygenation
and continuous venovenous haemodiafiltration on the pharmacokinetics of oseltamivir carboxylate
in critically ill patients with pandemic (H1N1) influenza. Ther Drug Monit 2012; 34:171-5
25) Eyler RF, Heung M, Pleva M et al. Pharmacokinetics of oseltamivir & oseltamivir carboxylate in
critically ill patients receiving continuous venovenous hemodialysis and/or extracorporeal
membrane oxygenation. Pharmacotherapy 2012; 32: 1061-9
26) Leung R. Q&A 168.5 - What factors need to be considered when dosing patients on renal
replacement therapies? South West Medicines Information & Training. Date prepared: January
2013. Accessed via https://www.evidence.nhs.uk/search?q=factors+dosing+renal+replacement
on 09/08/13.
27) Thacker M, Shulman R, O’Farrell B et al. Antiviral Management of Influenza A (H1N1) in Critical
Care. January 2011. Version 4.0. Critical Care Group & United Kingdom Clinical Pharmacy
Association. Accessed online via:
www.ukcpa.org.uk/docs/Antiviral%20management%20of%20H1N1%20in%20intensive%20care%
20V4%20January%202011.pdf on 11/11/11.
28) Personal communication with an author of the Renal Drug Handbook on 24/04/12.
Available through NICE Evidence Search at www.evidence.nhs.uk
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Quality Assurance
Prepared by
Julia Kuczynska (based on earlier work by Michèle Skipp), South West Medicines Information, Bristol
Date Prepared
13th September 2013
Checked by
Trevor Beswick
South West Medicines Information, Bristol
Date of check
20th September 2013
Search strategy
 Embase (*Oseltamivir OR oseltamivir.ti,ab) AND (exp*Kidney-Failure OR exp*Renal
Replacement Therapy).
 Medline (*Oseltamivir OR oseltamivir.ti,ab) AND (exp*Renal Insufficiency OR exp*Renal
Replacement Therapy).
 Manufacturer (Roche Products Ltd, Personal Communication, email 09/12/11).
 Internet search (NHS Evidence & Cochrane Library), search term “oseltamivir renal”;
“oseltamivir dialysis”.
 Internet search (Google “oseltamivir dialysis”; “oseltamivir renal”).
 In-house database. Keywords – Oseltamivir.
 In-house renal files and texts.
 The Renal Association website: www.renal.org
Available through NICE Evidence Search at www.evidence.nhs.uk
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