Medicines Q&As
Q&A 389.2
Can oseltamivir be used in adult patients with renal impairment?
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: 4th 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). 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). Therefore an increase in
plasma concentrations of OC can be expected in patients with severe renal impairment (CrCl<30
mL/min) (6).
Oseltamivir is generally well-tolerated, but gastrointestinal side effects and dizziness may appear with
increasing doses, particularly in patients with renal failure (7). 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).
Renal Impairment
The manufacturer of oseltamivir revised their dosing recommendations for the use of oseltamivir in
patients with renal impairment following a request by the Committee for Medicinal Products for
Human Use (CHMP). These changes to the license were based on clinical data from in-house
Available through NICE Evidence Search at www.evidence.nhs.uk
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pharmacokinetic studies and modelling and simulation analysis on pharmacokinetics of oseltamivir in
patients with varying degrees of renal function (10). Other reference sources may pre-date this
updated information. No dosage adjustment is needed in adults with a CrCl>60mL/min (1). A lower
dose is required in severe renal impairment (RI) due to accumulation of OC (4). Where there is any
concern about renal function, zanamivir may be the preferred option (11).
CrCl 30-60mL/min
The licensed dose for the treatment of influenza in adults with CrCl 30-60mL/min is 30mg twice daily.
For prevention of influenza in adults with CrCl 30-60mL/min, the licensed dose is 30mg once daily (1).
The manufacturer had previously recommended no dosage adjustment was necessary in this patient
group. The Renal Drug Handbook notes that the Renal Association guidance and the American data
sheet still suggest that no dosage adjustment is needed in adults with a CrCl>30mL/min (4).
CrCl 10-30mL/min
Dose information for this patient group is conflicting. The manufacturer recommends dose adjustment
for both treatment and prevention in adults with severe RI (CrCl 10-30mL/min). The area under the
plasma concentration-time curve (AUC) of OC was on average increased 10-fold in patients with
CrCl<30mL/min as compared with individuals without RI (7). The manufacturer recommends the
following dose reductions:
 For treatment of influenza: 30mg once daily (1).
 For prophylaxis of influenza: 30mg every second day (1).
The Renal Drug Handbook follows the manufacturer’s guidance, but additionally describes the higher
doses which have previously been safely and effectively used as recommended by the Renal
Association and American product literature (4). The Renal Association have previously
recommended the following dosing schedules:
 For treatment of influenza: 75 mg once daily, or 30 mg twice daily (12).
 For prophylaxis of influenza: 75mg every second day or 30 mg once daily (12).
CrCl <10mL/min
The use of oseltamivir in patients with RI with CrCl<10mL/min is not recommended by the
manufacturer because of an absence of data (10). As there are few data available there is no
definitive dose guidance available. However anecdotal dosing advice is available which is
extrapolated from pharmacokinetic data for CAPD patients (4,12,13).
 For the treatment of influenza, a single dose of 75mg oseltamivir has been suggested by the
Renal Association; and a dose of 30mg once a week (2 doses) has been recommended for
post-exposure prophylaxis (12).
Critical Care Setting
It has been noted that many critical care units are prescribing double the licensed usual dose of
oseltamivir for treatment (12). HPA guidance states that : the dose may be increased to 150 mg (this
is an off label dosage) in critically ill patients in an attempt to maximise drug levels in the lungs,
reduce shedding and prevent viral rebound. However as with complicated influenza, zanamivir should
be used when there is suspected poor GI absorption or failure to respond to oseltamivir (15).
The following dosing recommendations have been made for the treatment of critically ill patients.
For patients with CrCl>30mL/min oseltamivir 75-150mg twice daily for 5 days (12,14,15).
For patients with CrCl 10-30mL/min oseltamivir 75mg once or twice daily for 5 days (12,14).
For patients with CrCl<10mL/min oseltamivir 75mg STAT repeated every 5 days if required (14).
For critically ill patients who require prophylactic doses, the following recommendations have been
made (14).
For patients with CrCl>30mL/min oseltamivir 75 once daily for 10 days (14).
For patients with CrCl 10-30mL/min oseltamivir 75mg every second day for 10 days (14).
For patients with CrCl<10mL/min oseltamivir 30mg once a week (usually for 2 doses) (14).
It has been noted that these doses have been associated with an increase in adverse effects (16). A
study in adults (n=80) and children (n=246) admitted with severe influenza compared double (150mg
Available through NICE Evidence Search at www.evidence.nhs.uk
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twice daily in adults) versus standard dose oseltamivir (75mg twice daily in adults) on viral status and
clinical outcomes after 5 days of treatment. Doses were adjusted according to renal function but
patients with a CrCl<10mL/min were excluded from the study. Of 53 adults admitted to intensive care,
19 received double dose and 24 received the standard dose of oseltamivir. Overall, the study showed
no difference in virological and clinical outcomes between double dose and standard dose of
oseltamivir. No differences were found between double and standard dose groups in median days in
intensive care (4.5 [interquartile range 3-6] vs. 5 [2-11]). Despite the limitations of the study – the
authors caution against extending the results to different patient populations e.g. morbidly obese adults
or those with underlying chronic illnesses – the results do not support routine use of double dose
oseltamivir to treat severe influenza(17).
Summary
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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).
Adults with mild renal impairment (RI) (CrCl>60mL/min) can receive the normal adult dose.
The manufacturer of oseltamivir has revised their dosing recommendations for the use of
oseltamivir in patients with renal impairment.
The manufacturer recommends dose reduction for both treatment and prevention in adults with
moderate RI (CrCl 30-60mL/min):
o For treatment of influenza: 30mg twice daily.
o For prophylaxis of influenza: 30mg once daily.
The manufacturer recommends dose reduction for both treatment and prevention in adults with
severe RI (CrCl 10-30mL/min):
o For treatment of influenza: 30mg once daily.
o For prophylaxis of influenza: 30mg every second day.
Other (unlicensed) dose recommendations exist for patients with CrCl 10-60mL/min (see above)
but should be considered with caution as their advice may precede the updated licensed
manufacturer’s guidance.
The manufacturer states that oseltamivir is not recommended in patients with CrCl<10mL/min. In
these patients zanamivir is the preferred option for both prophylaxis and treatment. Please see
Q&A 270.2 zanamivir in renal impairment for more information about the use of zanamivir in
patients with RI or on RRT.
For patients with CrCl<10mL/min there is no definitive dosage guidance. Anecdotal dosing advice
exists:
o For treatment of influenza: a single dose of 75mg has been suggested.
o For prophylaxis of influenza doses of 30mg repeated weekly (2 doses) has been
suggested.
The decision to prescribe oseltamivir, and which dose to use, for patients with renal impairment lie
with the treating physician and should be based on an appropriate assessment of the likely risk
versus benefit ratio. If oseltamivir is prescribed in patients with CrCl<10ml/min or at doses higher
than those recommended by the manufacturer (which is outside of the product license) the patient
must be monitored closely for efficacy, adverse effects and signs of toxicity.
For patients in the critical care setting, many units are reported to be prescribing double the usual
dose (see above).
Limitations
The manufacturer of oseltamivir has updated their dosage recommendations for patient with renal
impairment. Many reference sources precede this information, and therefore caution should be
exercised when considering conflicting information from older reference sources. There are very few
data available for patients with severe renal impairment receiving oseltamivir. 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. Information relating to the use of oseltamivir in
Available through NICE Evidence Search at www.evidence.nhs.uk
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patients undergoing renal replacement therapies is described in Q&A 390.2 Can oseltamivir be used
in adult patients on renal replacement therapies?
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).
6) American Society of Health-System Pharmacists. AHFS Drug Information. August 2013 update.
Accessed online via: www.medicinescomplete.com on 28/8/13.
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. 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 28/8/13.
10) Personal Communication with Medical Information Specialist for Roche Products Ltd. Email, 9th
December 2011.
11) Clinical Knowledge Summaries (CKS) Influenza - seasonal. . Accessed online via:
http://cks.nice.org.uk/influenza-seasonal#!scenariorecommendation:1 on 28/08/13.
12) 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:
http://www.renal.org/pages/media/download_gallery/RenalFluPlanrev070709.pdf on 11/11/11
and 28/08/13.
13) 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. Accessed via:
http://ndt.oxfordjournals.org/content/21/9/2556.full.pdf+html on 11/11/11 and 28/08/13.
14) 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:
http://www.ukcpa.org.uk/docs/Antiviral%20management%20of%20H1N1%20in%20intensive%20
care%20V4%20January%202011.pdf on 11/11/11 and 13/08/13.
15) HPA Guidance on use of antiviral agents for the treatment and prophylaxis of Influenza Version 3.
12 December 2011 Reviewed October 2012. Accessed via
http://www.hpa.org.uk/Topics/InfectiousDiseases/InfectionsAZ/SeasonalInfluenza/InformationFor
HealthProfessionals/ on 28/08/13
16) Personal communication with an author of the Renal Drug Handbook 24/04/2012.
17) South East Asia infectious Diseases Clinical Research Network. Effect of double dose oseltamivir
on clinical and virological outcomes in children and adults admitted to hospital with severe
influenza: double blind randomised controlled trial. BMJ 2013;346:f3039 doi: 10.1136/bmj.f3039
(30 May 2013)
Quality Assurance
Prepared by
Julia Kuczynska (based on earlier work by Michèle Skipp), South West Medicines Information, Bristol
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
Date Prepared
4th September 2013
Checked by
Trevor Beswick, South West Medicines Information, Bristol
Date of check
17th 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 11/11/11).
 Internet search (Cochrane Library, NHS Evidence), search term “oseltamivir renal”;
“oseltamivir dialysis”.
 Internet search (Google “oseltamivir renal; oseltamivir dialysis”).
 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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