Download SW QA 174_4 Acitretin in RI or RRT

Medicines Q&As
Q&A 174.4
Can acitretin be given to patients with renal impairment or 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: September 2015
Background
Acitretin is an oral retinoid licensed to treat severe extensive psoriasis which is resistant to other
forms of therapy. It is also licensed for a number of other dermatological conditions, please refer to
the Summary of Product Characteristics (SPC) for full licensing details. It is recommended only to be
prescribed by a physician who is experienced in the use of systemic retinoids 1, 2. Doses are given
once daily, but there is wide variation in the absorption and rate of metabolism of acitretin 1. The
bioavailability of a single dose is approximately 60%1-3 but the range is quoted as 36-95%1-3 or even
15-95%4. Bioavailability is increased when given with food1-4. This therefore necessitates individual
dosage adjustment1, 2.
Answer
There are few data on the use of acitretin (and the parent compound etretinate) in patients with renal
impairment (RI) or in those undergoing renal replacement therapies (RRT). The two manufacturers of
acitretin offer conflicting advice about dosing in RI1, 2. One manufacturer contraindicates its use in all
stages of RI2, whilst the other contraindicates its use in severe RI only1. However, the Renal Drug
Database (RDD) offers empirical dosing guidance5.
Acitretin is the main active metabolite of etretinate, however this metabolic process is reversible and
acitretin may also be metabolised to its parent compound etretinate 6. The main metabolite of acitretin
is 13-cis-acitretin which is active3. In order to evaluate the safety of acitretin in RI and RRT it is
important to consider both the drug and its metabolites. Acitretin is excreted entirely as metabolites
via the kidneys and the bile1-3 and only 10-20% of etretinate is excreted in the urine3, 4. Multiple dose
studies in patients aged 21-70 years showed an elimination half-life of approximately 50 hours for
acitretin and 60 hours for 13-cis-acitretin1, 2. There are no data available on the half-life of acitretin in
end stage renal failure5.
Acitretin should only be prescribed by a physician who is experienced in the use of systemic retinoids
1, 2. The decision to prescribe acitretin to a patient with RI or on RRT lies with the physician and
should be based on an appropriate assessment of the likely risk versus benefit ratio. If acitretin is
prescribed in this situation (which may be outside of the product license) appropriate clinical caution
and monitoring should be used. If facilities are available, monitoring of acitretin serum levels is
suggested in patients with RI3. However another source suggests that a plasma assay is not helpful
as usually only the total drug (bound and free) is easily measurable and there may be significant
variations in the active free fraction of the drug4.
Renal Impairment
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Only limited data are available on the pharmacokinetics of acitretin in patients with renal failure 4. The
two manufacturers of acitretin offer conflicting advice about dosing in RI1, 2. One manufacturer
contraindicates its use in all stages of RI2, whilst the manufacturer of the reference product
contraindicates its use in severe RI only1, but does not offer a definition of ‘severe’7. The British
National Formulary (BNF) states that acitretin should be avoided in severe RI due to an increased risk
of toxicity8. Conversely, another source suggests that it should be avoided in moderate to severe RI
but this source does not define the grades of RI 9.
The national (NICE) and Scottish (SIGN) guidelines on the management of psoriasis do not give
guidance on the use of acitretin in RI10, 11, 12. European and Spanish guidelines on the management of
psoriasis state that acitretin is absolutely contraindicated in severe renal dysfunction 13, 14. The Spanish
guideline additionally advises that acitretin is relatively contraindicated in mild RI (but does not define
the grades of RI) and in these patients the risk-benefit ratio should be carefully assessed and the
dose adjusted14. The European guidelines state that limited data from randomized controlled trials do
not indicate acitretin is a nephrotoxic drug and CKD (any stage) would not be predicted to markedly
impact on drug disposition. The conclusion (based on expert opinion) is that acitretin could be used in
people with chronic kidney disease stage 2-3 (i.e. GFR=30-89 mL/min/1.73m2) but that collaboration
with a nephrologist is advised when treating patients with CKD stage 3 or more 13.
The RDD states that no data are available, and suggests that the dose of acitretin in all grades of RI
is as in normal renal function, but acknowledges that the manufacturer contraindicates its use in
severe renal failure. It also advises starting with the lowest dose possible and increasing cautiously.
Moreover, since patients with RI are at risk of hypervitaminosis, the RDD suggests monitoring liver
function closely5.
There are only three published case reports of the use of acitretin in patients with chronic renal failure
(CRF). In two of them a dose of 20mg on alternate days was used to treat Kyrle’s disease 15. Neither
safety nor efficacy could be fully evaluated as both patients died, although acitretin was reported to be
partially effective in one of the patients15. The third case report describes the use of infliximab in
combination with acitretin (35 mg/day) for treating progressive generalised pustular psoriasis (GPP) in
a patient with chronic renal insufficiency. The study showed a rapid resolution of GPP, which was
subsequently maintained by low-dose acitretin (10 mg/day) for over 24 months16. However, the study
does not give information about the level of RI and/or safety of treatment.
Adverse effects
The toxic dose of acitretin is close to the therapeutic dose and most patients experience some sideeffects during the initial period whilst dosage is being adjusted1. There is no dose of etretinate at
which therapeutic, but not adverse effects, are likely to appear 4. Therefore it is difficult to estimate the
range and extent of any adverse effects which patients with RI may experience if any accumulation
were to occur.
The manufacturer of acitretin notes that there have been two published case reports of RI thought to
be induced by treatment with etretinate17, 18. Also, 1-10% of patients receiving etretinate in
manufacturer-sponsored studies had raised mean serum creatinine concentrations 3, 6 and therefore
monitoring of residual renal function would be prudent. Additionally, reported adverse effects such as
oedema, with acitretin1, 2 ,6 or etretinate3, 6 may have implications for patients with RI. It is advisable to
consult the SPCs for full details of the adverse effect profile of acitretin1, 2 and to consider how these
may affect a patient with RI.
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Medicines Q&As
Intermittent Dialysis
During haemodialysis (HD) neither acitretin3, 4, 5 nor 13-cis-acitretin4 are thought to be removed by
the dialysing membrane. Acitretin is unlikely to be dialysed through intermittent haemodiafiltration
(HDF) or high-flux haemodialysis5. The RDD suggests that in patients undergoing standard or highflux HD or HDF, the dose used should be that which is used in normal renal function, with the same
cautions as previously described (see renal impairment section above)5.
One study investigated the pharmacokinetics of acitretin in patients on HD 19. Plasma concentrations
of acitretin and 13-cis-acitretin were measured in six patients on HD and six control subjects following
a single oral dose of acitretin 50mg. In the HD patients, the peak plasma concentration of acitretin and
the area under the curve of acitretin and 13-cis-acitretin, were lower than those of the control group19.
It is important to note that this was a single dose study in a small number of subjects with drug levels
only being measured for 96 hours post-dose. The timing of acitretin in relation to food varied between
the two groups, although the authors conclude that this did not affect the results19. Additionally, as
only total (bound and free) drug in plasma was measured, it is possible that significant changes in the
active free fraction may have been overlooked4. Therefore further studies of multiple doses of
acitretin, with measurement of both total and free (unbound) concentrations of acitretin and 13-cisacitretin, are needed in renal failure patients19.
There are three published case reports involving the use of acitretin in patients on HD 20, 21. In two
cases, patients had nephrogenic systemic fibrosis and were treated with acitretin in combination with
psoralens plus ultraviolet A (PUVA). The first patient displayed clinical improvement after 11 weeks of
acitretin in combination with PUVA. The second patient was treated with acitretin (10mg every other
day) and PUVA. Initial improvement was seen after 4 weeks, and after 12 months of therapy the
second patient continued to have small but clinically significant alleviation of her disease 20. The safety
of these regimens was not fully evaluated. The third case report involved a patient with Hurley Stage
3 hidradenitis suppurativa (HS), end stage renal disease (on intermittent dialysis) and several
comorbidities. After failure of multiple antibiotic therapies and etanercept, the HS was somewhat
stabilized when the patient was treated with clindamycin, rifampicin and acitretin 10 mg daily. After
two months, acitretin was increased to 10 mg twice daily and finally to 25 mg twice daily with added
effect. The acitretin dose could not be increased further because the patient could not tolerate it 21.
Continuous Ambulatory Peritoneal Dialysis (CAPD)
The RDD is the only source which provides dosing advice in CAPD, and states that the dose used
should be that used in normal renal function, with the same cautions as previously described (see
renal impairment section above)5.
There are two published case reports of acitretin being administered to patients on peritoneal dialysis
(PD)22, 23. In one report a 46 year-old patient presented with acquired perforating dermatosis. No
details were given about the patient’s PD regimen, however he was given oral acitretin 25mg daily
(plus topical tazarotene gel 0.1%). After 4 months of treatment with acitretin, there was improvement
in the patient’s pruritus and rash, but the patient died suddenly from severe cardiac disease22. The
second case report involved a 71 year old patient on PD (regimen not described) who was diagnosed
with eruptive keratoacanthoma (KA) and treated with 10mg acitretin orally three times per week. This
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Medicines Q&As
led to complete resolution of the KA over 3 months and no further recurrence. No details are given
about prolonged treatment with acitretin23.
Dialysability of acitretin is unlikely24 based upon its large volume of distribution (Vd ~ 9L/Kg) and high
degree of protein binding (Pb > 99%)3, 4, 5. For further details see Q&A 168.7 – What factors need to
be considered when dosing patients on RRT?25
Continuous arteriovenous / venovenous haemodialysis / haemofiltration
(CV/VVHD & CAV/VVH)
The RDD is the only source which provides dosing advice in CAV/VVHD, and states that acitretin has
unknown dialysability, but suggests the dose should be that which is used in normal renal function,
with the same cautions as previously described (see renal impairment section above)5. No published
information on the use of acitretin in patients undergoing CAV/VVHD or CAV/VVH was located.
Dialysability of acitretin is unlikely based upon its large Vd and high degree of Pb (See Q&A 168.7)25.
Etretinate
Etretinate is no longer actively marketed in the UK6. However, when considering the use of acitretin
in patients with RI, it is also necessary to consider the data relating to etretinate because a small
amount of acitretin is converted by esterification into etretinate (this reaction is enhanced by
alcohol)4,6. Also, there are several reports of detectable levels of etretinate in subcutaneous fat
following administration of acitretin3, even at times when the plasma concentrations of acitretin are
undetectable4. Etretinate appears to accumulate in adipose tissue after repeated dosing4 and has a
long elimination half-life of about 120 days3, 6. It has a prolonged half-life in obese patients3. There is
also evidence that etretinate can impair the elimination of acitretin, possibly by inhibiting its
metabolism4.
A study investigated the effect of CRF on the plasma levels of etretinate in four patients who were
receiving doses of 30-50mg daily26. The concentrations of etretinate, acitretin and 13-cis-acitretin
were monitored for 24-hours post-dose and compared with four non-CRF patients. The CRF patients
had statistically significantly higher peak levels of etretinate, but similar or lower levels of acitretin and
13-cis-acitretin. The authors suggest that elevated etretinate concentrations may increase the drug
accumulation in adipose tissues and prolong the time for final elimination. They propose that since
CRF patients run an increased risk of hypervitaminosis A and disturbances in plasma protein
metabolism, etretinate therapy should be restricted to the most urgent cases 26. Because of the short
duration of blood collection and the small number of subjects investigated, no definite conclusions can
be drawn from this study19.
A case report published in 2013 describes a maintenance haemodialysis patient with long-standing
severe psoriasis who was treated successfully with etretinate at a dose of 20-30 mg per day27. No
clinical or laboratory manifestations of hypervitaminosis A were observed. The authors conclude that
this suggests that vitamin A derivatives may be a safe and effective treatment option for severe
psoriasis in maintenance haemodialysis patients as long as toxicity and serum levels are monitored
properly27. However, it must be acknowledged that this single patient report is insufficient to determine
safety, efficacy and optimal dosing schedules for this patient group.
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Medicines Q&As
Summary
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There are very few data to support the use of acitretin in patients with renal impairment (RI) or
in those undergoing renal replacement therapy (RRT) and further studies are needed. The
information that is available is conflicting.
Acitretin should only be prescribed by a physician who is experienced in the use of systemic
retinoids. The decision to prescribe acitretin to a patient with RI or on RRT lies with the
physician and should be based on an appropriate assessment of the likely risk versus benefit
ratio. If acitretin is prescribed in this situation (which may be outside of the product license)
appropriate clinical caution and monitoring should be used.
Acitretin is the main active metabolite of etretinate, however this metabolic process is
reversible and acitretin may also be metabolised to etretinate. The main metabolite of acitretin
is 13-cis-acitretin which is active. It is important to consider all these compounds when
contemplating the use of acitretin in patients with RI or on RRT.
There is wide variation in the absorption and rate of metabolism of acitretin which
necessitates individual dosage adjustment. Therefore this document cannot make any
specific dosage recommendations.
The two manufacturers of acitretin offer conflicting advice about dosing in RI: one
manufacturer contraindicates its use in all stages of RI, whilst the other contraindicates its use
in severe RI only. The BNF states that acitretin should be avoided in severe RI due to an
increased risk of toxicity. However the Renal Drug Database (RDD) empirically suggests that
the normal dose may be used in all grades of RI and in patients undergoing RRT; it advises to
start with the lowest dose possible, increasing cautiously. Moreover, since patients with RI are
at risk of hypervitaminosis, the RDD suggests monitoring liver function closely.
NICE and SIGN guidelines on the management of psoriasis do not give guidance on the use
of acitretin in RI; however European and Spanish guidelines state that it is absolutely
contraindicated in severe renal dysfunction. Additionally, the European guidelines advise
(based on expert opinion) that acitretin could be used in people with CKD stage 2-3 (i.e.
GFR=30-80 mL/min/1.73m2), while collaboration with a nephrologist should be sought when
treating patients with CKD stage 3 or more.
During HD, no acitretin or 13-cis-acitretin is thought to be removed by the dialysing
membrane. Removal of acitretin through CAPD, CAV/VVHD or CAV/VVH is unproven but
unlikely based upon the physicochemical characteristics of the drug.
Any accumulation of acitretin may have significant consequences since the toxic dose is close
to the therapeutic dose.
If using acitretin in RI / RRT, it is prudent to consider the long half-lives of acitretin and its
metabolites and monitor carefully for any adverse effects (including RI).
There is conflict over whether the monitoring of acitretin serum levels is of benefit in patients
with RI.
Limitations
There are very few data available for patients with RI and patients undergoing RRT receiving acitretin
and insufficient information regarding long-term use. The use of acitretin in patients who have
undergone renal transplantation is outside of the scope of this document. Since etretinate is no longer
actively marketed in the UK, discussion is limited to its behaviour in RI as a metabolite of acitretin.
References
1. Summary of product characteristics for Neotigason 10mg capsules. Actavis UK Limited. Document
last updated on the eMC: 25th June 2015. Accessed online: http://www.medicines.org.uk/emc/ on
15/09/2015.
From the National Electronic Library for Medicines. www.nelm.nhs.uk
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Medicines Q&As
Summary of product characteristics for Neotigason 25mg capsules. Actavis UK Limited. Document
last updated on the eMC: 25th June 2015. Accessed online: http://www.medicines.org.uk/emc/ on
15/09/2015.
2. Summary of product characteristics for Acitretin 10mg capsules. Genus Pharmaceuticals.
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http://www.medicines.org.uk/emc/ on 11/08/2015.
Summary of product characteristics for Acitretin 25mg capsules. Genus Pharmaceuticals. Document
last updated on the eMC: 3rd February 2015. Accessed online: http://www.medicines.org.uk/emc/ on
11/08/2015.
3. Micromedex Solutions. DRUGDEX Drug Evaluations: Acitretin and Etretinate. Accessed
online via http://www.micromedexsolutions.com/home/dispatch on 16/09/2015.
4. Dollery C. editor. Therapeutic Drugs 2nd Ed, Edinburgh: Churchill Livingstone; 1999, p.A30-36,
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http://www.evidence.nhs.uk/formulary/bnf/current on 14/09/2015.
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to NICE clinical guideline 153 ‘The assessment and management of psoriasis’ (2012). NICE Evidence
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12. Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and management of psoriasis and
psoriatic arthritis in adults. A national clinical guideline. SIGN clinical guideline 121. Issue date:
October 2010. Accessed online via http://www.sign.ac.uk/pdf/sign121.pdf on 16/09/2015.
13. European Dermatology Forum (EDF). European S3-Guidelines on the systemic treatment of
psoriasis vulgaris. Update 2015. EDF in cooperation with EADV (European Academy of Dermatology
and Venereology) and IPC (International Psoriasis Council). Accessed on line at
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21/09/2015.
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Medicines Q&As
14. Carretero G, Ribera M, Belinchon I et al. Guidelines for the use of acitretin in psoriasis. Actas
Dermosifiliogr, 2013; 104(7):598-616. Accessed on line at http://www.actasdermo.org/en/guidelinesfor-the-use-of/articulo/90221065/?pubmed=true on 21/09/2015.
15. Harman M, Aytekin S, Akdeniz S et al. Kyrle’s disease in diabetes mellitus and chronic renal
failure. J Eur Acad Dermatol Venereol 1998; 11(1): 87-88.
16. Tang MM, Spanou Z, Tang H et al. Rapid downregulation of innate immune cells, interleukin-12
and interleukin-23 in generalized pustular psoriasis with infliximab in combination with acitretin.
Dermatology 2012; 225: 338-43.
17. Horber FF, Zimmermann A, Frey FJ. Impaired renal function and hypercalcaemia associated with
etretinate. Lancet 1984; 8411: 1093.
18. Cribier B, Welsch M, Heid E. Renal impairment probably induced by etretinate. Dermatology
1992; 185: 266-268.
19. Stuck AE, Brindley CJ, Busslinger A et al. Pharmacokinetics of acitretin and its 13-cis metabolite
in patients on haemodialysis. Brit J Clin Pharmac 1989; 27: 301-304.
20. Duffy KL, Green L, Harris R et al. Treatment of nephrogenic systemic fibrosis with Re-PUVA. J
Am Acad Dermatol 2008; 59 (Iss 2, Suppl); S39-40.
21. Scheinfeld N. Extensive hidradenitis suppurativa (HS) Hurly stage III disease treated with
intravenous (IV) linezolid and meropenem with rapid remission. Dermatology Online Journal 2015, 21
(2): 7.
22. Lynde CB and Pratt MD. Clinical Images. Acquired perforating dermatosis: association with
diabetes and renal failure. Canadian Med Assoc Journal 2009; 181 (9); 615.
23. Kurien A, Henderson C, Lee S. Case report. Recurrent keratoacanthoma with vascular invasion: A
diagnostic and management dilemma. Australian J of Dermatol 2009; 50; 194-97.
24. Bailie GR and Mason NA. 2014 Dialysis of Drugs. Renal Pharmacy Consultants, LLC.
25. Kuczynska J. Q&A 168.7 What factors need to be considered when dosing patients on renal
replacement therapies? South West Medicines Information & Training. Prepared February 2015,
partial revision October 2015. Accessed via www.evidence.nhs.uk on 05/11/2015.
26. Vahlquist A. Etretinate pharmacokinetics in chronic renal failure, a preliminary study in psoriasis
patients. Dermatologica 1987; 175: 224-228.
27. Inoue T, Nangaku M, Yamada K. Vitamin A treatment for psoriasis vulgaris in a dialysis patient.
American Journal of Kidney Diseases, November 2013; 62 (5); 1020-1.
Quality Assurance
Prepared by
Simona Perano, South West Medicines Information, Bristol (based on earlier work by Michèle Skipp
and Tiffany Barrett)
Date Prepared
September 2015
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Medicines Q&As
Checked by
Michèle Skipp, South West Medicines Information, Bristol
Date of check
November 2015
Search strategy
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Embase (exp Etretin OR acitretin.ti,ab OR exp Etretinate) AND (exp Kidney Failure OR exp
Renal Replacement Therapy). Limit to: Human and English Language and Publication Year
2012-current.
Medline (exp Acitretin OR exp Etretinate OR acitretin.ti,ab) AND (exp Renal Insufficiency OR
exp Renal Replacement Therapy). Limit to: Human and English Language and Publication
Year 2012-current.
NHS Evidence (acitretin renal; acitretin kidney; etretin kidney; etretin renal).
Manufacturer (Actavis UK Limited, Personal Communication, email dated 16th February 2015
and 27 July 2015).
Internet search (Google “renal acitretin; renal etretin; kidney acitretin; kidney etretin”)
In-house database. Keywords - Acitretin, Etretinate.
In-house renal files and texts.
British Association of Dermatologists Clinical Guidelines.
Clinical expert, Renal Pharmacist, Southmead Hospital, Bristol.
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