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  • 1. Medicines Q&As Q&A 174.2 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 Expiry: 19th January 2011 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 given by, or under the supervision of, a dermatological specialist. 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, 2, 3), but the range is quoted as 36-95% (1, 2) or even 15-95% (3). This therefore necessitates individual dosage adjustment (1). 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 manufacturer of acitretin states that it is contra-indicated in patients with RI (1). However the Renal Drug Handbook (RDH) offers empirical dosing guidance (4). 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 (5). The main metabolite of acitretin is 13-cis-acitretin which is active (2). 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 bile (1, 2) and only 10-20% of etretinate is excreted in the urine (2, 3). 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-acitretin (1). There are no data available on the half-life of acitretin in end stage renal failure (4). Acitretin should only be prescribed by, or under the supervision of a dermatological specialist (1). 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 is outside of the product license) the manufacturer advises appropriate clinical caution and monitoring (6). If facilities are available, monitoring of acitretin serum levels is suggested in patients with RI (2). Although it has been suggested that a plasma assay is not helpful as usually only the total drug is easily measurable (3). Therefore, where possible, monitoring of both total and free (unbound) concentrations of acitretin should be considered in patients with RI. Renal Impairment Only limited data are available on the pharmacokinetics of acitretin in patients with renal failure (3). The manufacturer and the British National Formulary (BNF) contra-indicate the use of acitretin in patients with RI (1, 7) due to an increased risk of toxicity (7). Conversely, other sources suggest that only severely impaired kidney function is a contra-indication to acitretin (2, 8) and that RI is a precaution with a possible need for dosing adjustment (2). However, these sources do not define the grades of RI. The RDH 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 contra-indicates its use in renal failure (4). From the National Electronic Library for Medicines. www.nelm.nhs.uk 1
  • 2. Medicines Q&As There are only two published case reports of the use of acitretin in patients with chronic renal failure (CRF). In both patients a dose of 20mg on alternate days was used to treat Kyrle’s disease (9). Neither safety nor efficacy could be fully evaluated as both patients died, although acitretin was reported to be partially effective in one of the patients (9). Adverse effects The toxic dose of acitretin is close to the therapeutic dose and most patients experience some side- effects during the initial period whilst dosage is being adjusted (1). There is no dose of etretinate at which therapeutic, but not adverse effects, are likely to appear (3). Therefore it is difficult to estimate the 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 etretinate (10, 11). Also 1-10% of patients receiving etretinate in manufacturer-sponsored studies had raised mean serum creatinine concentrations (2, 5) and therefore, monitoring of residual renal function would be prudent. Additionally, reported adverse effects such as oedema, with acitretin (1, 5) or etretinate (2, 5) may have implications for patients with RI. It is advisable to consult the SPC for full details of the adverse effect profile of acitretin (1) and to consider how these may affect a patient with RI. Intermittent Dialysis During haemodialysis (HD) neither acitretin (2, 3, 4) nor 13-cis-acitretin (3) are thought to be removed by the dialysing membrane. Acitretin is unlikely to be dialysed through intermittent haemodiafiltration (HDF) or high-flux haemodialysis (4). The RDH suggests that in patients undergoing standard or high- flux HD or HDF, the dose used should be that which is used in normal renal function (4). One study investigated the pharmacokinetics of acitretin in patients on HD (12). 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 50mg of acitretin (12). In the HD patients, the peak plasma concentration of acitretin and 13-cis-acitretin, and the area under the curve of acitretin, were lower than those of the control group, (12). 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 results. 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 overlooked (3). Therefore further studies of multiple doses of acitretin, with measurement of both total and free (unbound) concentrations of acitretin and 13-cis-acitretin, are needed in renal failure patients (12). There are two published case reports involving the use of acitretin in patients on HD (13). Both patients had nephrogenic systemic fibrosis (NSF) 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 (13). The safety of these regimens was not fully evaluated. Continuous Ambulatory Peritoneal Dialysis (CAPD) The RDH is the only source which provides dosing advice in CAPD, and states that the dose used should be that used in normal renal function (4). No published information regarding the use of acitretin in patients with CAPD was located. Dialysability of acitretin is unlikely (14) based upon its large volume of distribution (Vd ~ 9L/Kg) and high degree of protein binding (Pb > 99%) (2, 3, 4). For further details see Q&A 168.3 – What factors need to be considered when dosing patients on RRT? (15). Continuous arteriovenous/venovenous haemodialysis / haemofiltration (CV/VVHD & CAV/VVH) From the National Electronic Library for Medicines. www.nelm.nhs.uk 2
  • 3. Medicines Q&As The RDH 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 used in normal renal function (4). 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 168.3) (15). Etretinate Etretinate is no longer actively marketed in the UK (5). 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) (3, 5). Also, there are several reports of detectable levels of etretinate in subcutaneous fat following administration of acitretin (2), even at times when the plasma concentrations of acitretin are undetectable (3). Etretinate appears to accumulate in adipose tissue after repeated dosing (3) and has a long elimination half-life of about 120 days (2, 5). It has a prolonged half-life in obese patients (2). There is also evidence that etretinate can impair the elimination of acitretin, possibly by inhibiting its metabolism (3). A study investigated the effect of CRF on the plasma levels of etretinate in four patients who were receiving doses of 30-50mg daily (16). 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 (16). Because of the short duration of blood collection and the small number of subjects investigated, no definite conclusions can be drawn from this study (12). Summary ♦ 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, or under the supervision of a dermatological specialist. 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 is outside of the product license) the manufacturer advises appropriate clinical caution and monitoring. ♦ 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 manufacturer contra-indicates the use of acitretin in all degrees of RI, and the BNF states that acitretin should be avoided in RI due to an increased risk of toxicity. However the Renal Drug Handbook empirically suggests that the normal dose may be used in all grades of RI and in patients undergoing RRT. ♦ 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 renal impairment). From the National Electronic Library for Medicines. www.nelm.nhs.uk 3
  • 4. Medicines Q&As ♦ 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. Disclaimer • Medicines Q&As are intended for healthcare professionals and reflect UK practice. • Each Q&A relates only to the clinical scenario described. • Q&As are believed to accurately reflect the medical literature at the time of writing. • See NeLM for full disclaimer. References From the National Electronic Library for Medicines. www.nelm.nhs.uk 4
  • 5. 1 ) Summary of product characteristics for Neotigason 10mg capsules. Actavis UK Limited. Document last updated on the eMC: 24th September 2008. Accessed online: http://emc.medicines.org.uk on 30/10/08. Summary of product characteristics for Neotigason 25mg capsules. Actavis UK Limited. Document last updated on the eMC: 19th September 2008. Accessed online: http://emc.medicines.org.uk on 30/10/08. 2 ) DRUGDEX System: Acitretin and Etretinate Drugdex Drug Evaluations. In: DRUGDEX System (Volume 138). Thomson Micromedex, Greenwood Village, Colorado, USA. Accessed online via www.thomsonhc.com on 30/10/08 and by CD ROM. 3 ) Dollery C. editor. Therapeutic Drugs 2nd Ed, Edinburgh: Churchill Livingstone; 1999, p.A30-36, E108-112. 4 ) Ashley, C. Currie, A. editors. Renal Drug Handbook 3rd Edition. Oxford, Radcliffe Medical Press Ltd; 2009, p.16. 5 ) Sweetman SC (ed), Martindale: The Complete Drug Reference 35. [online] London: Pharmaceutical Press http://www.medicinescomplete.com/ accessed on 30/10/08. 6 ) Personal Communication with Medical Information Officer for Actavis UK Limited, 12th November 2008 7 ) Martin J, editor. British National Formulary No. 56. London: British Medical Association and Royal Pharmaceutical Society of Great Britain, September 2008. Accessed on-line via www.bnf.org on 30/10/08. 8 ) British Association of Dermatologists. Clinical guidelines for the general management of psoriasis. Accessed online via: http://www.bad.org.uk/healthcare/guidelines/psortables.asp on 06/11/08. 9 ) 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. 10 ) Horber FF, Zimmermann A, Frey FJ. Impaired renal function and hypercalcaemia associated with etretinate. Lancet 1984; 8411: 1093. 11 ) Cribier B, Welsch M, Heid E. Renal impairment probably induced by etretinate. Dermatology 1992; 185: 266-268. 12 ) 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. 13 ) Duffy KL, Green L, Harris R et al. Treatment of nephrogenic systemic fibrosis with Re-PUVA. J Am Acad Dermatol 2008; 59 (Iss 2, Suppl1); S39-40. 14 ) 2008 Dialysis of Drugs, accessed via http://www.ckdinsights.com/ on 30/10/08. 15 ) Kuczynska J. Q&A 168.3 What factors need to be considered when dosing patients on renal replacement therapies? South West Medicines Information & Training. Prepared 29/09/08.Partially revised 16/1/09 Accessed via www.nelm.nhs.uk on 19/1/09 16 ) Vahlquist A. Etretinate pharmacokinetics in chronic renal failure, a preliminary study in psoriasis patients. Dermatologica 1987; 175: 224-228. Quality Assurance Prepared by Michèle Skipp, South West Medicines Information, Bristol Date Prepared 13th November 2008
  • 6. Checked by Julia Kuczynska, South West Medicines Information, Bristol Date of check 21st January 2009 Search strategy • Embase (*Etretin AND exp*Kidney-Failure) OR (*Etretin AND exp*Renal Replacement Therapy). • Medline (*Acitretin AND exp*Renal Insufficiency) OR (*Acitretin AND exp*Renal-Replacement-Therapy). • Pharmline (Keywords: Acitretin AND [Peritoneal-Dialysis-continuous Ambulatory OR Peritoneal Dialysis]; Acitretin AND Dialysis; Acitretin AND [Kidney Function-impaired OR Kidney Failure OR Kidney Failure- chronic OR Kidney Failure-acute]; Acitretin AND [Kidney-artificial OR Haemodialysis OR Haemodialysis- home OR Haemodialysis-continuous Arteriovenous]). • Manufacturer (Actavis UK Limited, Personal Communication, email dated 12/11/08). • Internet search (National Library for Health & Cochrane Library), search term “acitretin”. • Internet search (Google “renal acitretin OR etretin –transplant”) • 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.