Report

Safety issues with cyclosporine Charles N. Ellis, MD

From the Department of Dermatology, University of Michigan Medicai School, Ann Arbor, Michigan Correspondence Charles N. Ellis, MD. Department of Dermatology, University of Michigan Medical School, 1910 A. Alfred Taubman Health Care Center, Ann Arbor, Ml 48109-0314

The tnore even absorption characteristics of the Neoral® fortnulatioti of cyclosporitie cotitribute to its itnproved safety profile when compared with Sandimtnune®. Excessive dose adjusttnents of cyclosporitie are reduced, stable absorption is offered, and variability in cyclosporine blood levels is avoided. Short-tertn use of Neoral, i.e. for treattnent up to i year, also enhances its overall safety. As discussed in other articles in this supplement, the potetirial for side-effects of Neoral may be reduced by careful patient selection and by proper dosing. The adverse effects that may be associated with appropriate dosing of Neoral are reviewed iti this article.

Hg, cati ofteti be managed with salt restrictioti, exercise, and fish oil; antibypertensive drug therapy is tised wben other tneasures fail. The incidence of drug-itiduced hirsvitism is —25% within the first 4 tnonths of treattnent.' The probletn appears to involve pritnarily tertnitial hair. Gingival hyperplasia occurs in = i o % - i 5 % of patietits' and can be ameliorated at least in part by careful dental hygiene. Table i lists the reasons why patients in clinical trials at our center discontinued therapy over an e.xtended treattnent period of 5 years. Eighty-five patients began the study. After =1, 2, and 3 years, 64, 27, and 16 patients, respectively, retnaitied iti the protocol. Curretitly, treattnetit periods of i year or less are recotntnetided.

Early vs persistent symptomatic adverse events The symptotnatic adverse reactions that occur with cyclosporitie therapy fall into two types. First are those reactions that occur iti a concentration-dependent fashion duritig initial therapy, includitig gastrointestinal distress, fatigue, headache, tnalaise, and joitit or tnuscle discomfort. These reactions typically resolve without treattnent after several weeks. Tremors and parestbesias have been reported, although they occur infrequendy at doses of cyclosporine recotiitiietided for dertnatologic conditions. When present, the syniptotns are likely to itnprove with titne duritig therapy. Second are the tnore persistent, clinically evident reactions that iticlude hypertension, hirsutistn, atid gitigival hyperplasia. The overall risk of developing hypertetision while oti cyclosporine therapy is variable. As would be expected, the risk is greater in older patients and in those who have higher baselitie blood pressures. Persistent hypertension, i.e. blood pressure greater than 140/90 tiitn © 1997 Biackweli Science Ltd

Serious adverse effects Laboratory values

The tnost cotntiion changes in laboratory test values associated with Neoral are showti in Table 2. Increases in uric acid or bilirubin are not getierally of conceni in patietits who are receivitig the doses of Neoral appropriate to dertnatologic cotiditions. Hyperlipidetiiia induced by cyclosporine is usually tnild and often can be tnanaged by dietary chatiges, by increased physical activity, or, wlieti necessary, by phartnacologic interventioti. Replacement tnagtiesiutn therapy may be ttecessary iti sotiic patietits. Renal toxicity

The pritnary concern with the recotnmettded use of Neoral is the potetitial for toxic effects on the kidney.-" *• The early and reversible vasocotistrictive activity of the drug tnay precipitate a rise in serum creatinine concentratiotis withiti tbe first few weeks of therapy.' After at least 1 year of treattnetit, cyclosporine therapy International Journal of Dermatology 1997, 36 (Suppi. 1), 7-10

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Report Safety issues with cyclosporine

Table 1 Reasons for stopping cyclosporine therapy during 3-year, single-center clinical trial"' Categoryt

Percentage of patients who left study (W = 69)

Patient vioiated protocol, moved away, or miscellaneous reasons Kidney-reiated side-effects^: Unreiated iiinesses Cardiovascuiar side-effecfs§ Lack of efficacy of cyciosporine Entered iong-term remission during cyciosporine therapy

33 33 14 10 4 4

Totai

9811

*The current recomtncndation is to treat for periods of r year or less. fThe author has cotnbitied various reasons for leaving the study into these categories. tlncludes elevations in scrum creatintne or urea nitrogen, decline in glotncrular filtration rate, renal biopsy evidence of fibrosis, and patients in whotn concern was raised about their requiretnent for coticurrent use of nephrotoxic agents such as nonsteroidal anti-inflammatory drugs. Pncludes hypertention, tnigraities, and other heart or vascular conditions. fDoes tiot total 100 because of rounditig.

Table 2 Laboratory chatiges associated with Neoral therapy Increased values

Decreased values

Creatinine Urea nitrogen (BUN) Cholesterol/triglyoerides Biiirubin Uric acid

Glomerular filtration rate Magnesium

is also associated with tubular atrophy and ititerstitial fibrosis.5^7 Notie of the patients in our clinical trials, including those receiving treattnent for as long as 3 years, required treattnetit for kidney disorders. Tbe lotig-terni potential for progressive retial failure requires further clarification, however, as does the itnpact of other variables, sucb as ageing or the use of such agetits as nonstcroidal anti-itiflamtnatory drugs on declining renal function. What are the clinical itnplications with regard to renal roxicity? In getieral, the potential for toxicity can bc tnitiitnized by doses that do not exceed 5 tng/kg per day of either Neoral or Satiditntnune, and by dosage reductioti iti the event that scrum creatinine rises tnore than 30% above baseline values. Fish oil suppletnents have been suggested to tninitnize renal toxicity.**''-" Measuretnent of glomerular filtration rate tnay be useful in tnonitoring renal function in patients with pre-existing risk factors for kidney disease or in patients receiving International Journal of Dermafology 1997, 36 (Suppl, 1), 7-10

cyclosporine beyond the recotntnended titne course. The use of short-tertn therapy would also be expected to avoid the occurrence of irreversible renal dysfunction. Cancer

The developtnent of cancer as a result of cyclosporine therapy is an extretnely rare pbenotnenoti,'° particularly when cotnpared with the tnore straightforward relationship between the drug and renal side-effects. The occurrence of lytnpbotna or other cancers more likely reflects the degree of deep itntnutiosuppressioti induced by this class of agetits, but tbis is not as great a concert! with the treattnent of psoriasis, where cyclosporine is adtninistered in doses below 5 tng/kg per day for intertnittent periods, and without other itntnunosuppressive agents. Cutaneous side-effects

Infections such as warts, itnpetigo, and titiea are of concern iti transplant patients receiving cyclosporine; however, tbis is not a substantive probletn in patients receiving low doses for treattnent of psoriasis.' Rare side-effects of Neoral include isolated case reports of severe acne, folliculitis, atid reversible benign lytnphocytic infiltrates.'°'"

Monitoring guidelines Table 3 contains tnonitoring recotntnendations prior to and duritig Neoral therapy. An accurate baseline serutn creatinitie tneasuretnent is important iti order to assess © 1997 Blackwell Science Ltd

Salety Issues with cyclosporine Report

Ellis

Table 3 Recotntnendations for tnonitoring prior to and during Neoral therapy Parameter Prior to therapy Serum creatinine

Action

Obtain at least two measurements within 10% of each other to determine true baseiine ievei

At baseline, after 2 and 4 weeks, and then at least monthly Treat hypertension or reduce cyciosporine Biood pressure dose if possibie Reduce cyclosporine dose if vaiue > 30% Creatinine over baseiine Assess kidney function further if significantiy Urea nitrogen and persistentiy abnormal Treat if signlficanfiy abnormal Lipids Expect increases, but dose reduction Biiirubin, liver function usually not indicated in biiirubin Treat if significantiy abnormal Uric acid Provide repiacement therapy if iow Magnesium Treat if significantly abnormal Eiectrolytes Determine if new medication affects or is New medications affected by cyciosporine metabolism

Adapted frotn F'Uis CN, Cyclosporitie iti the treatmetit of severe psoriasis. In: Weitisrein GD and Gottleib AB (eds). Therapy of Moderate-to-Severe Psoriasis. Portland, Ore: T h e N a t i o n a l Psoriasis F o u n d a t i o n , 1 9 9 3 : i t 5 .

The future literature on Neoral Now tbat Neoral is approved by the Food and Drug Adtninistration for use in psoriasis, it is likely that there will bc a sitbstantial increase in usage. This will likely lead to a nutnber of reports of side-effects published by dertnatologists in the dertnatologic literature. Readers of these reports should recogtiize that tnatiy of the sideeffects will occur once or rarely. Further, readers should tiot expect to sec a balancitig number of articles on the efficacy of cyclosporitie because the results of cyclosporitie therapy in tnatiy of the responsive disorders have already becti published.

Conclusions The tnajor organ at risk during cyclosporine therapy ts the kidney; however, risk to renal function cati bc reduced by attention to dosing and routine tneasures of kidney futicrion, specificalb' serutn crearitiinc. Wben used within the guidelines and for periods of 1 year or less, cyclosporitie, particularly the Neoral fortnulation, tnay provide substatitial benefit to patietits with psoriasis and other dertnatologic conditiotis. Neoral is a fortnulation of cyclosporine tbat provides consistent and predictable absorptioti.

References

cbanges during tberapy, and two separate baseline tests within 10% of each other help overcotne procedural itiaccuracies. Out-patietit urine creatinine clearance rests tend to be unreliable. Creatinine clearance cati be calculated frotn fortnulas based on serutn creatinitie but, for many patients, adds little practical itifortnation. Glotncrular filtratioti rates arc probably unnecessary iti tnost patietits wben cyclosporitie is used for the treattnent of psoriasis as recotiimended. Blood pressure should be followed every 2 weeks for the first 4 weeks' of therapy, atid tnonthly thereafter. It is not usually necessary to track blood levels of cyclosporine routinely, but tneasuretnent tnay be helpful itl tbe rare patietit who does not experience atiy clitiical itnproveinetit on therapy. In this case, the cyclosporitie blood level tnay differentiate a true nonresponder from a patient experiencing poor absorptioti. Because tnany laboratories use transplatitation indications as their reference for nortnal levels of cyclosporine, tbe reported laboratory "tiortnal range" tnay not be helpful. © 1997 Biackweli Science Ltd

1 Ellis CN, Fradin MS, Messann JM, etal. Cyclosporine for plaquc-rype psoriasis. Results of a tnultidose, double-blitid trial. N EngI J Med 1991; .324: Z77-284. 2 Powles AV, Cartnichael D, Hultne B, et al. Renal futicrion after long-tertn low-dose cyclosporni for psoriasis. Br j Dermatol 1990; 122: 665-669. 3 Messatta JM, Rocher LL, Fllis CN, et al. Fffecrs of cyclosporine on rennl function m psori.isis patients. J Am Acad Dermatol 1990; 23: 1288-1293. 4 Feutren G, Miiiarsch MG. Risk factors for cyclosporine-induced nephropathy in patients with autoimmune diseases. N F.ngl J Med 1992; 326: 16541660.

5 Miharsch MJ, Wolff K. Consensus conference on cyclosporine A for psoriasis, February 1992. Br j Dermatol 1991; 126: 621-623.

6 Zachariae Fl, Hansen HF, Kragballe K, et al. Morphologic renal chatiges during cyclosporine t:reartncnt of psoriasis. / Am Acad Dermatol 1992; 26: 415-419. 7 Young FW, Ellis CN, Messann JM, et al. A prospective study of renal structure atid futiction iti psoriasis patients trcared with cyciosporine. Kidney Int 1994; 46: 1216-1222.

8 Homan van der Heide JJ, Bilo HJ, Donker JM, etal. Fffect of dictarv Hsh oil on renal function and International Journal of Dermatology 1997, 36 (Suppl. 1), 7-10

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rejection in cyclosporine-recipients of renal transplants. N F2ngl J Med 1993; 329: 769-773. 9 Stoof TH, Korstatije MJ, Bilo HF, etal. Does fish oil protect renal function in cyclosporine-treated psoriasis patients? J Intern Med 1989; 226: 437-441. 10 f-radin MS, Ellis CN, Voorhees JJ. Management of

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patietits and side effects during cyclosporine therapy for cutaneous disorders. J Am Acad Dermatol 1990; 23: 1265-1275. 11 Gupta AK, Cooper KD, Ellis CN, etal. Lytnphocyttc infiltrates of the skin in association with cyclosportne therapy. J Am Acad Dermatol 1990; 23: 1137-1141.

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