Acute Porphyria Drugs

Acute Porphyria Drug Database

L04AD01 - Ciclosporin
Propably not porphyrinogenic
PNP
Important Information
Patients on immunosuppressive therapy have an increased risk of infections. Since infections have a potential to trigger acute porphyric attacks vigilance is motivated regarding signs or symptoms of infection and/or possible symptoms of a porphyric attack. Side effects like nausea and vomiting may potentially be porphyrinogenic through reduction in carbohydrate intake.
Side effects
Infections are common in patients using immunosuppressants and since infections might trigger an acute porphyric attack, vigilance regarding signs and symptoms of an infection and/ or a porphyric attack is recommended. Common adverse reactions of ciclosporin that can be confused with an acute porphyric attack are nausea and vomiting. These side effects may potentially be porphyrinogenic if leading to a decrease in carbohydrate intake.
Rationale
Ciclosporin does not induce cytochrome P450 enzymes. It is an inhibitor of CYP 3A4, but no evidence point to irreversible inhibition.
Chemical description
Cyclic polypeptide.
Therapeutic characteristics
Ciclosporin is a calcineurin inhibitor, used to prevent transplant rejection. It is also used in the treatment of other conditions where immunosuppression is desired. It is administered orally or as an intravenous infusion.
Hepatic exposure
Significant
Metabolism and pharmakokinetics
Ciclosporin is metabolized by CYP3A4 and in vitro and interaction studies show that ciclosporin is an inhibitor of CYP 3A4. Listet by Zhou et al. as a possible mechanism-based inhibitor, but due to lacking evidence it is not suspected to be an irreversible inhibitor. Ciclosporin does not induce cytochrome P450 enzymes.
Preclinical data
Experimental data on mice point to porphyrogenicity in the same class as barbiturate, which probably is the cause for warning against the drug in other drug lists.
Personal communication
C. Andersson; patient report: tolerated (n=1).
Published experience
One report of activation of possible porfyric symptoms in a previously undiagnosed female AIP patient immediately after a kidney transplant, with improvement after discontinuing ciclosporin (Marsden et al. 2008). However, because the symptoms occurred in connection with a surgical procedure it is likely that a number of other factors could be responsible. It is also possible that some of the patients symptoms was due to common side effects of ciclosporin. Reports of uneventful use: Barone et al 2001, Field 2006 et al, Turton-Weeks et al 2001 and Warholm et al 2003.
IPNet drug reports
Uneventful use reported in 1 patient with acute porphyria.

References

  1. Scientific articles
  2. Niwa T, Yamamoto S, Saito M, Shiraga T, Takagi A, Effect of cyclosporin and tacrolimus on cytochrome p450 activities in human liver microsomes. Yakugaku Zasshi. 2007 Jan;127(1):209-16 PMID 17202802. #4611
  3. Watkins PB, The role of cytochromes P-450 in cyclosporine metabolism. J Am Acad Dermatol. 1990 Dec;23(6 Pt 2):1301-9; discussion 1309-11. PMID 2277139. #4613
  4. Zhou ZW, Zhou SF, Application of mechanism-based CYP inhibition for predicting drugâ-drug interactions. Expert Opin Drug Metab Toxicol. 2009 Jun;5(6):579-605 PMID 19466877. #4614
  5. Zhou, S.F., Xue, C.C., et al. Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit 2007; 29(6):687:710. #1027
  6. Barone GM, Gurley BJ, Anderson KE, Ketel BL, Abul-Ezz SR. The tolerability of newer immunosuppressive medications in a patient with acute intermittent porphyria. Journal of Clinical Pharmacology 2001; 41(1):113-115. #2316
  7. Field JJ, Giannone L, Bessler M, Blinder MA. Immunosuppressive therapy for acute porphyria: Safety and efficacy in a patient with bone marrow failure. Pharmacotherapy 2006; 26(11): 1662-1666. #2315
  8. Marsden JT, Chowdhury P, Wang J, Deacon A, Dutt N, Peters TJ, Macdougall IC. Acute intermittent porphyria and chronic renal failure. Clin Nephrol. 2008 May;69(5):339-46. PMID 18538096. #4610
  9. Nunez DJ, Williams PF, Herrick AL, Evans DB, McColl KEL. Renal transplantation for chronic renal failure in acute porphyria. Nephrology Dialysis Transplantation 1987; 2(4):271-274. #2320
  10. Turton-Weeks S, Barone GW, Gurley BJ, Ketel BL, Lightfoot ML, Abul-Ezz SR et al. Pretransplant evaluation of a patient with acute intermittent porphyria. Progress in Transplantation 2001; 11(3):214-216. PMID 11949465. #4612
  11. Warholm C, Wilczek H. Renal transplantation in a case of acute intermittent porphyria. Journal of Clinical Pharmacology 2003; 43(10):1158-1160. #2324
  12. Drug reference publications
  13. Sweetman SC, editor. Martindale: The complete drug reference. Ciclosporin. Pharmaceutical Press 2009. #2321
  14. Summary of Product Characteristics
  15. Norwegian medicines agency. Summary of Product Characteristics (SPC). Sandimmun. #2319
  16. The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). Sandimmun. #2323
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