Monograph

L04AH01 - Sirolimus

Propably not porphyrinogenic

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 sirolimus 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

Sirolimus is a substrate of CYP3A4 and has been seen to inhibit CYP2C9 and CYP3A4, but only in concentrations much higher than therapeutic doses. Not listed as a mechanism based inhibitor. No pharmacokinetic porphyrinogenic effects are suspected.

Chemical description

Sirolimus is a macrolide compound obtained from Streptomyces hygroscopicus.

Therapeutic characteristics

Sirolimus is an immunosuppressive agent used for prevention of organ rejection in kidney transplantation and is being investigated for induction of remission in some auto-immune diseases. It is administered orally. Infections and infestations such as urinary tract infections, sepsis and pneumonia, as well as fever, are common in patients treated with sirolimus. Common adverse reactions of sirolimus that can be confused with an acute porphyric attack are abdominal pain, diarrhoea, constipation, and nausea. Side effects such as nausea and vomiting may be potentially porphyrinogenic through reduction in caloric intake.

Metabolism and pharmacokinetics

Sirolimus is metabolised by CYP3A4. Sirolimus inhibits human liver microsomal CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 in vitro (Zhou, 2007; Rendic, 2002), however the active substance is not expected to inhibit the activity of these isozymes in vivo since the sirolimus concentrations necessary to produce inhibition are much higher than those observed in patients receiving therapeutic doses of the drug.

Published experience

Sirolimus was used uneventfully after a kidney transplant in a 47 year old man with AIP (El-Haggan, 2002).

IPNet drug reports

Uneventful use reported in 1 patient with acute porphyria.

References

#	Citation details	PMID
*	Scientific articles
1.	Rendic, S. Summery of information on human CYP enzymes: human P450 metabolism. Drug metabolism reviews 2002; 34(1&2), 83â-448.
2.	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.
3.	Sirolimus tolerability in a kidney transplant recipient with acute intermittent porphyria. El-Haggan W, Lobbedez T, et al. Nephrol Dial Transplant. 2002;17(6):1147.
*	Drug reference publications
4.	McEvoy GK, editor. Bleomycin. The AHFS Drug Information 2008. Bethesda, MD: American Society of Health-System Pharmacists; 2009. Electronic version (23.08.10).
5.	Sweetman SC, editor. Martindale: The complete drug reference. Sirolimus. Pharmaceutical Press 2009.
*	Summary of Product Characteristics
6.	Norwegian medicines agency. Summary of Product Characteristics (SPC). Rapamune.

Citation details

PMID

Scientific articles

Rendic, S. Summery of information on human CYP enzymes: human P450 metabolism. Drug metabolism reviews 2002; 34(1&2), 83â-448.

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.

Sirolimus tolerability in a kidney transplant recipient with acute intermittent porphyria.

El-Haggan W, Lobbedez T, et al. Nephrol Dial Transplant. 2002;17(6):1147.

Drug reference publications

McEvoy GK, editor. Bleomycin. The AHFS Drug Information 2008. Bethesda, MD: American Society of Health-System Pharmacists; 2009. Electronic version (23.08.10).

Sweetman SC, editor. Martindale: The complete drug reference. Sirolimus. Pharmaceutical Press 2009.

Summary of Product Characteristics

Norwegian medicines agency. Summary of Product Characteristics (SPC). Rapamune.

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