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Mykofenolsyra

Klassificering: C!

Preparat: CellCept®, Myclausen, Mycophenolate mofetil Accord, Mycophenolate mofetil Arrow, Mycophenolate mofetil Cross Pharma, Mycophenolate mofetil Sandoz, Myfenax, Myfortic, Myfortic®, Mykofenolatmofetil 2care4, Mykofenolatmofetil Accord, Mykofenolatmofetil Actavis, Mykofenolatmofetil EQL, Mykofenolatmofetil Orifarm, Mykofenolatmofetil Stada, Mykofenolsyra Accord

ATC kod: L04AA06

Substanser: mykofenolsyra

Sammanfattning

Bland patienter som behandlats med mykofenolsyra tycks fler kvinnor än män drabbas av biverkningar. Detta är särskilt tydligt för gastrointestinala biverkningar, som tenderar att vara mer frekventa och allvarliga hos kvinnor. Data tyder på att takrolimus som samtidig immunosuppression kan leda till en högre exponering för mykofenolsyra och mer negativa effekter hos kvinnor än hos män.

Det finns motstridiga uppgifter om könsskillnader i farmakokinetik för mykofenolsyra.

Mykofenolsyra kan orsaka fosterskador hos barn som exponerats under graviditet. Av denna anledning är mykofenolsyra kontraindicerat under graviditet. För mer information, se kunskapsstödet Janusmed fosterpåverkan.
Mykofenolsyra ska undvikas till flickor och kvinnor som kan tänkas bli gravida om de inte använder ett högeffektivt preventivmedel.

Additional information

Pharmacokinetics and dosing

According to the pharmaceutical company, there are no clinically significant sex differences in the pharmacokinetics of mycophenolic acid (MPA) given as mycophenolate mofetil (MMF) immediate-release formulation, or as a delayed release formulation of mycophenolate sodium (MPS) [1, 2].

Nevertheless, patient’s sex has been suggested to contribute to the significant interpatient pharmacokinetic variability of MPA [3]. Sex differences in mycophenolate exposure may depend on sex differences in rate and extent of MPA glucuronidation to a main pharmacologically inactive glucuronide metabolite (MPAG) by UDP glucuronosyl transferases (UGT) [4]. Men was found to have nearly two-fold higher glucuronidation rate as compared to women [4]. However, a recently published study suggested that effect of co-administered calcineurin inhibitor (CNI, cyclosporin or tacrolimus) has more pronounced effect on exposure to MPA than patient’s sex (3). Due to the different effects on enterohepatic circulation, tacrolimus often does and cyclosporin does not increase the MPA exposure [3]. In addition, the efflux activity of P-glycoproteins is lower in women compared to men and may contribute to accumulation of CNI and thus increased incidence of adverse events [5].

There are conflicting results regarding sex differences in the pharmacokinetics of MPA.  In a study of stable renal transplant patients receiving MMF and cyclosporin (47 men, 35 women) there were no sex differences in MPA exposure (both dose-adjusted and non-adjusted AUC0–12) [7].

In a cross-sectional observational study of 67 stable renal transplant recipients (38 men, 29 women) receiving enteric coated MPS and tacrolimus, there were no sex differences for total MPA AUC0-12h, but women had lower MPA clearance adjusted for body mass index (CL/BMI) and higher AUC/dose (6). The same group of patients was included in another population study of 147 clinically stable renal transplant recipients receiving MMF and cyclosporin (66 men, 14 women) or MPS and tacrolimus (38 men, 29 women) [3]. In this study, women had greater dose-normalized MPA AUC0-12h compared to men, irrespective of calcineurin inhibitor, but there were no sex differences in MPA clearance or MPA clearance adjusted for BMI. Among Caucasian and African American men and women in this study, African American women had the lowest MPA clearance [3].    

Pharmacokinetics of MPA were similar for girls and boys in pediatric renal transplant patients (1-18 years, 34 boys, 20 girls) [8].

Effects

A large study of registry data for 73,477 primary renal transplants (40% women) showed that in general, regardless of the type of immunosuppression, women have higher risk of acute rejection and lower risk of developing chronic allograft failure than men [9]. Mycophenolate mofetil (MMF) was shown to decrease the risk of developing chronic allograft failure to a significantly greater extent in women (RR 0.53) than in men (RR=0.79) [9].

The U.S. Food and Drug Administration (FDA) concluded that the sample sizes were insufficient to rule out possibly meaningful sex differences in combined analysis of three pivotal randomized studies of MMF in kidney transplant patients (587 men, 408 women ) [10].

Analysis of graft loss (the primary efficacy variable) in a randomized double-blind pivotal study of MMF in liver transplant patients (159 men, 119 women), showed no clinically relevant differences by sex compared to the total study population [11]. Rejection was higher in women at 6-month regardless of type of immunosuppression (MMF or azathioprine) [12], and no sex differences was found at the 12-month timepoint [11].

In the pivotal randomized double-blind study of MPA for prevention of acute rejection in cardiac transplantation, 83% of patients were men, which reflects heart transplantation registry. No outcome analysis based on patient’s sex were presented in the New Drug Application to FDA [10].

Adverse effects

In a pivotal study of MPA in liver transplant patients (159 men, 119 women) there were similar frequencies of adverse effects (AE) and discontinuation of drug due to AE for men and women [11].

Numerically more women than men had anemia, diarrhea, nausea and herpes simplex in both MMF and azathioprine treatment groups in three pivotal studies of MMF in kidney transplant patients [10]. However, it is unclear if the lower normal hemoglobin range in women was considered.

In a population study of renal transplant patients on MMF and cyclosporin (66 men, 14 women) or  MPS and tacrolimus (38 men, 29 women), gastrointestinal adverse effects (AE) scores were higher in women. This was particularly pronounced in the tacrolimus group, where women had 36% higher score than men [3]. In the same study there were more men than women with lymphopenia [3]. The same research group reports in an earlier publication that analysis of all patients receiving MMF and cyclosporine (68 men, 14 women) or MPS and tacrolimus (38 men, 29 women), revealed that women had also higher aesthetic (such as acne, hirsuitism, and gingival hyperplasia), neurologic and cumulative AE scores (5). No associations between CNI, MPA trough concentrations and individual AE were detected in this study.

In a study of stable renal transplant recipients, in the group that received >720 mg MPA (16 men, 12 women), women demonstrated higher gastrointestinal AE scores. Women had also higher scores of diarrhea and skin changes [13]. Most of the patients (>80%) in this study had tacrolimus as CNI.

Reproductive health considerations

MPA is contraindicated in women of childbearing potential who are not using highly effective contraception and should not be initiated without negative pregnancy test [14]. The pharmaceutical company recommends that additional birth control methods are used if oral contraceptives are co-administered with MPA drugs, even though company considers that MPA is unlikely to influence the ovulation suppression of oral contraceptives [1, 12]. Malformations (microtia, external auditory canal atresia, cleft lip and congenital heart effects) is well documented in children carried by women exposed to MPA in the first trimester. Use of MPA is contraindicated during pregnancy unless there are no other options to prevent graft rejection [14].

MPS manufacturers and European Medicines Agency (EMA) recommend that men (including vasectomized) use condoms during MPA treatment and for 90 days thereafter [15]. Their partners of childbearing potential should use highly effective contraception for the same period of time. However, the available evidence does not confirm that children of the fathers taking MPA have an increased risk of malformations or miscarriage [16-18]. Regarding additional teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Försäljning på recept

Fler män än kvinnor hämtade ut läkemedel innehållande mykofenolsyra (ATC-kod L04AA06) på recept i Sverige år 2018, totalt 5 126 män och 3 712 kvinnor. Det motsvarar 1,0 respektive 0,7 personer per tusen invånare. Andelen som hämtat ut läkemedel var högst i åldersgruppen 60-74 år hos män och 55-69 år hos kvinnor. I genomsnitt var läkemedel innehållande mykofenolsyra 1,5 gånger vanligare hos män [19].

Uppdaterat: 2019-12-05

Litteratursökningsdatum: 2019-07-30

Referenser

  1. Cellcept (mycophenolate mofetil). DailyMed [www]. US National Library of Medicine. [updated 2019-03-14, cited 2019-07-30]. länk
  2. Myfortic (mycophenolate acid). DailyMed [www]. US National Library of Medicine. [updated 2018-11-03, cited 2019-07-30]. länk
  3. Meaney CJ, Sudchada P, Consiglio JD, Wilding GE, Cooper LM, Venuto RC et al. Influence of Calcineurin Inhibitor and Sex on Mycophenolic Acid Pharmacokinetics and Adverse Effects Post-Renal Transplant. J Clin Pharmacol. 2019;59(10):1351-1365. PubMed
  4. Momper JD, Misel ML, McKay DB. Sex differences in transplantation. Transplant Rev (Orlando). 2017;31(3):145-150. PubMed
  5. Venuto RC, Meaney CJ, Chang S, Leca N, Consiglio JD, Wilding GE et al. Association of Extrarenal Adverse Effects of Posttransplant Immunosuppression With Sex and ABCB1 Haplotypes. Medicine (Baltimore). 2015;94(37):e1315. PubMed
  6. Tornatore KM, Meaney CJ, Wilding GE, Chang SS, Gundroo A, Cooper LM et al. Influence of sex and race on mycophenolic acid pharmacokinetics in stable African American and Caucasian renal transplant recipients. Clin Pharmacokinet. 2015;54(4):423-34. PubMed
  7. Pescovitz MD, Guasch A, Gaston R, Rajagopalan P, Tomlanovich S, Weinstein S et al. Equivalent pharmacokinetics of mycophenolate mofetil in African-American and Caucasian male and female stable renal allograft recipients. Am J Transplant. 2003;3(12):1581-6. PubMed
  8. Clinical Pharmacology and Biopharmaceutics Review - Cellcept (mycophenolate mofetil). Drugs@FDA [www]. US Food and Drug Administration (FDA). [updated 2000-12-19, cited 2019-07-30]. länk
  9. Meier-Kriesche HU, Ojo AO, Leavey SF, Hanson JA, Leichtman AB, Magee JC et al. Gender differences in the risk for chronic renal allograft failure. Transplantation. 2001;71(3):429-32. PubMed
  10. US Food and Drug Administration (FDA). Medical Review - Cellcept (mycophenolate mofetil). Drugs@FDA [www]. [updated 2000-12-20, cited 2019-07-30]. länk
  11. US Food and Drug Administration (FDA). Medical Review - Cellcept (mycophenolate mofetil). Drugs@FDA [www]. [updated 2000-12-20, cited 2019-07-30]. länk
  12. European Medicines Agency (EMA). Cellcept (mycophenoalte mofetil) EPAR - Scientific Discussion. EMA [www]. [updated 2006-04-05, cited 2019-07-30]. länk
  13. Spasić A, Catić-Đorđević A, Veličković-Radovanović R, Stefanović N, Džodić P, Cvetković T. Adverse effects of mycophenolic acid in renal transplant recipients: gender differences. Int J Clin Pharm. 2019;41(3):776-784. PubMed
  14. Myfortic (mycophenolate acid). Summary of Product Characteristics. Swedish Medical Products Agency [updated 2019-04-16, cited 2019-07-30]
  15. European Medicines Agency (EMA). EMA recommends additional measures to prevent use of mycophenolate in pregnancy. EMA [www]. [updated 2015-10-24, cited 2019-09-11]. länk
  16. Kuypers DR, Van Mieghem T, Meijers B, Claes K. Updated Manufacturer and European Medicines Agency Recommendations on the Use of Mycophenolate Acid: Balancing the Risks for Male Allograft Recipients. Transplantation. 2016;100(9):e50-1. PubMed
  17. Midtvedt K, Åsberg A. Mycophenolate Acid and Balancing the Risk for Male Allograft Recipients. Transplantation. 2017;101(1):e39. PubMed
  18. Cellcept (mycophenolate mofetil). Summary of Product Characteristics. European Medicines Agency (EMA). [updated 2018-08-31, cited 2019-09-11].
  19. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2018 [cited 2019-10-29.] länk

Författare: Katri Rosenthal Aizman, Linnéa Karlsson Lind

Faktagranskat av: Mia von Euler

Godkänt av: Karin Schenck-Gustafsson