Drug products: 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, Mykofenolsyra Medartuum
ATC code: L04AA06
Substances: mycophenolic acid
Among mycophenolic acid treated patients more women than men seem to suffer adverse effects. This is particularly evident for gastrointestinal adverse effects, which tend to be more frequent and severe among women. Data suggests that tacrolimus as a concomitant immunosuppression may lead to a higher exposure to mycophenolic acid and more adverse effects in women than in men.
There are conflicting data regarding sex differences in pharmacokinetics of mycophenolic acid.
Mycophenolic acid can cause malformations in the children exposed during pregnancy. Due to this, mycophenolic acid is contraindicated during pregnancy. For Swedish readers, more information can be found in Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Mycophenolic acid should be avoided in girls and women who may become pregnant unless they are using a highly effective contraception.
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 . 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) . Men was found to have nearly two-fold higher glucuronidation rate as compared to women . 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 . 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 .
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) .
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) . 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 .
Pharmacokinetics of MPA were similar for girls and boys in pediatric renal transplant patients (1-18 years, 34 boys, 20 girls) .
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 . 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) .
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 ) .
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 . Rejection was higher in women at 6-month regardless of type of immunosuppression (MMF or azathioprine) , and no sex differences was found at the 12-month timepoint .
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 .
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 .
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 . 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 . In the same study there were more men than women with lymphopenia . 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 . Most of the patients (>80%) in this study had tacrolimus as CNI.
MPA is contraindicated in women of childbearing potential who are not using highly effective contraception and should not be initiated without negative pregnancy test . 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 .
MPS manufacturers and European Medicines Agency (EMA) recommend that men (including vasectomized) use condoms during MPA treatment and for 90 days thereafter . 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).
Date of litterature search: 2019-07-30
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson