Comparative effectiveness of risk mitigation strategies to prevent fetal exposure to mycophenolate

Abstract

BackgroundIn 2012, the US Food and Drug Administration approved a Risk Evaluation and Mitigation Strategy (REMS) programme including mandatory prescriber training and a patient/provider acknowledgement form to prevent fetal exposure to mycophenolate. Prior to the REMS, the teratogenic risk was solely mitigated via written information (black box warning, medication guide (MG period)). To date, there is no evidence on the effectiveness of the REMS.MethodsWe used a national private health insurance claims database to identify women aged 15–44 who filled ≥1 mycophenolate prescription. To compare fetal exposure during REMS with the MG period, we estimated the prevalence of pregnancy at treatment initiation in a pre/post comparison (analysis 1) and the rate of conception during treatment in a retrospective cohort study (analysis 2). Pregnancy episodes were measured based on diagnosis and procedure codes for pregnancy outcomes or prenatal screening. We used generalised estimating equation models with inverse probability of treatment weighting to calculate risk estimates.ResultsThe adjusted proportion of existing pregnancy per 1000 treatment initiations was 1.7 (95% CI 1.0 to 2.9) vs 4.1 (95% CI 3.2 to 5.4) during the REMS and MG period. The adjusted prevalence ratio and prevalence difference were 0.42 (95% CI 0.24 to 0.74) and −2.4 (95% CI −3.8 to −1.0), respectively. In analysis 2, the adjusted rate of conception was 12.5 (95% CI 8.9 to 17.6) vs 12.9 (95% CI 9.9 to 16.9) per 1000 years of mycophenolate exposure time in the REMS versus MG periods. The adjusted risk ratio and risk difference were 0.97 (95% CI 0.63 to 1.49) and −0.4 (95% CI −5.9 to 5.0), respectively. Sensitivity analyses on the estimated conception date demonstrated robustness of our findings.ConclusionWhile the REMS programme achieved less pregnancies at treatment initiation, it failed to prevent the onset of pregnancy during treatment. Enhanced approaches to ensure effective contraception during treatment should be considered.

Risk of pregnancy loss in patients exposed to mycophenolate compared to azathioprine: A retrospective cohort study

“…Pregnancy episodes in our database were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification codes and Current Procedural Terminology, and Healthcare Common Procedure Coding System codes on maternal inpatient and outpatient claims which were adapted from previously validated algorithm 15‐17 . For pregnancies with the live birth outcome, we used the specific preterm/post‐term diagnosis codes to determine gestational age (GA).…”

REMS in pregnancy: system perfectly designed to the get the results it gets

“…The outcomes of interest were twofold: (1) the period prevalence of mycophenolate initiation in pregnant women and (2) rates of conception while receiving mycophenolate. Compared with the period prior to REMS initiation, Sarayani et al found fewer mycophenolate exposures in pregnancy after REMS (4.2 per 1000 treatment episodes vs 1.9 per 1000 treatment episodes), but no difference in the incidence of new pregnancies in women already taking mycophenolate (13.1 new pregnancies per 1000 years of treatment pre-REMS vs 12.1 per 1000 years post-REMS) 4. This pattern suggests that the REMS for mycophenolate prevented new drug starts in pregnant women but did not stop women already taking it from becoming pregnant.…”

“…In this issue of BMJ Quality & Safety , Sarayani et al 4 examine the real-world effectiveness of implementing the REMS for mycophenolate, an immunosuppressant drug commonly used for solid organ transplant recipients and patients with autoimmune diseases. Mycophenolate should be avoided in pregnancy because of its association with first-trimester loss and an increased risk of congenital anomalies 5.…”

“…Using a database of private health insurance claims in the USA, Sarayani et al used a pre-post study design to examine mycophenolate exposures in patients 15–44 years old before and after the REMS implementation 4. The outcomes of interest were twofold: (1) the period prevalence of mycophenolate initiation in pregnant women and (2) rates of conception while receiving mycophenolate.…”

“…Studies have demonstrated that among women taking potential teratogens, less than one-third receive appropriate contraception 18 19. An important but sobering finding of the study by Sarayani et al was the similar rates of contraceptive use among women preimplementation and postimplementation of the REMS for mycophenolate 4. Unplanned pregnancies are, unfortunately, a clinical reality, even during treatment with a known teratogen.…”