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The Critical Role of Pharmacists in Mycophenolate Pharmacovigilance: Addressing the Associated REMS Program

Mycophenolate REMS: Implementing Effective Patient Counseling and Education (Part 2)

An Interactive Monograph

Overview

Concerns regarding the safety of prescription drugs in the wake of post-marketing celecoxib toxicity spurred the Institute of Medicine (IOM) of the National Academies to study prescription drug safety. The subsequent IOM report on drug safety published in 2007 included recommendations for changes to the US Food and Drug Administration (FDA) drug approval process.¹ As part of the response to the IOM report, Congress passed the Food and Drug Administration Amendments Act of 2007, which established the Risk Evaluation and Mitigation Strategy (REMS) program.^2,3 The FDA may institute REMS programs in situations where an approved drug has risks of serious adverse effects, but there are certain situations or patient populations in which the benefits of the drug may outweigh those risks. Most REMS programs are, at their core, communication strategy programs. Some may require specific activities or clinical interventions performed prior to prescribing or dispensing the medication. As described on the FDA website, “REMS are designed to help reduce the occurrence and/or severity of certain serious risks, by informing and/or supporting the execution of the safe use conditions described in the medication's FDA-approved prescribing information.”⁴ At the time of this publication, there were 62 drugs with active REMS programs including the immunosuppressant, mycophenolic acid (MPA [used in this article interchangeably for mycophenolate mofetil and mycophenolate sodium as well, unless specifically indicated]).⁵ Of those 62 drugs, 56 “require clinicians or health care settings to become certified prior to prescribing and to participate in additional REMS activities, such as training, patient counseling, and monitoring” through “elements to assure safe use” (ETASU).⁶ The ETASU designation represents the most stringent requirements for REMS activities and includes prescriber training on the risks associated with a particular drug.⁷

MPA, either in the form of mycophenolate sodium or the prodrug, mycophenolate mofetil, is used to prevent organ rejection in solid organ (e.g., kidney, heart, liver) transplant patients. The immunosuppressant effects of MPA occur through the inhibition of inosine 5’-monophosphate dehydrogenase in the purine biosynthesis pathway to reduce T-cell and B-cell proliferation.^8,9 First approved by the FDA in 1995, current MPA dosage formulations include capsules, tablets, delayed-release tablets, oral suspensions, and intravenous solutions.^10,11 The capsule, tablet, oral suspension, and intravenous solution formulations contain mycophenolate mofetil, whereas the delayed-release tablet formulations contain the sodium salt of MPA. As discussed in the next section, the risks of fetal harm and adverse pregnancy outcomes from MPA prompted the FDA to require a REMS program for the drug. This activity (Part 2 of 2) will focus on implementing effective patient counseling and education for the Mycophenolate REMS program.

Mycophenolate REMS Program Information

Brief Review of MPA and Its Risks During Pregnancy

Based on post-marketing data on MPA and evidence from the National Transplantation Pregnancy Registry (subsequently named the Transplant Pregnancy Registry International [https://www.transplantpregnancyregistry.org/about-us]), in 2007 the FDA changed the pregnancy safety category (that was in use at the time) of MPA to Category D, indicating that there were sufficient indications that MPA could pose risks to the developing human fetus.^9,12 Additionally, the FDA required a black box warning about the increased risk of pregnancy loss and congenital malformations in pregnancies be added to MPA prescribing information.^10,13 In 2014, the FDA changed their pregnancy and lactation labeling rules, and the categories (A, B, C, D, and X) were eliminated¹⁴; however, the categories are often referenced in the literature. With the expiration of patents for the prodrug and free acid forms of MPA, a number of generic products came to market. In 2012, the FDA approved a single, shared REMS program for all MPA-containing products¹⁵ ostensibly to streamline and coordinate safety information for the drug and its related name brand and generic products. As of November 28, 2021, there were 45 products listed on the FDA REMS page for MPA.¹¹

The need for a REMS program stems from the observed teratogenicity and increased risk of miscarriage with MPA. The first case report of human teratogenicity of MPA appears to be from Pérgola and colleagues¹⁶ in 2001; they describe a female child with hypoplastic nails and shortened fifth fingers who was born to a mother who was taking a combination of prednisone, tacrolimus, and mycophenolate mofetil. Many of the subsequent cases reported a range of teratogenic outcomes in children born to mothers treated with MPA, including hearing loss, cleft palate, heart defects, and various malformations of the face and head.^9,17,18 In addition to the aberrant fetal outcomes, negative pregnancy outcomes—particularly, increased risk of miscarriage—have been attributed to the use of MPA in pregnant women.^9,12 Sifontis and colleagues¹⁷ described an initial estimated first trimester pregnancy loss rate with MPA exposure of 42.3% (11 spontaneous abortions out of 26 pregnancies). In a recent systematic review, Le and colleagues⁹ indicated that precise estimates of the rates of congenital malformations and miscarriages are not well established, but range from 23% to 27% for congenital malformations and 40% to 52% for miscarriages. Furthermore, that review summarized data on discontinuing MPA prior to conception in which the rate of miscarriages decreased, the rate of live births increased, and the rate of birth defects returned to normal levels.⁹

With the teratogenicity of MPA established in pregnant women, the potential teratogenic risk when MPA is administered to men became a natural question. Appropriate recommendations for sexually active men who are using MPA may have been muddled in part due to recommendations from the European Medicines Agency (EMA). In 2015, the EMA recommended that sexually active men use condoms and for their female partners to use effective contraception methods while the man is taking MPA therapy and for 90 days after the end of treatment.¹⁹ The EMA subsequently updated their position in 2017 to recommend “that either [emphasis added] the male patient or [emphasis added] his female partner use reliable contraception during mycophenolate treatment and for at least 90 days after stopping treatment.”²⁰ The prescribing information and medication guides for MPA formulations also recommend that sexually active men who are taking MPA use effective contraception during treatment and for at least 90 days post-treatment.^10,13,21 However, several studies arrived at the conclusion that there is no observable increased risk in neonatal outcomes (e.g., congenital malformations) in children fathered by men who are taking MPA.^9,22-25

The Mycophenolate REMS program provides materials and mechanisms for educating multiple stakeholders: prescribers, other healthcare professionals, and patients. The Mycophenolate REMS specifies 5 steps for the prescribers (Table 1), 3 steps for other healthcare professionals (Table 2), and 4 components of information for patients (Table 3).²¹ For each stakeholder, education is the underpinning component. As part of the Mycophenolate REMS program, prescribers and other healthcare professionals are guided to provide pregnancy and contraceptive counseling to women who will be prescribed MPA.²¹

Education of Patients Using Patient Counseling Materials

The Mycophenolate REMS program includes a website (mycophenolaterems.com) and educational materials for prescribers, other healthcare professionals, and patients. Prepared patient education materials on the Mycophenolate REMS website include a patient information brochure, medication guides, and a frequently asked question sheet on the MPA Pregnancy Registry. The website also includes a link for reporting pregnancies. As part of reproductive counseling prior to initiating MPA therapy, prescribers should give female patients of reproductive potential the brochure titled, Patient Information Brochure: What You Need to Know About Mycophenolate. When the patient fills the prescription for MPA, pharmacists should include the specific medication guide for the prescribed MPA product.²¹ Documentation of participation in the Mycophenolate REMS by prescribers, other healthcare professionals, or patients is encouraged, but not required. Prescribers and other healthcare professionals prescribing MPA are encouraged to read the prescribing information and the Healthcare Provider Brochure and complete the Prescriber Training Confirmation Form in order to prescribe mycophenolate-containing medicines. By participating, stakeholders will help ensure the success of education efforts, particularly with respect to patients.

Key REMS Counseling Topics

The need for contraceptive and family planning counseling for solid organ transplant patients is growing as the numbers of patients of reproductive potential, particularly women, requiring a transplant increases.²⁶ In addition to potential risks of post-transplantation pregnancies, there are teratogenic and pregnancy risks associated with a number of commonly prescribed immunosuppressive drugs, including, but not limited to, MPA.^26-29 While healthcare professionals are likely aware of such risks, there may be gaps in providing family planning counseling (e.g., pregnancy and contraceptive counseling) to patients. There appears to be a dearth of data on the percentage of organ transplant patients who receive family planning counseling. However, Phillips and colleagues³⁰ conducted one such study on the frequency of counseling in a cohort of liver transplant patients (n=365; 164 women, 201 men) and found that counseling was documented in only approximately 7% of patients (14% of women, 0.5% of men). This study emphasizes the deficits in one particular healthcare facility. As the authors highlight, the need for counseling in patients taking MPA was evident from the 2016 Transplant Pregnancy Registry International Annual Report, in which 17% of the female liver transplant patients who had a miscarriage were being treated with MPA.³⁰ Other studies highlight gaps in providing family planning or contraceptive counseling. French and colleagues³¹ reported that 43% of solid organ transplant patients received contraceptive counseling prior to transplant. And, Ritchie and colleagues³² found similar results in their study on family planning and knowledge among liver transplant patients and transplant healthcare professionals. Although 82% of patient respondents indicated that they received reproductive counseling, only 37% received such counseling prior to transplant. On the other hand, 64% of the healthcare professionals indicated that they provided reproductive counseling.³² Such data emphasize the need for healthcare professionals and patients to participate in the Mycophenolate REMS program.

The effectiveness of eliminating MPA exposure during pregnancy is highlighted in data from the 2017 Annual Report of the Transplant Pregnancy Registry International. Pregnancy outcomes in female kidney transplant recipients were compared based on MPA exposure during pregnancy or discontinuation of MPA 6 weeks before conception. The percentage of live births was substantially and statistically greater in those who discontinued MPA 6 weeks prior to conception (78%) compared with those who had MPA exposure during pregnancy (48%; P < .001).³³ In addition, the percentage of miscarriages was statistically greater in the MPA exposure group (48%) compared with the population that discontinued MPA 6 weeks before conception (20%; P < .001).³³

Pregnancy Counseling

As part of the Mycophenolate REMS program, prescribers and other healthcare professionals are guided to provide pregnancy counseling to female patients of reproductive potential before they start MPA therapy. The Healthcare Provider Brochure of Mycophenolate REMS defines women of reproductive potential as “girls who have entered puberty and all women who have a uterus and ovaries and have not passed through menopause.”²¹ Pregnancy counseling should consist of education on the risks of MPA exposure to pregnant women and the developing fetus. Importantly, pregnancy counseling should also include pregnancy testing (sensitivity of at least 25 IU/mL), with results communicated to the patient, at the following time points: (1) immediately prior to beginning MPA treatment; (2) 8 to 10 days after starting MPA therapy; and (3) at routine follow-up visits.

Contraceptive Counseling

Given the potential risks associated with post-transplantation pregnancy and the risks associated with certain medications used in transplant patients, contraceptive counseling is crucial in those patients who are women of reproductive potential. The patient educational material on contraception options on the Mycophenolate REMS website suggests 3 option categories for women of reproductive potential who continue with MPA treatment. Methods in Option 1 (considered most effective; < 1 per 100 women in 1 year) are an intrauterine device (IUD), tubal sterilization, or vasectomy for a male partner. For methods in Option 2 (4-7 pregnancies per 100 women in 1 year), 2 forms of contraception are suggested: a hormonal contraception method (i.e., progesterone only [injection, transdermal patch, or implant], combination hormonal tablets, or vaginal ring) and a barrier method (i.e., female condom, male condom, diaphragm with spermicide, sponge contraceptive, or cervical cap with spermicide). The methods in Option 3 (considered least effective; ≥ 13 pregnancies per 100 women in 1 year), 2 forms of contraception are suggested: a condom (female or male) and either a diaphragm with spermicide, sponge contraceptive, or cervical cap with spermicide.²¹

Clinicians may find additional guidance on contraceptive options from the Centers for Disease Control and Prevention (CDC), which has recommendations on the use of various contraceptive methods for a variety of patient populations including solid organ transplant patients. CDC recommendation levels are categorized by medical eligibility criteria for a particular medical condition (i.e., 1 = no restrictions, 2 = advantages of contraceptive methods outweigh risks, 3 = risks of contraceptive method outweigh advantages, 4 = unacceptable health risk associated with contraceptive method).²⁷ For solid organ transplant patients, the CDC recommendations delineate between uncomplicated cases and complicated cases (i.e., acute or chronic graft failure, rejection, or cardiac allograft vasculopathy). Table 4 lists the CDC recommendations for solid organ transplant patients for various contraception methods.²⁷ For uncomplicated solid organ transplant patients, the CDC recommendation levels are either 1 or 2. On the other hand, for complicated solid organ transplant patients, the CDC recommendation level is 3 for initiation of contraception with IUDs (copper-containing or levonorgestrel-releasing) and for emergency contraception with a copper-containing IUD. The only level 4 recommendation is for combined hormonal contraceptives in complicated cases of solid organ transplant.²⁷

Patient Communication Strategies

Effective patient communication is critical to conveying the severity of risks associated with MPA use during pregnancy as well as educating on effective contraceptive methods. Comparing data between the time periods before and after implementing the Mycophenolate REMS program, Sarayani and colleagues³⁴ explored the effectiveness of the Mycophenolate REMS program on preventing fetal exposure. Their results suggest that the Mycophenolate REMS program is effective in preventing the initiation of MPA treatment in pregnant women but minimally effective in preventing pregnancies in patients. They calculated a prevalence ratio for pregnancy on the initial day of MPA therapy of 0.42 (95% CI: 0.24-0.74), whereas the prevalence ratio for pregnancy during MPA treatment was 0.97 (95% CI: 0.63-1.49).³⁴ Ritchie and colleagues³² report that even when patients do receive reproductive counseling, they may not use the most effective contraceptive methods. In the 1 year after liver transplant, 32% of patients used contraceptive methods with high failure rates (e.g., condoms only, rhythm method, withdrawal method).³² The researchers also found that discussion with a transplant healthcare professional was the preferred method of communication (89%) compared with an obstetrician/gynecologist (61%) or other less desirable modes with 33% fewer patients preferring online resources, handouts, or links to videos.³²

Ensuring REMS Compliance in Other Healthcare Practices

Given the nature of the use of MPA and the emphasis the Mycophenolate REMS places on the role of the prescribers, physicians will likely be responsible for reporting of REMS in a variety of settings. However, the need to comply with the Mycophenolate REMS is not limited to prescribers/physicians. In today’s multidisciplinary healthcare system, many types of healthcare professionals will interact with transplant patients who may be prescribed MPA. Because REMS is a drug safety program, pharmacists are actively involved in implementing REMS. In the Mycophenolate REMS, pharmacists are required to provide the corresponding medication guide for the dispensed formulation.²¹ Pharmacists can help ensure compliance by other means. Kostrzewa outlined a 6-step approach for REMS compliance at an academic-based healthcare network: (1) establish institutional workflows; (2) use a pharmacist-led survey/focus group; (3) optimize interventions; (4) perform an internal compliance audit; (5) conduct a gap analysis; and (6) ensure continued oversight.³⁵ At a Veterans Affairs healthcare system, a multidisciplinary team implemented an electronic teratogen alert system to help improve patient counseling when a teratogenic drug is prescribed. As Shroff and colleagues³⁶ emphasized, an important part of their process was the ability to request a pharmacy consult on teratogens within 72 hours. Such initiatives highlight important roles of other healthcare professionals, including pharmacists, in the implementation and compliance with REMS programs, including that for MPA.

Reporting to the Mycophenolate Pregnancy Registry

Importance of Reporting

The Mycophenolate Pregnancy Registry should be used if a person becomes pregnant while taking MPA or within 6 weeks of stopping treatment. Reporting pregnancies will provide additional data to advance the knowledge on the effects of MPA during pregnancy.²¹ Such data may be useful for improving recommendations on the use of MPA in women of reproductive potential.

Step-by-Step Instructions

Prescribers and other healthcare professionals can report pregnancies to the Mycophenolate Pregnancy Registry. As a reasonable practice, upon reporting a pregnancy to the registry, a healthcare professional should communicate with the MPA prescriber and obstetrician/gynecologist to ensure they are informed. There are 2 straightforward ways to report a pregnancy: (1) by phone via the Mycophenolate Pregnancy Registry 1-800-617-8191; and (2) online via the Mycophenolate Pregnancy Registry at mycophenolaterems.com, then selecting the “Report a Pregnancy” tab. Either mechanism can be used. Prior to reporting a pregnancy, a reporting professional should have ready access to certain data, which the Mycophenolate Pregnancy Registry collects, including (non-exhaustive list) demographics, MPA exposure (including dose and timing), maternal and fetal outcomes, root cause analysis to help identify the circumstances surrounding the exposure, frequency of educational counseling, and infant development up to 12 months.²¹ Data collected for the Mycophenolate Pregnancy Registry are collected at up to 8 time points: baseline; first trimester; second trimester; third trimester; time of expected delivery; and when the infant is age 2 months, 6 months, and 12 months.²¹

Additional Educational Resources for Patients and Other Healthcare Professionals

Patients

While prescribers and other healthcare professionals are expected to provide education directly to patients, the “Patient Overview” section of the Mycophenolate REMS website is a specific area designated for patients. The 3 specific pieces of patient education literature are the patient information brochure, a list of frequently asked questions for the Mycophenolate Pregnancy Registry, and the medication guide, which may be found in other sections of the Mycophenolate REMS website. Medication guides are available for any of the FDA-approved MPA formulations—brand name or generic.²¹ Although patients can download the materials directly from the website, prescribers and other healthcare professionals are expected to provide the printed materials to their patients. The “Additional Resources” section of the Mycophenolate REMS website also includes links to the CDC, the FDA, and Planned Parenthood.²¹

Other Healthcare Professionals

Besides prescribers, other healthcare professionals also participate in the Mycophenolate REMS. In addition to familiarizing themselves with the risks of MPA during pregnancy, other healthcare professionals may provide contraceptive counseling to patients as well as report pregnancies (Table 2).²¹ As noted earlier, pharmacists are also expected to provide medication guides to patients for the corresponding formulation that is dispensed.²¹ Although pharmacists in every practice area should be prepared to counsel patients on contraceptive options, there are 16 US states and the District of Columbia that also allow pharmacists to prescribe contraceptives with a collaborative practice agreement.³⁷

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