INTRODUCTION

The success of solid organ transplantation procedures requires a careful application of immunosuppression pharmacotherapy to avoid rejection of the transplanted organ by the recipient. Immunosuppression pharmacotherapy typically involves multiple agents with varying mechanisms of action.^1-3 One of the most commonly used immunosuppressants in certain solid organ transplant protocols is mycophenolate, which is used in >80% of immunosuppression regimens for adult kidney transplant patients.⁴ Mycophenolate, however, also increases the risks of undesirable fetal and maternal outcomes with drug exposure in pregnancy.^5,6 The United States (US) Food and Drug Administration (FDA), therefore, requires special precautions for the prescribing and dispensing of mycophenolate through a Risk Evaluation and Mitigation Strategy (REMS) program, which focuses on educating health care professionals and persons who may become pregnant on the potential fetal and maternal risks of mycophenolate.⁷

The Mycophenolate REMS program encompasses all approved mycophenolate products, brand name and generic (totaling 47 products as of November 3, 2022),⁸ and focuses on educating health care professionals and patients on the increased risks associated with mycophenolate when taken during pregnancy.⁹ Clinicians, particularly those involved in solid organ transplantation, should be acutely aware of mycophenolate’s potential for fetal and maternal toxicity as well as details on the REMS program for the drug. This activity, therefore, will focus on patient education and the roles of pharmacists in improving patient understanding of the fetal and maternal risks associated with mycophenolate.

MYCOPHENOLATE REMS PROGRAM INFORMATION

Overview of Mycophenolate and Pregnancy Risks

First approved in 1995 as the prodrug mycophenolate mofetil, there are 2 chemical forms of the drug currently available in the US—mycophenolate mofetil (as the free base or hydrochloride salt) and mycophenolic acid (as the sodium salt).¹⁰ Mycophenolate mofetil for oral administration is available in capsule, tablet, and suspension forms, and mycophenolate mofetil hydrochloride is available for intravenous (IV) administration as a preservative-free, lyophilized powder for reconstitution.^10,11 Mycophenolic acid (as mycophenolate sodium) is available in delayed-release, enteric-coated, tablet formulations.^10,12 Mycophenolate’s immunosuppressive action occurs via inhibition of inosine monophosphate dehydrogenase, thus decreasing the production of guanine nucleotide and ultimately leading to attenuation of T-cell/B-cell proliferation.^13,14

While mycophenolate is an effective immunosuppressant, evidence has shown that the drug can cause fetal and maternal harm when administered while pregnant.^15,16 Much of this evidence was obtained from postmarketing data as well as data collected by the Transplant Pregnancy Registry International (at the time named National Transplantation Pregnancy Registry).⁵ In 2007, using pregnancy categories in use at the time, the FDA designated mycophenolate with pregnancy safety Category D, ie, “There ispositive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.”¹⁷ Prior to changing the pregnancy and lactation labeling rules in 2014, the FDA required special precautions for the prescribing and dispensing of mycophenolate through a single, shared REMS program (approved in 2012) that encompasses all mycophenolate products, and this requirement exists to this day.⁷

REMS programs are medication safety programs required by the FDA when a drug may have desirable therapeutic benefits but also serious risks of adverse reactions, particularly in specific patient populations.^18,19 Notably, mycophenolate products also require black box warnings on the increased fetal and maternal risks, the increased risk of lymphomas and other cancers, and the increased risk of severe and opportunistic infections.^11,12 For mycophenolic acid delayed-release tablets, there is an additional black box warning emphasizing that “Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe” the drug.¹²

Mycophenolate products are indicated for the prophylaxis of organ rejection in adults and children with slight differences in indications between the prodrug and the main chemical moiety. Mycophenolate mofetil is indicated in combination immunosuppressant therapies for allogeneic kidney, heart, or liver organ rejection prophylaxis in adults and children (≥3 months of age).¹¹Mycophenolic acid is indicated for use in combination with cyclosporine and corticosteroids for prophylaxis of organ rejection in kidney transplant patients—adults and children who are ≥5 years of age (6 months after transplantation).¹² With potential application to other immune-related diseases, clinicians should also be aware that mycophenolate products may be prescribed off-label for conditions including rheumatic connective tissue diseases, systemic lupus erythematosus, polyarteritis nodosa, atopic dermatitis, lichen planopilaris, and myasthenia gravis, among others.^20-23 No matter the indication, prescribing (including off-label) and dispensing of mycophenolate requires adherence to the established REMS program.

Fetal Risks

Mycophenolate use during pregnancy is associated with increased risk of congenital malformations of the developing fetus. The risk of fetal malformations rises from 4% to 5% without mycophenolate to 15% to 27% with exposure to mycophenolate.^5,6,19,24-26 The number of recorded mycophenolate fetal exposures remains relatively small, which may lead to an incomplete picture of potential fetal risk. The first published report of such fetal defects associated with mycophenolate exposure appears to be from Pérgola et al.²⁷ In this case report, a kidney transplant patient was determined to be 6 to 7 weeks pregnant at the time of transplantation. The patient had been receiving combination pharmacotherapy for immunosuppression: mycophenolate mofetil (1000 mg twice daily), tacrolimus (7 mg twice daily), and prednisone (25 mg daily). Upon confirmation of the pregnancy (100 days posttransplant), the mycophenolate mofetil dose was decreased to 500 mg twice daily. The mother delivered a preterm infant (estimated at 34 3/7 weeks) who presented with physical abnormalities—hypoplastic fingernails and toenails and bilateral shortened fifth fingers. At 3 years old, the authors state that the child “developed well and has achieved all developmental milestones.”²⁷

Subsequently, with additional reports of fetal defects associated with mycophenolate exposure, certain patterns of malformations came to light.^5,28,29 Coscia et al broadly described a phenotype of mycophenolate-induced malformations that includes “microtia-external auditory canal atresia, facial clefts, cardiac, skeletal, eye, tracheoesophageal, and facial anomalies” that are typically observed in combination.⁵ Perez-Aytes and colleagues catalogued the pattern of mycophenolate embryopathy to a common triad of defects affecting the ears (75% of reported cases), lip/palate (44% of reported cases), and eyes (34% of reported cases).²⁹ Other types of fetal outcomes include premature birth, low birth weight, cardiac anomalies, pulmonary malformation, multicystic kidney, and digital malformations.^{5,6,19,24-26,30}

Maternal Risks

Miscarriage is the major established maternal risk associated with mycophenolate exposure in pregnancy. The first trimester is the most common timeframe for the increased risk of miscarriage. The rates of miscarriage with mycophenolate exposure vary widely from 28% to 64%.^5,6,19,31 In comparison, the miscarriage rate for all pregnancies in the general population is estimated to be between 8% to 26%,^5,32 and the estimated miscarriage rates in transplant recipients without mycophenolate exposure ranges from 13% to 22%.⁵

In the earliest report that catalogued miscarriage, Sifontis and colleagues⁶ described the outcomes of 26 pregnancies of 18 kidney transplant patients who received mycophenolate therapy. Of those 26 pregnancies, there were 11 miscarriages (42.3%), and 10 of the 15 live births were premature (66.7%).⁶ In their retrospective study of a claims database, Thai et al³¹ compared the outcomes of pregnancies with mycophenolate exposure in the first trimester to those with exposure to azathioprine, a common substitution for mycophenolate. Exposure to mycophenolate essentially doubled the risk of pregnancy loss (miscarriage or still birth) compared to azathioprine, with an adjusted relative risk of 1.9 (95% CI, 1.6-2.3).³¹

PATIENT EDUCATION USING COUNSELING MATERIALS

Key REMS Counseling Topics

Pregnancy Counseling

Pregnancy counseling is a key component of the Mycophenolate REMS program,⁹ and such counseling should be provided to all patients of pregnancy potential prior to initiation of mycophenolate therapy regardless of their intent to become pregnant. A key component of the pregnancy counseling is testing for pregnancy. In the Healthcare Provider Information Brochure, the Mycophenolate REMS program specifies that the health care provider test for pregnancy with a test having sensitivity of at least 25 mIU/mL prior to and throughout mycophenolate treatment. Pregnancy testing and communication of testing results to patients should occur: a) immediately before initiation of mycophenolate therapy; b) 8 to 10 days after beginning mycophenolate therapy; and c) at routine follow-up visits.⁹

Besides pregnancy testing, pregnancy counseling would also include patient education on the increased fetal and maternal risks associated with mycophenolate.⁹ One potential concern for patients who are taking mycophenolate for immunosuppression and who desire to become pregnant is the long-term effects of mycophenolate on pregnancy and fetal outcomes. Prescribing information for mycophenolate products emphasize the use of contraception for 6 weeks after discontinuing mycophenolate therapy.^11,12 Observing the 6-week washout period prior to conceiving appears to reduce the risks of birth defects.^19,33

Contraception Counseling

Contraception counseling is an essential component of the Mycophenolate REMS program,⁹ with the goal of reducing drug exposure in pregnancy. As indicated in the Mycophenolate REMS Healthcare Provider Brochure, contraception counseling must be provided throughout mycophenolate treatment, for 6 weeks after ending mycophenolate treatment, and when emergency contraception is necessary. A range of contraception options are outlined in the patient education material available on the Mycophenolate REMS program website (Table 1).⁹

Abbreviation: REMS, Risk Evaluation and Medication Strategy.

The options are categorized into 3 levels of effectiveness. Option 1 suggests using 1 of 3 birth control options with estimated effectiveness of <1 pregnancy per 100 women in 1 year: intrauterine device, tubal sterilization, or vasectomy. Option 2 suggests the use of a hormonal contraceptive in addition to a barrier method for an estimated effectiveness of 4 to 7 pregnancies per 100 women in 1 year. Hormonal contraceptive options include progesterone injections, patches, or implants; birth control pills; or vaginal ring. Barrier method options are female condom, male condom, female diaphragm with spermicide, female birth control sponge, or cervical cap with spermicide. Option 3 would have the least effectiveness with ≥13 pregnancies per 100 women in 1 year. These options would be the use of a condom (female or male) coupled with another barrier method (female diaphragm with spermicide, female birth control sponge, or cervical cap with spermicide).⁹

The Centers for Disease Control and Prevention (CDC) provided another resource for navigating contraception options in people with various medical conditions including solid organ transplantation. The CDC categorizes the use of various contraception methods in medical conditions on a risk versus benefit basis ranging from Category 1 (no restrictions for the contraceptive method for a particular condition) to Category 4 (the use of the contraceptive method as an unacceptable health risk for a particular condition) (Table 2).³⁴

Abbreviation: CDC, Centers for Disease Control and Prevention.

The CDC differentiates solid organ transplantation cases as complicated or uncomplicated based on the presence or absence of particular factors. Uncomplicated transplantations have no additional factors, while complicated transplantations have acute or chronic graft failure, rejection, or cardiac allograft vasculopathy. Table 3 outlines the CDC’s contraceptive recommendations for solid organ transplant patients.³⁴

Although the Mycophenolate REMS program focuses on education of female patients, concerns have also been raised about the potential impact of male exposure to mycophenolate on pregnancies to their sexual partners. A number of published reports and reviews suggest that mycophenolate exposure to the sexually active males does not appear to increase the risk of fetal or maternal risks in their female sexual partners.^19,35-40 Regardless, clinicians should be aware of the prescribing information documents of mycophenolate products, which recommend that males receiving mycophenolate and/or their female sex partners use effective contraception during treatment and ≥90 days posttherapy.^11,12

Options If Pregnancy Occurs

Even with proper use of contraception, pregnancies may still occur during or within 6 weeks of stopping mycophenolate treatment. Upon learning of a pregnancy, the Mycophenolate REMS guidelines advises the patient to contact their physician right away and to continue with mycophenolate therapy until they discuss options with their physician.⁹ Pregnancy information should also be provided by the physician to the Mycophenolate Pregnancy Registry (see section below).⁹ If the Mycophenolate REMS guidelines were followed, a physician-patient discussion on the fetal and maternal risks would have been completed at the beginning of mycophenolate therapy. An additional conversation with the patient on those risks would be warranted to ensure the information is reinforced.

Given the fetal and maternal risks, discontinuation of mycophenolate therapy may be recommended if the patient decides to continue with the pregnancy.⁹ Clinicians should discuss the risks and benefits for continuing and discontinuing mycophenolate therapy. Continuation of mycophenolate therapy may not be uncommon. In their evaluation of claims data, Thai et al estimated that 60% of transplant patients with a pregnancy that progressed past the first trimester continued with mycophenolate therapy for at least part of the remaining pregnancy.³¹

Alternative immunosuppressant agents may also be considered. Immunosuppression agents commonly used after solid organ transplant include antiproliferative agents, calcineurin inhibitors, mechanistic target of rapamycin (mTOR) inhibitors, and corticosteroids. Azathioprine is the most common drug substitution for mycophenolate.^1,31,41 The risks and benefits of using azathioprine in pregnant patients should be carefully weighed since the drug exhibits teratogenic effects in mice and rabbits. Furthermore, the prescribing information states the azathioprine can cause fetal harm and that use in pregnant patients “should be avoided.”⁴² Prednisone and the calcineurin inhibitors, cyclosporine and tacrolimus, are commonly used in pregnant patients.^1,41 The mTOR inhibitor, sirolimus, while commonly used in immunosuppression regimens, is not recommended for use in pregnancy based on animal data demonstrating embryo-fetal toxicity.⁴³

With the emphasis on fetal and maternal toxicities during pregnancy, another concern would be on the potential adverse effects of breastfeeding while on mycophenolate pharmacotherapy. Mycophenolate can be found in breast milk from animal studies⁵ and a single case study measured substantial amounts of the drug in human breast milk.⁴⁴ Very limited published data of breastfeeding with mycophenolate therapy comes from several case reports, none of which have described adverse reactions in infants (although it should be noted that follow up on infant progress appears minimal).^45-48 The prevailing recommendations in the literature and prescribing information are to avoid breastfeeding while on mycophenolate therapy.^5,11,12,30

PATIENT COMMUNICATION STRATEGIES

Recent analyses of the effectiveness of the Mycophenolate REMS program suggests the ongoing need for effective patient education. Sarayani and colleagues^49,50 compared the differences in mycophenolate exposure in pregnancy during the use of the black box warning (in use for mycophenolate before the REMS program) versus the Mycophenolate REMS program. The main takeaway messages were that: 1) the REMS program was effective in decreasing the initiation of mycophenolate therapy in pregnant people, and 2) there was no difference preventing pregnancy after mycophenolate therapy was initiated. The researchers concluded that effective provider education produced the decrease in mycophenolate therapy initiation, while more effective patient education is needed to decrease pregnancy rates during mycophenolate therapy.^49,50

The Transplant Pregnancy Registry International compiles information on pregnancy outcomes in transplant recipients. Their 2020 Annual Report describes a total of 3321 pregnancies to kidney, liver, kidney-pancreas, heart, or lung transplant recipients from July 1967 to October 2020, where approximately 32% of the pregnancies were unplanned (range 30% to 54% per transplant type) and approximately 8.7% (range 7% to 20% per transplant type) of all reported pregnancies were receiving mycophenolate therapy at the time of conception.³⁰ This data suggests the continued need for education of patients and health care providers.

Methods to Improve Patient Understanding

In recent years, there has been an emphasis on patient-centered approaches to health care with shared decision-making. Such approaches appear to lead to increased patient satisfaction, improved patient health literacy, and improvements in adherence to therapy.⁵¹ Multiple factors affect patient’s health literacy and understanding of medical information. As outlined by Chisholm-Burns et al, these factors include—but are not limited to—primary language, individual culture, health beliefs, religion or spirituality, socioeconomics, health insurance status, as well as the combination of verbal ability, cognitive functioning, and vision/hearing ability.⁵² Clinicians should be aware of the myriad factors affecting health literacy and patient understanding so that education efforts can be properly and individually tailored.⁵³

With respect to mycophenolate and its associated REMS program, 3 main areas of patient understanding are crucial: 1) the fetal and maternal risks of mycophenolate in pregnancy; 2) contraceptive options; and 3) adherence to therapy. Improving patient understanding of those areas may be improved by applying health literacy universal precautions—ensure that information is easier to understand, confirm comprehension of information, and reduce difficulty of tasks⁵⁴—along with using the common educational methods of open-ended questions and Teach-Back techniques.⁵² As reviewed by Pazol and colleagues^55,56 for contraceptive education, multiple types of interventions should be considered and tried to provide the best chances to improve patient knowledge. Interventions can include interactive tools, written materials, audio-visual tools, and text messages.^55,56

Encouraging results from a study by Al-Husayni and colleagues⁵⁷ suggest there is a positive impact of the Mycophenolate REMS program on patient education in adolescents. The researchers surveyed a cohort of adolescents (n = 125, 12 to 20 years old) who were prescribed mycophenolate for immunosuppression, systemic lupus erythematosus (off-label), or other conditions (off-label). Comparing the post-REMS time period to the pre-REMS time period, the percentages of patients receiving several forms of reproductive health care increased significantly—teratogenicity counseling (68% post vs 32% pre, P < .001); contraceptive counseling (62% post vs 32% pre, P < .001); getting tested for pregnancy (51% post vs 24% pre, P < .01); and documented menarchal status (51% post vs 16% pre, P < .05).⁵⁷

ENSURING REMS COMPLIANCE IN OTHER HEALTH CARE PRACTICES

The implementation of the Mycophenolate REMS program appears to have improved the knowledge and compliance with fetal exposure mitigation measures among clinicians who prescribe mycophenolate for posttransplantation immunosuppression.^49,50 Sarayani et al point out that there be a gap in such knowledge with clinicians who prescribe mycophenolate for off-label indications.⁴⁹ While pharmacists and pharmacies do not register with the Mycophenolate REMS program, the Medication Guide should be provided to patients upon dispensing mycophenolate regardless of the indication.^9,58 However, a pharmacist would not have access to information on, nor have authority to, verify a prescriber’s compliance with REMS protocols.

Multidisciplinary efforts to improve health care provider compliance with REMS appear to meet with some success. An electronic teratogen alert system was implemented at a Veterans Affairs health care system through a multidisciplinary effort.⁵⁹ When a clinician prescribes a potential teratogen to a person of childbearing potential in the electronic medical records (EMR) system, multiple prompts guide the prescriber through the process to consider alternative therapies and includes the ability to request consultation with a pharmacist within 72 hours.⁵⁹ Another EMR-based approach appeared to improve provider adherence to contraceptive counseling and prescribing. As described by Sadun et al,⁶⁰ clinicians implemented a multipronged approach that included interprofessional education, performance feedback, EMR updates, and patient questionnaires. The efforts produced increases in contraceptive documentation (46% at baseline to 64%), patient counseling (30% at baseline to 45%), and provider interventions post-counseling (33% at baseline to 46%).⁶⁰

REPORTING TO THE MYCOPHENOLATE PREGNANCY REGISTRY

Since pregnancies can still occur even with effective counseling and contraceptive use, a Mycophenolate Pregnancy Registry was established to continue collecting data on pregnancy outcomes with mycophenolate exposure.⁹ While voluntary, clinicians and mycophenolate patients who become pregnant are strongly encouraged to report such pregnancies to the registry. The Mycophenolate REMS program website includes information for reporting pregnancies to the Mycophenolate Pregnancy Registry. Persons taking mycophenolate or who are within 6 weeks of stopping mycophenolate treatment who become pregnant (whether planned or unplanned) should inform their doctors about such pregnancy. The physician can then provide information to the Mycophenolate Pregnancy Registry via phone (1-800-617-8191), online (www.MycophenolateREMS.com), or by mail (Mycophenolate Pregnancy Registry, 200 Pinecrest Plaza, Morgantown, WV, 26505-8065).⁹ The steps for reporting pregnancies and the types of information collected by the registry are listed in the Sidebars.

ADDITIONAL EDUCATIONAL RESOURCES FOR PATIENTS AND HEALTH CARE PROVIDERS

The Patient Overview section of the Mycophenolate REMS website provides patient education literature.⁹ The website also has a section on Additional Resources. As of November 3, 2022, those resources covered information on: 1) birth defects with a link to the CDC (www.cdc.gov); 2) information on birth control with links to Planned Parenthood (www.plannedparenthood.org) and a FDA webpage on birth control (www.fda.gov/consumers/free-publications-women/birth-control); and 3) emergency birth control where patients are simply advised to contact their health care provider.⁹

Other organizations and their websites can be helpful for patients and health care providers. MotherToBaby (https://mothertobaby.org), a service of the Organization of Teratology Information Specialists, provides “evidence-based information on medications and other exposures during pregnancy and while breastfeeding” applicable to patients, health care professionals, and media.⁶¹ In addition, MotherToBaby provides the same information in Spanish (https://mothertobaby.org/es/sitio-web-en-espanol/), which can help address health disparities. Drugs.com, which provides peer-reviewed data on drugs, over-the-counter (OTC) medicines, and natural products, can be another resource for professionals and patients. The website also has an archived webpage on mycophenolate in Spanish.⁶²

SUMMARY

Although mycophenolate is an important and effective immunosuppressant commonly used in posttransplantation pharmacotherapy, the drug demonstrates fetal and maternal toxicities when taken during pregnancy. Given these toxicities, the FDA has mandated a Mycophenolate REMS program to mitigate fetal and maternal exposures. Prescribers, other health care professionals, and patients all have important roles in adhering to the REMS program. Patient counseling focuses on education about the risks of mycophenolate exposure during pregnancy, the contraceptive options available to avoid such exposure, and the pharmacotherapy alternatives to mycophenolate. If a pregnancy does occur during mycophenolate treatment, health care professionals should inform the Mycophenolate Pregnancy Registry to provide additional patient support and to improve clinical knowledge about the effects of mycophenolate in pregnancy. Multidisciplinary strategies that involve physicians, pharmacists, and other health care professionals are important to help ensure adherence to the REMS requirements and help reduce the incidence of mycophenolate exposure during pregnancy.

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