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

Understanding and Mitigating the Risk of Mycophenolic Acid in Pregnancy: What Pharmacists Need to Know (Part 1)

An Interactive Monograph

Overview

Immunosuppression is a critical component of post-transplantation medical care to prevent acute and chronic organ rejection. Many immunosuppression protocols include combinations of medicines. One common medication is the T-cell/B-cell proliferation inhibitor, mycophenolic acid (MPA). There are two chemical forms of MPA that are currently found in products approved by the Food & Drug Administration (FDA) – mycophenolate mofetil and mycophenolic acid (in the form of the sodium salt, mycophenolate sodium).¹ Clinical observations on the risks to pregnancies and to fetuses upon MPA exposure during pregnancy led the FDA to institute a Risk Evaluation and Mitigation Strategy (REMS) program for products containing the drug.² REMS programs were created by the FDA as part of the Food and Drug Administration Amendments Act of 2007 to address concerns about drug product safety.³ REMS are instituted when medications may have serious adverse effects but still have potential benefits in certain patient populations.⁴ The FDA may require one to three elements in a REMS program: medication guide or patient package insert, communication plan, and/or elements to assure safe use (ETASU), which is the most intensive REMS requirement.⁵ The FDA has required ETASU for the Mycophenolate REMS program. This activity (Part 1 of 2) will focus on understanding and mitigating the risks of MPA in pregnancy for the Mycophenolate REMS program.

MPA and Pregnancy

MPA Mechanism of Action and Approved Indications

Research on MPA has a more than 100-year-old history. As outlined by Broen and van Laar, initial reports on the free acid form of MPA were published in the early 20^th century.⁶ Subsequently, while MPA demonstrated antibiotic, antiviral, and anti-inflammatory activity, adverse drug reactions hindered further development until the mofetil ester prodrug form was developed.⁶ The condensed view of MPA’s mechanism of action is the suppression of T-cell and B-cell proliferation via the reversible, noncompetitive inhibition of inosine 5’-monophosphate dehydrogenase in the purine biosynthesis pathway.⁷ Of the two forms of inosine 5’-monophosphate dehydrogenase (type I and type II), MPA selectively and potently inhibits type II by a factor of approximately 5.^8,9 MPA’s mechanism of action in suppressing the proliferation of T-cells and B-cells is based on that selective inhibition as well as the differential expression of inosine 5’-monophosphate dehydrogenase type II in activated T-cells and B-cells.⁸ Allison and Eugui detail a more comprehensive view of MPA’s mechanisms of action that underlie the efficacy of MPA in preventing acute and chronic allograft transplant rejection and point toward additional promising medical applications. Anti-inflammatory activity of MPA may contribute to prevention of organ rejection via additional mechanisms of action, such as induction of T-cell apoptosis, inhibition of lymphocyte and monocyte recruitment, and inhibiting nitric oxide production.⁷

MPA is currently approved as combination therapy to prevent organ rejection in certain solid organ transplant patients. Mycophenolate mofetil is approved for use in allogeneic kidney, heart, and liver transplant cases in combination with other immunosuppressants.¹⁰ As specified in the prescribing information, safety and efficacy in pediatric populations (3 months of age and older) have been established only in allogeneic kidney transplant cases, not in heart or liver transplantation.¹⁰ Mycophenolic acid delayed-release tablet, on the other hand, is approved for only adults and children (5 years of age and older) kidney transplant recipients in combination with cyclosporine and corticosteroids.¹¹ Manufacturers’ dosing guidelines for mycophenolate mofetil formulations and mycophenolate acid delayed-release tablet are listed in Table 1.^10,11

Researchers continue to describe actions of MPA beyond selective inhibition of inosine 5’-monophosphate dehydrogenase type II.^7,12 The identification of multiple biochemical effects has spurred interest in the potential use of MPA for the treatment of other disease states including systemic lupus erythematosus, systemic sclerosis, antisynthetase syndrome, interstitial lung disease related to rheumatic disease, lupus nephritis, cancer, and others.^6,12–14 In rheumatology-related applications, MPA’s activity on decreasing proliferation of fibroblasts appears to be a key factor.⁶ The selective inhibition of inosine 5’-monophosphate dehydrogenase type II by MPA may contribute to the drug’s potential anticancer activity.¹² Clinical application of MPA in conditions beyond solid organ transplant is an off-label use of the drug, and, while off-label use of MPA (or any drug) may be within the purview of prescribing clinicians, the Mycophenolate REMS program should still be followed.

When using MPA, clinicians should be aware of the pharmacokinetics and pharmacodynamics (PK/PD) of the drug. When administered orally, the mycophenolate mofetil prodrug undergoes esterase-mediated hydrolysis (primarily in the intestine and liver) to MPA.^15,16 The oral bioavailability of MPA after mycophenolate mofetil administration can range from 81% to 94%, while MPA bioavailability after enteric-coated mycophenolate sodium formulations has been reported at 72%.¹⁵ MPA is highly protein bound to serum albumin and is subject to enterohepatic recirculation.^15,16 The PK of MPA (10-fold or greater difference in AUC) can vary substantially between patients as well as within the same patient.¹⁵ The PK parameters of MPA can change based on particular disease state treated, changing physiology post-transplantation, patient age, and drug interactions.^16–19 Of note, some commonly used drugs in immunosuppression post-transplantation (e.g., cyclosporine, tacrolimus) can affect MPA PK parameters.^15,18 Other potential drug interactions as indicated in the prescribing information include decreased MPA exposure with co-administration of aluminum or magnesium hydroxide antacids, proton pump inhibitors (mycophenolate mofetil interaction only), calcium-free phosphate binders, drugs that modulate glucuronidation, and drugs that interfere with enterohepatic recirculation.^10,11 In addition, MPA may affect other drugs including oral contraceptives and drugs eliminated by renal tubular secretion.^10,11 With the observed inter- and intra-patient variability in MPA PK and low correlation between dose and AUC, therapeutic drug monitoring of MPA may be warranted but is not common practice within the United States.^16,20,21

Increased Risks with MPA in Pregnancy

Maternal Risks

The primary maternal risk associated with MPA use in pregnancy is increased risk of miscarriage, particularly in the first trimester. The Transplant Pregnancy Registry International (TPRI), a division of the Gift of Life Institute, collects and analyzes data “on the effects of pregnancy on transplant recipients and the effects of immunosuppressive medications on fertility and pregnancy outcomes.”²² The annual report of TPRI describes valuable information on MPA exposure during pregnancy. As an indicator of the effect of MPA on miscarriage risk, the 2020 annual report of TPRI stated that the rate of miscarriage in pregnancies to kidney transplant recipients with MPA exposure was 48% compared to 20% in pregnancies where MPA was discontinued at least 6 weeks before conception (P < 0.001).²³ In a literature review of MPA use in pregnancies, Coscia et al reported estimated ranges of miscarriage rates of 28% to 64% with MPA exposure and 13% to 22% without MPA exposure.²⁴

Fetal Risks

Use of MPA during pregnancy subjects the fetus to increased risk of congenital malformations. The rate of malformation in transplant patients with MPA exposure has been estimated in the range of 15% to 26% compared to 4% to 5% without MPA exposure.^24–26 Congenital defects observed in offspring and stillbirths of women exposed to MPA include craniofacial malformations, digital malformations, cardiac anomalies, and skeletal malformations.^24–26 Other birth defects such as pulmonary malformation and multicystic kidney have also been observed.²³ Additional fetal risks due to MPA exposure include premature birth and low birth weight.²⁶

What To Do if a Patient Wishes To Become or Becomes Pregnant

Alternative Treatment Options

With the multiple steps involved in planning for a transplant operation, the physician and other members of the healthcare team have opportunities to discuss the risks and benefits of the procedure and subsequent pharmacotherapy options among themselves and with their patients. During such conversations, the team should learn about the family planning goals of the patient. Whether a woman of reproductive potential states a goal of becoming pregnant post-transplantation, plans for alternative treatment options in the event of a planned or unexpected pregnancy should be discussed prior to initiating MPA therapy. For those women who plan to become pregnant after solid organ transplantation or do become pregnant while on MPA therapy, alternative treatment options must be considered. Potential options for maintenance immunosuppression following organ transplant include calcineurin inhibitors (cyclosporine, tacrolimus), antiproliferative agents (azathioprine, MPA formulations), mTOR inhibitors (sirolimus, everolimus), belatacept, and corticosteroids.^27,28 The lack of data on the use of belatacept in pregnancy prevents recommendations on its use when a woman becomes pregnant.^28–30 Based on animal studies and the known mechanism of action, sirolimus and everolimus are not recommended for use in pregnant patients.^31,32 On the other hand, prednisone, azathioprine, cyclosporine, and tacrolimus are commonly used during pregnancy.^28,33 If a woman becomes pregnant while on MPA therapy, azathioprine is most frequently substituted for MPA since this medication has a similar antiproliferative mechanism of action.^27,28 As with any medication, the risks and benefits should be weighed before starting or changing a course of therapy.

REMS Program Information

The Mycophenolate REMS program was established in 2012 to cover all MPA-containing products.² The FDA also requires a black box warning on MPA products to highlight the increased risks of congenital defects and pregnancy risks if MPA exposure occurs during pregnancy.^10,11 The website, https://mycophenolaterems.com/, contains sections with overviews for prescribers, patients, and other healthcare professionals. Other information included here is REMS literature for each broad class of stakeholder, ways to report a pregnancy, additional resources, and frequently asked questions. In addition, the website provides links to prescribing information for MPA products and a link to forward Mycophenolate REMS information to a colleague.³⁴

Education – of prescribers, other healthcare professionals, and patients – is the critical foundation for successful implementation of the Mycophenolate REMS program. Prescriber participation in the Mycophenolate REMS consists of 5 steps per the Healthcare Provider Brochure available on the website: Step 1 – Document training in Mycophenolate REMS; Step 2 – Educate women of reproductive potential; Step 3 – Check pregnancy status; Step 4 – Reassess treatment options for patients who are considering becoming pregnant; and Step 5 – Report pregnancies to the MPA pregnancy registry.³⁴ For other healthcare professionals, there are 3 steps: Step 1 – Understand the increased risks of MPA in pregnancy; Step 2 – Counsel women of reproductive potential; and Step 3 – Report pregnancies to the MPA pregnancy registry. For patients, there are 5 key components for their education and participation: (1) Understand the increased risks of MPA in pregnancy; (2) Need for birth control; (3) Need for a pregnancy test; (4) What can a patient do if they are considering getting pregnant; and (5) What should a patient do if they become pregnant. Each of the steps and components of each step are clearly listed on the Mycophenolate REMS website.³⁴

Brief Summary of REMS Counseling Topics and Patient Counseling Materials

The 3 areas of patient education described by Mycophenolate REMS are (1) the risks associated with the use of MPA during pregnancy; (2) pregnancy planning; and (3) contraception counseling. As described above, the risks associated with MPA use in pregnancy include risks to the pregnancy (e.g., increased rates of miscarriage, premature birth) and risks to the fetus (e.g., birth defects, low birth weight). Both prescribers and other healthcare professionals can provide this patient education. Patients can also self-educate by accessing information on the Mycophenolate REMS website, as well as other sources. Multiple approaches toward providing the education may be helpful in order to reinforce the topics. Printed materials in the form of the Patient Information Brochure: What You Need To Know About Mycophenolate and the Mycophenolate Pregnancy Registry Frequently Asked Questions for Patients should be provided to patients as part of the education efforts when discussing MPA as a therapeutic option. When dispensing MPA at the retail pharmacy level, pharmacists are required to provide the corresponding medication guide of the particular product dispensed.³⁴

While the emphasis on Mycophenolate REMS rightfully focuses on women of reproductive potential and possible pregnancies, the prescribing information for MPA also recommend that sexually active men and/or their female partners use effective contraception methods while the male patient is undergoing MPA therapy and for at least 90 days post-treatment.^10,11 These recommendations are similar to those of the European Medicines Agency.³⁵ Despite these recommendations, it is notable that there is a body of literature that suggests no observable risk of negative neonatal and pregnancy outcomes when a man using MPA fathers a child.^36–40

An unfortunate gap in the Mycophenolate REMS program is the lack of education material in languages other than English. Drugs.com has an archived MPA information page in Spanish.⁴¹ Another MPA resource in Spanish comes from MotherToBaby.org, a service of the Organization of Teratology Information Specialists.⁴² US-based educational literature in other languages may be more limited. While some web browsers have the functionality to translate webpages from one language to another, one concern would be the accuracy of that translation. Ideally, the FDA and manufacturers of MPA would increase the availability of REMS information in languages besides English.

Reporting to the Mycophenolate Pregnancy Registry

Importance of Reporting

The risks to pregnant women and to developing fetuses with MPA exposure during pregnancy are established. Regardless, MPA exposures during pregnancies still occur.²³ While one goal for ongoing education efforts is to decrease the number of pregnancies with MPA exposure, continual collection of relevant data is important. For any pregnancies with MPA exposure that do occur, each additional data point contributes to the understanding of MPA risk and potentially on the mechanisms underlying those risks.^34,43 Regarding concerns about potential Health Insurance Portability and Accountability Act (HIPAA) violations, reporting pregnancies and related protected health information to the MPA Pregnancy Registry is covered by a HIPAA waiver.⁴³

Step-by-step Instructions

Reporting pregnancies to the Mycophenolate Pregnancy Registry can be done by phone or online by prescribers or other healthcare professionals. The Mycophenolate REMS webpage lists the information for both methods. By phone, one can call 1-800-617-8191. Otherwise, the link under the “Report a Pregnancy” section of the Mycophenolate REMS website can also be used. As indicated on the website, several items of information will be collected including 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.³⁴ Having that information on hand prior to reporting a pregnancy would be helpful. Reporters should also be prepared to add data at as many time points as possible at: baseline; 1st trimester; 2nd trimester; 3rd trimester; time of expected delivery; and at 2-month, 6-month, and 12-month age of the infant.³⁴

Additional Educational Resources for Patients and Healthcare Providers

The Mycophenolate REMS webpage can be considered a hub for MPA-related information. Several other resources are available for both patients and healthcare professionals. The Mycophenolate REMS webpage has a section titled, Additional Resources, which lists links for the Centers for Disease Control and Prevention (CDC) (for more information on birth defects) and for Planned Parenthood and the FDA page on birth control (for more information about birth control).³⁴ Besides those educational resources, other websites may also be helpful such as the aforementioned MotherToBaby.org for information on potential teratogens and Drugs.com for consumer and healthcare professional information on medications. Many websites for health/hospital systems may also contain information both for the general public and healthcare providers on a wide range of topics including contraception, family planning, and side effects of drugs.

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