Vietbao Phan, BS, PharmD Candidate 2025, Jefferson College of Pharmacy, Thomas Jefferson University

Domenic D’Alessandro, PharmD, MBA, BCPS, CDCES, LCDR, U.S. Public Health Service, Consumer Safety Officer, Office of Unapproved Drugs Labeling and Compliance 

“This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.”

I completed an APPE rotation at the FDA, specifically in the Office of Unapproved Drugs and Labeling Compliance (OUDLC), part of the Office of Compliance, within the Center for Drug Evaluation and Research (CDER). Under the supervision of a devoted preceptor, I immersed myself in the important tasks carried out by this office and learned about its role in protecting the public health.

Understanding the Mission and Scope of OUDLC

The mission of the OUDLC is centered on ensuring that prescription drugs and over-the-counter drug products marketed in the United States comply with established scientific and legal standards, and that fraudulent and potentially dangerous drugs are identified and addressed. OUDLC is also responsible for overseeing and maintaining FDA’s drug registration and listing database, which includes publishing the list of all drug establishment current registration sites and the National Drug Code (NDC) directory for all finished and unfinished drug products available in the United States. OUDLC’s mission is essential for maintaining public trust and to minimize consumer exposure to unsafe unapproved new drugs. OUDLC executes its mission by engaging in strategic, risk-based, compliance and enforcement activities.¹

What is a Fraudulent Drug?

My preceptor’s main responsibilities in OUDLC are to identify and address fraudulent drugs marketed in the U.S. for human use. First, it’s helpful to explain and define both the terms, “fraudulent” and “drug.” A product, whether it is a drug, device, food, or cosmetic for human or animal use, is considered to be “fraudulent” by the FDA when it has unproven effectiveness to improve health, well-being, or appearance, but it is promoted for these uses. The term “drug” is legally defined in the Federal Food, Drug, and Cosmetic Act, in part, as an article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals, or an article (other than food) intended to affect the structure or any function of the body of man or other animals.²

Therefore, considering FDA’s definition of “fraudulent” and the legal definition of a “drug,” fraudulent (“fraud”) drugs addressed by my preceptor are products marketed to consumers to diagnose, prevent, cure, treat, or mitigate disease (or other condition), or affect the structure/function of the body, but which have not been scientifically proven safe and effective for such purposes.

Because these products have not been scientifically proven to be safe and effective, fraud drugs present the risks of a direct or indirect health hazard to people who consume these products. If the fraud drug is used in a customary manner and the product is likely to cause injury, death, or other serious adverse event, the product presents a direct health hazard. An example of a direct health hazard would be a person who takes a fraud drug that claims to treat high blood pressure, but as a result, the patient experiences a gastrointestinal bleed. If the fraud drug does not present a direct harm through its use, but the consumer denies or delays proven effective treatment for a condition, the product presents an indirect health hazard. An example of an indirect health hazard would be a person with skin cancer who uses a topical fraud drug product and stops all skin cancer treatments recommended by their healthcare provider because the product they purchased claims to treat skin cancer. Simply put, consumers who purchase fraud drugs are misled by exaggerated or false claims.

Fraud drugs violate the Federal Food, Drug, and Cosmetic Act in several ways. First, fraud drugs are not approved by the FDA for any of their promoted uses. Second, they are not generally recognized among experts as safe and effective for their promoted uses, and therefore, according to the Federal Food, Drug, and Cosmetic Act, these products are “new drugs.” Since all new drugs require an FDA application to be legally marketed in the United States, marketing and selling fraud drugs violates the Federal Food, Drug, and Cosmetic Act.

Sometimes products marketed and sold as dietary supplements are actually fraud drugs. My preceptor explained a common example of this situation. He also explained the laws and regulations for dietary supplements.

What is a Dietary Supplement?

According to the Federal Food, Drug, and Cosmetic Act, dietary supplements include vitamins, minerals, herbs or other botanicals, and similar products that consumers take to supplement their diet. Also, according to the Federal Food, Drug, and Cosmetic Act, dietary supplements must be ingested or swallowed, so a topical or inhaled product is not a dietary supplement. Furthermore, according to the Federal Food, Drug, and Cosmetic Act, dietary supplements must not be represented for use as a conventional food, or as a sole item of a meal or the diet. Dietary supplements are not regulated as drugs, and the Dietary Supplement Health and Education Act of 1994 (DSHEA) defined dietary supplements as a category of foods. Therefore, the regulation of dietary supplements mainly falls under FDA’s Center for Food Safety and Applied Nutrition (CFSAN). Unlike drugs, FDA does not approve dietary supplements or their product labeling before they are sold to the public.

It is legal for dietary supplements to be promoted with structure/function claims, such as statements on the product labeling that “calcium builds strong bones,” or “fiber maintains bowel regularity.” However, it would be illegal for dietary supplements to make claims that the product is meant to diagnose, cure, mitigate, treat, or prevent a disease (i.e., drug claims). If a dietary supplement makes structure/function claims, the company must have information to support the claim is truthful, and the product labeling must include a disclaimer statement that the statement has not been evaluated by FDA, and the product is not intended to diagnose, treat, cure, or prevent any disease.

While CFSAN works to address dietary supplements that are illegally marketed using disease claims, OUDLC works to address products that are labeled as dietary supplements but are found to contain hidden drug ingredients, which also is a violation of the Federal Food, Drug, and Cosmetic Act. These products are often referred to as “tainted,” since they contain ingredients that are undeclared on the label and are “hidden” since consumers do not know they are found within the product.

When Purported Dietary Supplements Are Actually Drugs

It is illegal for dietary supplements to contain hidden (i.e., not listed on the label) drug ingredients. For example, if the drug ingredient dexamethasone is found in a dietary supplement marketed to treat joint pain, the company marketing and selling the product would be violating the Federal Food, Drug, and Cosmetic Act, since dexamethasone is FDA-approved as a drug. FDA can test dietary supplements on the market for drug ingredients, and frequently does so to protect the public health.

One way that OUDLC notifies the public regarding products marketed as dietary supplements or foods that contain hidden drug ingredients is through issuing Immediate Public Notifications (IPNs), which is somewhat similar to press statements. These products are typically promoted for sexual enhancement, weight loss, and body building, and are often represented as being “all natural.”

During my rotation, my preceptor assigned me three mock (i.e., “made-up”) products found to be tainted with drug ingredients such as sildenafil, nortadalafil, sibutramine, theophylline, acetaminophen, dexamethasone, and diclofenac. He provided me with mock lab reports that listed out the ingredients and their amounts found within the products, as well as website captures of online marketplaces where the products were being sold. I then followed other examples of published IPNs on FDA’s website https://www.fda.gov/consumers/health-fraud-scams/public-notifications-health-fraud to write the IPNs assigned to me, which were for sexual enhancement and energy, weight loss, and arthritis/pain relief products. These mock "dietary supplements" made drug claims on their labels and contained undisclosed active pharmaceutical ingredients.

When Fraud Drugs are not marketed as Dietary Supplements: A Case Study

Sometimes fraud drugs are not marketed or labeled as dietary supplements, but are unapproved new drugs based on the claims found in their labeling. For example, a product that claims to “treat cancer” but is not FDA-approved to treat cancer and is not generally recognized as safe and effective for treating cancer would be considered an unapproved new drug, and a fraud drug.

Not only does OUDLC assess claims and statements found on the product packaging, but OUDLC also assesses claims and statements found on the product’s websites and social media. In these types of situations, a company manufacturing and selling a fraud drug may be a small-owner operated business (“mom and pop”) or be a large-scale firm.

Often, OUDLC will issue warning letters to firms, regardless of their size, in this type of situation. A warning letter from FDA is an official correspondence notifying a firm that they have violated the Federal Food, Drug, and Cosmetic Act, and/or federal regulations. Warning letters provide an opportunity for the firm to address FDA’s concerns and requests a response within a certain timeframe. The response could consist of plans for correction that FDA would then verify to ensure the corrections are adequate, and that the firm is complying with federal law.

To review a warning letter case that involved a small business selling a fraud drug that was not marketed as a dietary supplement, my preceptor assigned me to read and present to him on the April 8, 2020, warning letter issued to Genesis 2 Church.³ The founders of the church were promoting and selling Mineral Miracle Solution (MMS), which contained chlorine dioxide, a chemical similar to bleach. Genesis 2 Church falsely claimed that their MMS product could cure COVID-19. OUDLC determined the Mineral Miracle Solution (MMS) was an unapproved new drug, based on the claims of the intended use of the product for treating COVID-19, the product’s lack of safety and effectiveness for this intended use, and the fact the product was not FDA-approved. By selling this unapproved new drug in various states (i.e., “interstate commerce”), Genesis 2 church violated the Federal Food, Drug, and Cosmetic Act.

After being issued the warning letter, the Grenons and Humble were given 48 hours to respond and take corrective actions, due to the national public health emergency of COVID-19. However, they did not take corrective action, and eventually the Department of Justice became involved, arresting Jonathan, Jordan, Mark, and Joseph Grennon.⁴ They were ultimately found guilty and were sentenced to various lengths of prison time, ranging from 60 to 151 months. I learned from this case that FDA regulatory actions, such as a warning letter, play a key role in protecting public health.

My rotation at the FDA’s CDER, OUDLC has been an incredibly eye-opening learning experience. It deepened my understanding of regulatory oversight of drugs and gave me practical knowledge about unapproved new drugs. It also reinforced the importance of drug safety and efficacy, and that I must devote my future career as a pharmacist to ensure both.

In sharing these reflections, I hope it brings to light the important work conducted by OUDLC and I encourage my fellow pharmacy students and healthcare professionals to learn more about drug regulation, as it is not a topic typically taught in pharmacy school. Public health and drug safety are a shared social system, and as pharmacists, it is our duty to educate ourselves on relevant regulatory activity to better serve our patients.

References

• Center for Drug Evaluation and Research: The Office of Unapproved Drugs and Labeling Compliance (OUDLC). [Internet]. U.S. Food and Drug Administration, FDA; [cited 2024 Jun 26]. Available from: https://www.fda.gov/about-fda/cder-offices-and-divisions/office-unapproved-drugs-and-labeling-compliance.
• Drugs@FDA Glossary of Terms [Internet]. U.S. Food and Drug Administration, FDA; [cited 2024 Jun 26]. Available from: https://www.fda.gov/drugs/drug-approvals-and-databases/drugsfda-glossary-terms.
• Center for Drug Evaluation and Research. Genesis 2 Church Warning Letter. [Internet]. U.S. Food and Drug Administration, FDA; [cited 2024 Jun 26]. Available from: https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/genesis-2-church-606459-04082020.
• U.S. Attorney’s Office. Leaders of “Genesis II Church of Health and Healing,” who sold toxic bleach as fake “Miracle” cure for COVID-19 and other serious diseases, sentenced to more than 12 years in federal prison. [Internet]. U.S. Department of Justice; [cited 2024 Jun 26]. Available from https://www.justice.gov/usao-sdfl/pr/leaders-genesis-ii-church-health-and-healing-who-sold-toxic-bleach-fake-miracle-cure.

Erin Torrance, PharmD Candidate, Mohamed Elkaeid, PharmD Candidate, Nicole M. Sifontis, PharmD, MPH, FCCP, BCPS, Clinical Professor, Department of Pharmacy Practice, Temple University School of Pharmacy

Introduction

Chronic kidney disease (CKD) leads to various complications that can impact the quality of life of patients. Among these complications are mineral and bone disorders (CKD-MBD), in which the balance of calcium, phosphate, and parathyroid hormone (PTH) is disrupted.^1,2 Patients with CKD, especially those undergoing dialysis, frequently experience hyperphosphatemia, which is a potentially life-altering condition that can lead to cardiovascular calcification, metabolic bone disease, and the development of secondary hyperparathyroidism (SHPT).^1,2 Persistent hyperphosphatemia can induce the development of hypertension, vascular calcification, cardiac valvular calcification, atherosclerosis, left ventricular hypertrophy, and myocardial fibrosis.² Therefore, managing and controlling hyperphosphatemia is crucial to improving cardiovascular outcomes and bone health in CKD patients.

Management of Hyperphosphatemia

Current strategies for managing hyperphosphatemia in dialysis patients consist of more frequent hemodialysis, dietary phosphate restriction, and phosphate binder therapy.¹ Despite implementing these strategies, achieving target serum phosphorus levels remains a persistent challenge with data suggesting that 42% of patients are unable to achieve target serum phosphorus levels in any given month.^2,3 Moreover, 77% of patients are unable to consistently achieve and maintain target serum phosphorus levels over 6 months.³ This data emphasizes the urgent need for new and innovative therapies to better control hyperphosphatemia.

Clinical Pharmacology Profile

Unlike phosphate binders already on the market which work by binding dietary phosphate in the gastrointestinal tract to form insoluble complexes excreted in the feces, tenapanor provides a novel, non-binder mechanism of action that blocks phosphate absorption through the paracellular pathway in the gastrointestinal tract.³ It is a locally acting inhibitor that targets the sodium/hydrogen exchanger 3 (NHE3), an antiporter expressed on the apical surface of the epithelium of the small intestine and colon.^3,4 Inhibition of NHE3 by tenapanor results in reduced sodium absorption and decreased phosphate absorption by reducing phosphate permeability through the paracellular pathway, which is the primary pathway for phosphate absorption.^3,4

Clinical Trial Summary Data

In October 2023, the FDA approved tenapanor (XPHOZAH®), the first drug of its kind designed to reduce serum phosphate in adults with CKD on dialysis.³ This approval is specifically for patients receiving maintenance dialysis who have an inadequate response to phosphate binders or who may be allergic to or unable to tolerate phosphate binders due to side effects.³ Three randomized clinical trials were conducted evaluating the efficacy and safety of tenapanor in patients with uncontrolled hyperphosphatemia and on maintenance dialysis.^5-7

Contraindications and Drug Interactions

Tenapanor is contraindicated in patients younger than 6 years old due to the risk of diarrhea and serious dehydration and in patients with known or suspected mechanical gastrointestinal obstruction due to the risk of worsening the obstruction and causing serious gastrointestinal complications.³ Tenapanor (an inhibitor of intestinal OATP2B1) has demonstrated drug-drug interactions with OATP2B1 substrates such as enalapril, atorvastatin, rosuvastatin and glyburide.³ Due to this effect, there is a possibility of reduced exposure of these substrates, leading to decreased efficacy and potential need for dose adjustments.³ Drug-drug interaction with sodium polystyrene sulfonate (SPS) was also noted, and guidelines suggested separating both medications by at least 3 hours.³ As shown in the AMPLIFY trial, tenapanor can be used in combination with other phosphate binders.⁵ Since loose stools and increased bowel movements are expected side effects of tenapanor given its ability to inhibit intestinal NHE3 activity, resulting in increased sodium and water content of stools, patients should be advised to discontinue the use of laxatives and stool softeners when starting treatment with tenapanor since.^3,5

Summary

Clinical trials in patients with end stage renal disease receiving maintenance hemodialysis support the use of tenapanor in the reduction of serum phosphate levels and is associated with a limited adverse effect profile. The most seen adverse effect with tenapanor use was diarrhea, some of which was transient and resolved after dose titrations. ⁵ Tenapanor also has the potential to reduce pill burden in CKD patients given its comparatively smaller pill size and twice daily dosing compared to the three times a day dosing with traditional phosphate binders. Future studies in CKD patients not on maintenance dialysis are warranted.

The authors do not have any financial conflicts to disclose related to the content of this article.

References

1. Ketteler M, Block GA, Evenepoel P, et al. Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what's changed and why it matters. Kidney Int. 2017;92(1):26-36. doi:10.1016/j.kint.2017.04.006
2. Zhou C, Shi Z, Ouyang N, Ruan X. Hyperphosphatemia and Cardiovascular Disease. Front Cell Dev Biol. 2021;9:644363. doi:10.3389/fcell.2021.644363
3. Xphozah. Package insert. Ardelyx, Inc; 2023.
4. Kovesdy CP, Adebiyi A, Rosenbaum D, Jacobs JW, Quarles LD. Novel treatments from inhibition of the intestinal sodium-hydrogen exchanger 3. Int J Nephrol Renovasc Dis. 2021;14:411-420.Table
5. Pergola PE, Rosenbaum DP, Yang Y, Chertow GM. A Randomized Trial of Tenapanor and Phosphate Binders as a Dual-Mechanism Treatment for Hyperphosphatemia in Patients on Maintenance Dialysis (AMPLIFY). J Am Soc Nephrol. 2021;32(6):1465-1473. doi:10.1681/ASN.2020101398
6. Block GA, Bleyer AJ, Silva AL, et al. Safety and Efficacy of Tenapanor for Long-term Serum Phosphate Control in Maintenance Dialysis: A 52-Week Randomized Phase 3 Trial (PHREEDOM). Kidney360. 2021;2(10):1600-1610. doi:10.34067/KID.0002002021
7. Block GA, Rosenbaum DP, Yan A, Chertow GM. Efficacy and Safety of Tenapanor in Patients with Hyperphosphatemia Receiving Maintenance Hemodialysis: A Randomized Phase 3 Trial. J Am Soc Nephrol. 2019;30(4):641-652. doi:10.1681/ASN.2018080832

Sarah John, PharmD Candidate ’24, Temple University School of Pharmacy

Yirgalem Gizachew, PharmD Candidate ’24, Temple University School of Pharmacy

Nicole M. Sifontis, PharmD, MPH, FCCP, BCPS – Clinical Professor, Department of Pharmacy Practice, Temple University School of Pharmacy

In the United States, kidney disease is the 10th leading cause of death.¹ In 2021, approximately 85% of patients with end stage kidney disease (ESKD) were initiated on lifesaving in-center hemodialysis.² However, it is not uncommon for ESKD patients to receive their first few sessions of hemodialysis in the hospital setting before they are transitioned to in-center intermittent hemodialysis. Renal replacement therapy via hemodialysis is an effective method of removing metabolic waste in these patients, but it is important to remember that the process utilizes a semipermeable membrane to conduct blood purification and removal of uremic toxins. Thrombocytopenia is often observed in patients undergoing hemodialysis due to a myriad of factors including platelet adhesion and complement activation induced by said dialysis membrane itself as well as heparin use. Although there have been advances in biocompatibility of hemodialysis membranes, reports of thrombocytopenia linked to membranes still exist.^3-5  Newer synthetic membranes, like polysulfone (PSf) based membranes, developed by blending polymers, have led to improved biocompatibility, however, these membranes can still reduce platelet count through platelet activation.^3-5 While the exact mechanism is unknown, blood contact with the hemodialysis membrane is generally believed to be the main trigger of the coagulation cascade generating thrombin and contributing to platelet consumption.^3,5-8

Most of the synthetic membranes widely used in hemodialysis are made with variants of PSf because they have demonstrated better biocompatibility, low cytotoxicity, successful removal of a broad range of uremic toxins, good sieving property and less requirement for anticoagulation.⁸  However, differences in polysulfone membranes depending on the microarchitecture and the mechanism of membrane desterilization such as gamma radiation sterilization or steam sterilization exist, and may also contribute to thrombocytopenia.^3,4 Table 1 illustrates a comparison of the most commonly used commercial dialyzers in the United States adapted from Said et al.⁵

* BPA = bisphenol A; PA = polyamide; PAES = polyarylethersulfone; PSf = polysulfone; PVP = polyvinylpyrrolidone.

Recently, at our institution, we encountered a patient who demonstrated transient thrombocytopenia within 4 days of dialysis initiation as an inpatient. The dialysis membrane in question was polysulfone based Revaclear ™. At the time, the patient had been exposed to prophylactic subcutaneous heparin for 25 days during the hospital stay. The platelet count, which had been stable initially, had a peak at 258 x 10³ platelets/uL, but precipitously dropped by 62% within 4 days of initiating dialysis, prompting a differential for heparin induced thrombocytopenia (HIT). Pertinent laboratory findings included a HIT score of 4, haptoglobin and d-dimer levels were normal, and fibrinogen was slightly elevated. There was no evidence of bleeding. Other medications administered to the patient prior to the event were aspirin, atorvastatin, bumetanide, calcitriol, carvedilol, gabapentin, insulin, levothyroxine, and sevelamer carbonate. The only notable confounder was the use of aspirin 81 mg chewable tablet once daily. Heparin was discontinued while the platelet serotonin release assay (SRA) was pending, and the patient was initiated on argatroban for presumed HIT. Six days later, the SRA assay returned negative, suggestive of low suspicion for HIT in this patient and presumption of dialysis membrane associated platelet activation/consumption given that the patient was newly initiated on hemodialysis. Argatroban was discontinued and a recovery of platelet count was noted. In addition to this case report, there are a few published cases demonstrating similar findings presumed to be dialyzer membrane associated thrombocytopenia in which thrombocytopenia resolved after switching to a different type of dialysis membrane in some instances.^3,9-13

While dialyzer associated thrombocytopenia is rare, such iatrogenic causes of thrombocytopenia should be considered when evaluating patients with an acute drop in platelet count on initiation of hemodialysis in light of unremarkable laboratory findings consistent with other etiologies, such as HIT. Although not widely recognized by clinicians due to incomplete understanding of its pathophysiology, appreciation for dialysis membrane associated thrombocytopenia can prevent patients from being exposed to direct thrombin inhibitors and other high-risk medications. Pharmacists should be aware of the clinical assessment necessary to evaluate thrombocytopenia in the hemodialysis population and be able to recognize factors associated with thrombocytopenia in this population other than heparin use.

References:

1. Xu JQ, Murphy SL, Kochanek KD, Arias E. Mortality in the United States, 2021. NCHS Data Brief, no 456. Hyattsville, MD: National Center for Health Statistics. 2022. Accessed April 9, 2024. https://www.cdc.gov/nchs/products/databriefs/db456.htm.
2. ‌United States Renal Data System. 2023 USRDS Annual Data Report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2023. Accessed April 9, 2024. https://usrds-adr.niddk.nih.gov/2023.

1. De Prada L, Lee J, Gillespie A, Benjamin J. Thrombocytopenia Associated with one type of polysulfone hemodialysis membrane: a report of 5 cases. Am J Kidney Dis. 2013;61(1):131-133.
2. Salvadè I, Del Giorno R, Gaetano D, Gabutti L. Assessing the contact-activation of coagulation during hemodialysis with three different polysulfone filters: A prospective randomized cross-over trial. Hemodial Int. 2017;21(3):375-384.
3. Said N, Lau WJ, Ho YC, Lim SK, Zainol Abidin MN, Ismail AF. A Review of Commercial Developments and Recent Laboratory Research of Dialyzers and Membranes for Hemodialysis Application. Membranes. 2021;11(10):767.
4. Hoenich NA, Woffindin C, Mathews JNS, Vienken J. Biocompatibility of membranes used in the treatment of renal failure. Biomaterials 1995; 16:587-592.
5. Vienken J, Diamantoglou M, Hahn C, Kamusewitz H, Paul D. Considerations on developmental aspects of biocompatible dialysis membranes. Artificial Organs 1995; 19(5):398-406.
6. Zaman SU, Rafiq S, Ali A et al. Recent advancement challenges with synthesis of biocompatible hemodialysis membranes. Chemosphere 2022; 37:135626

1. Olafiranye F, Kyaw W, Olafiranye O. Resolution of dialyzer membrane-associated thrombocytopenia with use of cellulose triacetate membrane: a case report. Case Rep Med. 2011;2011: 134295.
2. Gameiro J, Jorge S, Lopes JA. Haemodialysis-related-heparin-induced thrombocytopenia: case series and literature review. Nefrologia (Engl Ed). 2018;38(5):551-557
3. Claudio-Gonzalez I, Ravindranathan D, Kempton CL, Bailey JL, Wall SM. Thrombocytopenia induced by polysulfone dialysis membranes. Am J Case Rep. 2021;22: e932045.
4. Duayer IF, Araújo MJCLN, Nihei CH, et al. Dialysis-related thrombocytopenia: a case report. J Bras Nefrol. 2022;44(1):116-120.
5. Batalini F, Aleixo GF, Maoz A, Sarosiek S. Haemodialysis-associated thrombocytopenia: interactions among the immune system, membranes and sterilisation methods. BMJ Case Rep. 2019;12(9):e229594.

Sarah Uddin, PharmD Candidate 2025, Temple University School of Pharmacy

Francesca Graziano, PharmD Candidate 2024, Temple University School of Pharmacy

Emma Herb, PharmD Candidate 2024, Temple University School of Pharmacy

Susan Romann, PharmD, BCGP, Clinical Associate Professor at Temple University School of Pharmacy

Katherine H. Cho, PharmD, BCACP, Clinical Assistant Professor at Temple University School of Pharmacy

In early 2024, the FDA will launch the first over-the-counter (OTC) oral contraceptive pill (OCP) – a revolutionary shift in reproductive health in the U.S. Initially approved in 1973, Opill^® (norgestrel 0.075 mg tablets) sought an Rx-to-OTC switch in 2015 and received FDA approval for OTC use in July 2023. Broader access to effective contraception offers more protection against unintended pregnancies. Unintended pregnancy poses significant burden and may result in increased maternal depression, hemorrhage, and infant mortality.¹ Nearly half of annual pregnancies were unintended, but unintended pregnancy rates were disproportionately higher in females aged 15-19 (75%), living below the federal poverty level (60%), or from racial/ethnic minority groups.² Thus, national Healthy People 2030 goals include improving pregnancy planning and preventing unintended pregnancy, and interventions to increase contraceptive access are key.³

Inadequate contraception access may be due to lack of insurance, difficulties in scheduling and attending appointments with Health Care Providers (HCPs), and overall discomfort regarding contraception use. A 2022 survey found over one-third of missed OCP doses were due to insufficient medication supply, and most women expressed a preference for an OTC option.⁴ A 2021 user experience survey of U.S. OTC progestin-only pill (POP) users reported the OTC method as similar to or better than previously used contraception (77%) with acceptable adverse effects (80%).⁵ OTC users reported key benefits such as reduced pregnancy concerns, easier access, fewer side effects, and increased decision-making autonomy. Adult users preferred web/app information for OTC POPs, while teens favored consulting pharmacists or healthcare providers.⁶ Safety and tolerability have been replicated in other OTC OCP studies, and OTC OCP availability may increase rates of contraceptive use and continuation.⁷ Thus, pharmacists are uniquely positioned to support improved outpatient reproductive and sexual health outcomes.

Pharmacologic Profile

Opill^® is a once-daily OCP containing a progestin: norgestrel. Progestin-only-pills like Opill^® prevent pregnancy by thickening cervical mucus to inhibit sperm transmission, decreasing luteinizing hormone and follicle-stimulating hormone peaks, slowing ovum movement within the fallopian tubes, and overall altering the endometrium to inhibit the implantation of the fertilized egg.^8,9 POPs are still used in people where estrogen-containing products are contraindicated (e.g., lactation, increased thromboembolic risk), but combined oral contraceptives (COCs) (e.g., Alesse^®, Aviane^®) that include estrogen plus levonorgestrel, the active levo-enantiomer of norgestrel, are more common due to their higher efficacy (>99% vs 98%).¹⁰ However, norgestrel’s efficacy is clinically meaningful, and Rx-to-OTC switch studies have also demonstrated positive outcomes.³ Compared to COCs, Opill^® has a slightly longer time to peak serum levels (2 hours vs ~1.5 hours) and shorter half-life (21 hours vs 36 hours); therefore, it is essential that people take Opill® at the same time (± 3 hours) each day for optimal efficacy. Additionally, a backup method (e.g., condoms) should be used for the first two days after starting use.^8-11 Opill^® will be available as 28-tablet blister packs with counseling points listed on the package similar to other OCPs (Figures 1 & 2). Opill^® is a CYP3A4 substrate, so if taking a moderate or strong CYP3A4 inducer, an alternative or backup contraception method (e.g., condoms) should be used during coadministration for 28 days after the last dose.¹²

Common side effects are similar to other OCPs and include changes in menstrual bleeding patterns, breast tenderness, and mood changes.⁹ Patients taking Opill^® also have increased risk of headache, dizziness, nausea, increased appetite, vaginal discharge, and acne. POPs are safe to use in patients that are obese, and data does not indicate an association between BMI/weight and effectiveness of hormonal contraception.¹³ POPs can be safely used during lactation without the need to switch to another contraceptive method or pill.¹⁴ However, Opill^® is contraindicated in known or suspected pregnancy, current or past history of breast cancer or other progestin-sensitive cancers, undiagnosed abnormal uterine bleeding, hypersensitivity to any of the drug components, benign or malignant liver tumors, or acute liver disease.

Figure 1. Proposed Drug Facts Label for OTC Opill^®

Figure 2. Missed dose instructions for Opill®

Opill^® (norgestrel): Rx-to-OTC Switch Studies

Products to be considered for an FDA Rx-to-OTC switch are already approved for prescription use; thus, the switch to OTC status assesses user ability to independently read a drug facts label (DFL) determine appropriateness for use. This is done through three studies: 1) Label Comprehension Studies (LCS); 2) Self-Selection Studies (SSS); and 3) Actual Use Trials (AUT) (Figure 3).¹⁵

Figure 3. The OTC label development and approval process

In the Opill^® LCS, 90% of users reported understanding the OTC labeling.¹⁵ Specifically, participants correctly understood 9 of the 14 evaluated directions and statements, including those related to contraindications, adherence, and directions for use. The most misunderstood directions were related to missed dose instructions and guidance upon experiencing severe adverse events with 14.8% of participants answering incorrectly.¹⁵ These results demonstrate a diverse consumer sample can effectively comprehend the Opill^® DFL, though limitations include potential memory recall bias.

The Opill^® Adherence with Continuous-dose Oral Contraceptive: Evaluation of Self-Selection and Use (ACCESS) trial was the pivotal SS/AUT.¹⁶ It was a single-arm, non-randomized, open-label, multicenter, 24-week prospective study including female patients 11 years or older without vision deficits and able to read the label (n=1246).⁹ The SS population was mostly white (60%), aged 20-34 years old (53%), with normal health literacy (87%), and prior history of oral contraceptive use (65%). The study found 99%made a clinically correct selection to start Opill^® after reading the label, and performance was consistent across all subgroups.

SS participants continued to the second (AUT) phase to assess Opill’s^® pragmatic use upon OTC purchase.^15,16 Individuals were instructed to purchase and use Opill^®, record Opill^® and backup contraception usage, and attend follow-up interviews. Baseline participant characteristics were similar to the SS phase. Primary endpoints included percentage of days Opill^® was taken (85% target) and percentage of days Opill^® was taken consistently (i.e., ± 3 hours from time of day of last dose) (80% target). In total, 92.5% of participants were adherent to daily Opill^® (95% CI, 92.3-92.6%), and patients reported taking Opill^® consistently 95.7% of the time (95% CI: 95.6-95.9). This demonstrates the product labeling sufficiently guides customers for safe and effective use in an OTC setting mimicking real-world use. Although ACCESS included a racially and ethnically diverse population spanning a wide range of education and income levels, a low acceptable adherence threshold was used. This threshold was selected based on national statistics of consumer daily medication adherence. ACCESS found positive adherence results, and 68% of episodes of missed pills were single missed pill episodes: pills were taken the day before and the day after the missed day. Based on available data, Opill^® is effective within 3 hours of the normal dosing window; however, the implications of a missed or delayed dose beyond this window are unclear. This prompted the Delayed Pill Intake Study during the RX-to-OTC switch.¹⁷ This prospective, multicenter, randomized, crossover pharmacodynamic study assessed the impact of missed or 6-hour delayed Opill^® dose on cervical mucus characteristics and ovarian activity compared to the correct daily Opill^® use. Results showed no significant difference in contraceptive efficacy defined as percent of women with suppressed ovulation was suppressed and the frequency of fertile cervical mucus. These results suggest Opill^® is effective in contraception even after a delayed or missed pill; nevertheless, given the use of surrogate endpoints, the recommendations for a 3-hour dosing window for optimal contraceptive efficacy remain.

These trials support Opill^® use in female patients of childbearing potential, and the approved labeling demonstrates appropriate wording and instructions to support safe and effective use without HCP involvement.

Clinical & Financial Considerations

Pharmacists already play a vital role in public health and patient education. Some states and nations, such as Canada, already permit pharmacist contraceptive prescribing without a physician prescription. These community pharmacists are more involved in the continuum of reproductive care and ensure convenient and timely access to healthcare.¹⁴ FDA approval will highlight the pharmacy as a healthcare destination and encourage patient engagement and education regarding safe and effective Opill^® use. Trial data support the consumer’s ability to select and use Opill^® appropriately, and pharmacists can further help identify contraindications to use (e.g., prior history of stroke, VTE, migraines, certain cancers, uncontrolled hypertension)¹¹ and encourage patients to report taking this medication to all HCPs. Additionally, regardless of practice setting, pharmacists should be knowledgeable regarding Opill^® use and emphasize medication adherence, obtain accurate medication histories, and support safer sex practices to prevent sexually transmitted infections in patient interactions.

Pharmacy personnel can help direct patient concerns regarding Opill^® cost, which is yet unknown. The Affordable Care Act provides contraceptive coverage at no cost, but Opill^® insurance coverage may vary state-by-state due to its OTC status. States with OTC contraception coverage by private plans and Medicaid will likely need to request Opill^® at the pharmacy counter. For private payers, patients may have the option to purchase Opill^® and then submit a request for reimbursement. However, this approach could pose financial and administrative challenges for consumers and is infrequently utilized for other OTC products. Pharmacy staff can encourage patient use of insurance-finding resources (e.g., healthcare navigators), application of discount cards, and utilizing correct billing techniques.

Conclusion

Given the current challenges surrounding contraceptive access in the U.S. and the negative impacts of unintended pregnancy, there is an unmet need for more equitable and convenient access to effective contraceptives. Opill^® aims to address existing gaps in the current reproductive health landscape by providing females nationwide with a more convenient, accessible, safe, and effective form of contraception. Pharmacists can support these goals by obtaining accurate medication histories, providing patient education, and encouraging safer sex practices to improve health outcomes.

References

1. Guttmacher Institute. Unintended pregnancy and abortion: United States (2022). https://www.guttmacher.org/regions/northern-america/united-states (accessed 2023 Nov 20).
2. Finer LB, Zolna MR. Declines in unintended pregnancy in the United States, 2008-2011. N Engl J Med. 2016;374:843-852.
3. Family Planning – Healthy People 2030. https://health.gov/healthypeople/objectives-and-data/browse-objectives/family-planning (accessed 2023 Dec 20).
4. Kaiser Family Foundation. Interest in using over-the-counter contraceptive pills: findings from the 2022 KFF Women’s Health Survey. https://www.kff.org/womens-health-policy/issue-brief/interest-using-over-the-counter-oral-contraceptive-pills-findings-2022-kff-womens-health-survey/ (accessed 2023 Dec 20).
5. Grindlay K, Key K, Zuniga C, et al. Experiences using a progestin-only pill in an over-the-counter environment in the United States: a cross-sectional survey BMJ Sexual & Reproductive Health 2023;49:27-34.
6. Kennedy CE, Yeh PT, Gonsalves L, et al. Should oral contraceptive pills be available without a prescription? A systematic review of over-the-counter and pharmacy access availability. BMJ Global Health. 2019;4:e001402.
7. Soon JA. Enhancing access to contraception through pharmacist prescribing across Canada. Canadian Pharmacists Journal / Revue des Pharmaciens du Canada. 2021;154(6):356-362.
8. Opill^® (norgesterel) package label. Paris, France: HRA Pharma, 2017 Aug. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017031s035s036lbl.pdf
9. Norgestrel [monograph]. In: Lexicomp Online [online database]. Hudson, OH: Lexi-Comp (accessed 2023 Nov 17)
10. Glasier A, Sober S, Gasloli R, et al. A review of the effectiveness of a progestogen-only pill containing norgestrel 75 μg/day. Contraception. 2022;105:1-6.
11. Alesse® package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc, 2008.
12. Jusko WJ. Clarification of contraceptive drug pharmacokinetics in obesity. Contraception. 2019; 99:256-263.
13. Visness CM, Rivera R. Progestin-only pill use and pill switching during breastfeeding. Contraception. 1995;51(5):279-281.
14. Stanczyk FZ, Lobo RA. Treatment of the postmenopausal women. 3^rd ed. St. Louis: Academic Press; 2007:779-798.
15. Opill ^® (norgestrel 0.075mg tablets) for Rx-to-OTC switch. Sponsor briefing document shared at the joint meeting of the NDAC and the ORUDAC. 2023 May.
16. Clinicaltrials.gov. Adherence with continuous-dose oral contraceptive: Evaluation of self-selection and use (ACCESS); https://clinicaltrials.gov/study/NCT04112095?tab=table. (accessed 2023 Nov 20)
17. Glasier A, Edelman A, Creinin MD, et al. The effect of deliberate non-adherence to a norgestrel progestin-only pill: A randomized, crossover study. Contraception. 2023;117:1-6.

Sarah Uddin, PharmD Candidate 2025, Temple University School of Pharmacy

Francesca Graziano, PharmD Candidate 2024, Temple University School of Pharmacy

Emma Herb, PharmD Candidate 2024, Temple University School of Pharmacy

Susan Romann, PharmD, BCGP, Clinical Associate Professor at Temple University School of Pharmacy

Katherine H. Cho, PharmD, BCACP, Clinical Assistant Professor at Temple University School of Pharmacy

In early 2024, the FDA will launch the first over-the-counter (OTC) oral contraceptive pill (OCP) – a revolutionary shift in reproductive health in the U.S. Initially approved in 1973, Opill^® (norgestrel 0.075 mg tablets) sought an Rx-to-OTC switch in 2015 and received FDA approval for OTC use in July 2023. Broader access to effective contraception offers more protection against unintended pregnancies. Unintended pregnancy poses significant burden and may result in increased maternal depression, hemorrhage, and infant mortality.¹ Nearly half of annual pregnancies were unintended, but unintended pregnancy rates were disproportionately higher in females aged 15-19 (75%), living below the federal poverty level (60%), or from racial/ethnic minority groups.² Thus, national Healthy People 2030 goals include improving pregnancy planning and preventing unintended pregnancy, and interventions to increase contraceptive access are key.³

Inadequate contraception access may be due to lack of insurance, difficulties in scheduling and attending appointments with Health Care Providers (HCPs), and overall discomfort regarding contraception use. A 2022 survey found over one-third of missed OCP doses were due to insufficient medication supply, and most women expressed a preference for an OTC option.⁴ A 2021 user experience survey of U.S. OTC progestin-only pill (POP) users reported the OTC method as similar to or better than previously used contraception (77%) with acceptable adverse effects (80%).⁵ OTC users reported key benefits such as reduced pregnancy concerns, easier access, fewer side effects, and increased decision-making autonomy. Adult users preferred web/app information for OTC POPs, while teens favored consulting pharmacists or healthcare providers.⁶ Safety and tolerability have been replicated in other OTC OCP studies, and OTC OCP availability may increase rates of contraceptive use and continuation.⁷ Thus, pharmacists are uniquely positioned to support improved outpatient reproductive and sexual health outcomes.

Pharmacologic Profile

Opill^® is a once-daily OCP containing a progestin: norgestrel. Progestin-only-pills like Opill^® prevent pregnancy by thickening cervical mucus to inhibit sperm transmission, decreasing luteinizing hormone and follicle-stimulating hormone peaks, slowing ovum movement within the fallopian tubes, and overall altering the endometrium to inhibit the implantation of the fertilized egg.^8,9 POPs are still used in people where estrogen-containing products are contraindicated (e.g., lactation, increased thromboembolic risk), but combined oral contraceptives (COCs) (e.g., Alesse^®, Aviane^®) that include estrogen plus levonorgestrel, the active levo-enantiomer of norgestrel, are more common due to their higher efficacy (>99% vs 98%).¹⁰ However, norgestrel’s efficacy is clinically meaningful, and Rx-to-OTC switch studies have also demonstrated positive outcomes.³ Compared to COCs, Opill^® has a slightly longer time to peak serum levels (2 hours vs ~1.5 hours) and shorter half-life (21 hours vs 36 hours); therefore, it is essential that people take Opill® at the same time (± 3 hours) each day for optimal efficacy. Additionally, a backup method (e.g., condoms) should be used for the first two days after starting use.^8-11 Opill^® will be available as 28-tablet blister packs with counseling points listed on the package similar to other OCPs (Figures 1 & 2). Opill^® is a CYP3A4 substrate, so if taking a moderate or strong CYP3A4 inducer, an alternative or backup contraception method (e.g., condoms) should be used during coadministration for 28 days after the last dose.¹²

Common side effects are similar to other OCPs and include changes in menstrual bleeding patterns, breast tenderness, and mood changes.⁹ Patients taking Opill^® also have increased risk of headache, dizziness, nausea, increased appetite, vaginal discharge, and acne. POPs are safe to use in patients that are obese, and data does not indicate an association between BMI/weight and effectiveness of hormonal contraception.¹³ POPs can be safely used during lactation without the need to switch to another contraceptive method or pill.¹⁴ However, Opill^® is contraindicated in known or suspected pregnancy, current or past history of breast cancer or other progestin-sensitive cancers, undiagnosed abnormal uterine bleeding, hypersensitivity to any of the drug components, benign or malignant liver tumors, or acute liver disease.

Figure 1. Proposed Drug Facts Label for OTC Opill^®

Figure 2. Missed dose instructions for Opill®

Opill^® (norgestrel): Rx-to-OTC Switch Studies

Products to be considered for an FDA Rx-to-OTC switch are already approved for prescription use; thus, the switch to OTC status assesses user ability to independently read a drug facts label (DFL) determine appropriateness for use. This is done through three studies: 1) Label Comprehension Studies (LCS); 2) Self-Selection Studies (SSS); and 3) Actual Use Trials (AUT) (Figure 3).¹⁵

Figure 3. The OTC label development and approval process

In the Opill^® LCS, 90% of users reported understanding the OTC labeling.¹⁵ Specifically, participants correctly understood 9 of the 14 evaluated directions and statements, including those related to contraindications, adherence, and directions for use. The most misunderstood directions were related to missed dose instructions and guidance upon experiencing severe adverse events with 14.8% of participants answering incorrectly.¹⁵ These results demonstrate a diverse consumer sample can effectively comprehend the Opill^® DFL, though limitations include potential memory recall bias.

The Opill^® Adherence with Continuous-dose Oral Contraceptive: Evaluation of Self-Selection and Use (ACCESS) trial was the pivotal SS/AUT.¹⁶ It was a single-arm, non-randomized, open-label, multicenter, 24-week prospective study including female patients 11 years or older without vision deficits and able to read the label (n=1246).⁹ The SS population was mostly white (60%), aged 20-34 years old (53%), with normal health literacy (87%), and prior history of oral contraceptive use (65%). The study found 99%made a clinically correct selection to start Opill^® after reading the label, and performance was consistent across all subgroups.

SS participants continued to the second (AUT) phase to assess Opill’s^® pragmatic use upon OTC purchase.^15,16 Individuals were instructed to purchase and use Opill^®, record Opill^® and backup contraception usage, and attend follow-up interviews. Baseline participant characteristics were similar to the SS phase. Primary endpoints included percentage of days Opill^® was taken (85% target) and percentage of days Opill^® was taken consistently (i.e., ± 3 hours from time of day of last dose) (80% target). In total, 92.5% of participants were adherent to daily Opill^® (95% CI, 92.3-92.6%), and patients reported taking Opill^® consistently 95.7% of the time (95% CI: 95.6-95.9). This demonstrates the product labeling sufficiently guides customers for safe and effective use in an OTC setting mimicking real-world use. Although ACCESS included a racially and ethnically diverse population spanning a wide range of education and income levels, a low acceptable adherence threshold was used. This threshold was selected based on national statistics of consumer daily medication adherence. ACCESS found positive adherence results, and 68% of episodes of missed pills were single missed pill episodes: pills were taken the day before and the day after the missed day. Based on available data, Opill^® is effective within 3 hours of the normal dosing window; however, the implications of a missed or delayed dose beyond this window are unclear. This prompted the Delayed Pill Intake Study during the RX-to-OTC switch.¹⁷ This prospective, multicenter, randomized, crossover pharmacodynamic study assessed the impact of missed or 6-hour delayed Opill^® dose on cervical mucus characteristics and ovarian activity compared to the correct daily Opill^® use. Results showed no significant difference in contraceptive efficacy defined as percent of women with suppressed ovulation was suppressed and the frequency of fertile cervical mucus. These results suggest Opill^® is effective in contraception even after a delayed or missed pill; nevertheless, given the use of surrogate endpoints, the recommendations for a 3-hour dosing window for optimal contraceptive efficacy remain.

These trials support Opill^® use in female patients of childbearing potential, and the approved labeling demonstrates appropriate wording and instructions to support safe and effective use without HCP involvement.

Clinical & Financial Considerations

Pharmacists already play a vital role in public health and patient education. Some states and nations, such as Canada, already permit pharmacist contraceptive prescribing without a physician prescription. These community pharmacists are more involved in the continuum of reproductive care and ensure convenient and timely access to healthcare.¹⁴ FDA approval will highlight the pharmacy as a healthcare destination and encourage patient engagement and education regarding safe and effective Opill^® use. Trial data support the consumer’s ability to select and use Opill^® appropriately, and pharmacists can further help identify contraindications to use (e.g., prior history of stroke, VTE, migraines, certain cancers, uncontrolled hypertension)¹¹ and encourage patients to report taking this medication to all HCPs. Additionally, regardless of practice setting, pharmacists should be knowledgeable regarding Opill^® use and emphasize medication adherence, obtain accurate medication histories, and support safer sex practices to prevent sexually transmitted infections in patient interactions.

Pharmacy personnel can help direct patient concerns regarding Opill^® cost, which is yet unknown. The Affordable Care Act provides contraceptive coverage at no cost, but Opill^® insurance coverage may vary state-by-state due to its OTC status. States with OTC contraception coverage by private plans and Medicaid will likely need to request Opill^® at the pharmacy counter. For private payers, patients may have the option to purchase Opill^® and then submit a request for reimbursement. However, this approach could pose financial and administrative challenges for consumers and is infrequently utilized for other OTC products. Pharmacy staff can encourage patient use of insurance-finding resources (e.g., healthcare navigators), application of discount cards, and utilizing correct billing techniques.

Conclusion

Given the current challenges surrounding contraceptive access in the U.S. and the negative impacts of unintended pregnancy, there is an unmet need for more equitable and convenient access to effective contraceptives. Opill^® aims to address existing gaps in the current reproductive health landscape by providing females nationwide with a more convenient, accessible, safe, and effective form of contraception. Pharmacists can support these goals by obtaining accurate medication histories, providing patient education, and encouraging safer sex practices to improve health outcomes.

References

1. Guttmacher Institute. Unintended pregnancy and abortion: United States (2022). https://www.guttmacher.org/regions/northern-america/united-states (accessed 2023 Nov 20).
2. Finer LB, Zolna MR. Declines in unintended pregnancy in the United States, 2008-2011. N Engl J Med. 2016;374:843-852.
3. Family Planning – Healthy People 2030. https://health.gov/healthypeople/objectives-and-data/browse-objectives/family-planning (accessed 2023 Dec 20).
4. Kaiser Family Foundation. Interest in using over-the-counter contraceptive pills: findings from the 2022 KFF Women’s Health Survey. https://www.kff.org/womens-health-policy/issue-brief/interest-using-over-the-counter-oral-contraceptive-pills-findings-2022-kff-womens-health-survey/ (accessed 2023 Dec 20).
5. Grindlay K, Key K, Zuniga C, et al. Experiences using a progestin-only pill in an over-the-counter environment in the United States: a cross-sectional survey BMJ Sexual & Reproductive Health 2023;49:27-34.
6. Kennedy CE, Yeh PT, Gonsalves L, et al. Should oral contraceptive pills be available without a prescription? A systematic review of over-the-counter and pharmacy access availability. BMJ Global Health. 2019;4:e001402.
7. Soon JA. Enhancing access to contraception through pharmacist prescribing across Canada. Canadian Pharmacists Journal / Revue des Pharmaciens du Canada. 2021;154(6):356-362.
8. Opill^® (norgesterel) package label. Paris, France: HRA Pharma, 2017 Aug. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/017031s035s036lbl.pdf
9. Norgestrel [monograph]. In: Lexicomp Online [online database]. Hudson, OH: Lexi-Comp (accessed 2023 Nov 17)
10. Glasier A, Sober S, Gasloli R, et al. A review of the effectiveness of a progestogen-only pill containing norgestrel 75 μg/day. Contraception. 2022;105:1-6.
11. Alesse® package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc, 2008.
12. Jusko WJ. Clarification of contraceptive drug pharmacokinetics in obesity. Contraception. 2019; 99:256-263.
13. Visness CM, Rivera R. Progestin-only pill use and pill switching during breastfeeding. Contraception. 1995;51(5):279-281.
14. Stanczyk FZ, Lobo RA. Treatment of the postmenopausal women. 3^rd ed. St. Louis: Academic Press; 2007:779-798.
15. Opill ^® (norgestrel 0.075mg tablets) for Rx-to-OTC switch. Sponsor briefing document shared at the joint meeting of the NDAC and the ORUDAC. 2023 May.
16. Clinicaltrials.gov. Adherence with continuous-dose oral contraceptive: Evaluation of self-selection and use (ACCESS); https://clinicaltrials.gov/study/NCT04112095?tab=table. (accessed 2023 Nov 20)
17. Glasier A, Edelman A, Creinin MD, et al. The effect of deliberate non-adherence to a norgestrel progestin-only pill: A randomized, crossover study. Contraception. 2023;117:1-6.

Stroke, a debilitating cerebrovascular event, occurs when there is a disruption in blood supply to the brain, leading to a sudden loss of neurological function. It is a major global health concern, ranking among the leading causes of mortality and long-term disability.¹ The two main types of stroke, ischemic and hemorrhagic, differ in their underlying mechanisms, but share the urgency of rapid intervention. Ischemic strokes, which constitute most cases, result from a blocked blood vessel, often due to a blood clot. Time is of the essence in stroke management, as the longer the brain is deprived of oxygen and nutrients, the greater the extent of irreversible brain damage.² Thrombolytic therapy has emerged as a critical intervention, where the administration of thrombolytic agents, such as alteplase and tenecteplase, aims to rapidly dissolve clots and restore blood flow to the brain. The success of thrombolytic treatment depends on prompt administration within a narrow window of time to maximize the benefits while minimizing the risks associated with bleeding complications. Thrombolytic therapy has long been a cornerstone of treatment, with alteplase serving as the gold standard for decades. However, recent trends suggest a growing inclination among hospitals to transition from alteplase to tenecteplase for acute ischemic stroke management.

Tenecteplase is a first-line fibrinolytic used in acute myocardial infarction (MI) and is FDA approved for this indication.³ Since its approval for MI, more recently the EXTEND-IA trial was the first randomized trial of alteplase and tenecteplase where it showed superiority of tenecteplase over alteplase, specifically in the setting of large vessel occlusion.⁴ Subsequently, there have been meta-analyses of tenecteplase to alteplase showing non-inferiority compared to alteplase.³ The question then arises: if non-inferiority is established, why the preference for tenecteplase? There are a few reasons why tenecteplase may be preferred. Firstly, its easier administration facilitates more rapid treatment and transfer, crucial in stroke management as previously highlighted. Moreover, tenecteplase is delivered as a five-second intravenous (IV) bolus, eliminating the need for post-administration infusion. Cost-effectiveness is another factor to consider, where a 50 mg vial of tenecteplase is around $6,300 and 100 mg vial of alteplase is around $9,200.³

Comparing tenecteplase and alteplase, tenecteplase is produced from native alteplase using recombinant DNA. Tenecteplase is modified protein in three different locations, giving it favorable pharmacokinetics and pharmacological profile when compared to alteplase. Tenecteplase has a 15-fold higher specificity for fibrin which is important because it allows for targeted clot dissolution at the site of thrombosis, reducing the potential risk for bleeding complications.⁵ Tenecteplase also exhibits greater resistance to inactivation by plasminogen activator inhibitor-1 (PAI-1), which gives it longer half-life and allows it to be administered as a single IV bolus rather than a bolus followed by an infusion like alteplase. Overall, the pharmacokinetic profile is favorable in tenecteplase primarily because of its increased fibrin specificity.⁵

Based on the 2019 acute ischemic stroke guidelines, tenecteplase appears in two places. The first recommendation is it may be reasonable to choose tenecteplase at a dose of 0.25 mg/kg over traditional dosing of IV alteplase in patients who are eligible for thrombolysis and are also undergoing mechanical thrombectomy.⁶ This recommendation is based on the EXTEND-IA TNK trial. Notably, this is only in the setting of patients presenting with large vessel occlusion that are then going to have mechanical thrombectomy. The second place that tenecteplase is mentioned in the guidelines is it states tenecteplase administered as a 0.4mg/kg single bolus dose is not superior or non-inferior to alteplase but may be considered as an alternative in patients with minor neurologic impairment and no major intracranial occlusion.⁶

Over the years, several studies have been carried out to evaluate the effectiveness and safety of tenecteplase in comparison to alteplase. Among these studies, two pivotal trials, the EXTEND-IA TNK trial, and the TRACE 2 trial, have prominently highlighted the benefits of tenecteplase and subsequently influenced institutions to prefer its use of over alteplase for acute ischemic stroke.

EXTEND-IA TNK aimed to assess the effectiveness of tenecteplase versus alteplase for acute ischemic stroke patients with large-vessel occlusion. The trial was a multicenter, prospective, randomized, open-label, blinded-outcome non-inferiority trial that enrolled patients from March 2015 to October 2017 at 13 centers in Australia and New Zealand.⁴ Eligible patients had ischemic stroke within 4.5 hours of onset, large-vessel occlusion, and were suitable for IV thrombolysis and endovascular thrombectomy. Patients with severe pre-existing disability, which was defined as a modified Rankin scale (mRS) score greater than 3, were excluded. Patients were randomly assigned to receive either tenecteplase 0.25 mg/kg IV or  alteplase 0.9 mg/kg IV. The primary outcome of the study was substantial reperfusion, which was defined as the restoration of blood flow to more than 50% of the affected brain territory or the absence of retrievable blood clots in the target vessel during the initial angiographic assessment. Perfusion was evaluated using the modified Treatment in Cerebral Ischemia classification, which ranges from 0 (no flow) to 3 (normal flow). The secondary outcomes included the mRS score at 90 days, assessed centrally through telephone conversations with clinicians. Additionally, early neurologic improvement was considered as a secondary outcome, characterized by a reduction of at least 8 points or achieving a score of 0 or 1 on the National Institutes of Health Stroke Scale (NIHSS) at 72 hours. The safety outcomes consisted of death due to any cause and symptomatic intracranial hemorrhage. Symptomatic intracranial hemorrhage encompassed both subarachnoid hemorrhage with associated clinical symptoms and intracerebral hemorrhage that was determined by a panel as parenchymal hematoma type 2 within 36 hours post-treatment, and an increase of at least 4 points from baseline in the NIHSS score.⁴

Study participants were similarly distributed in both groups, with 57% in the tenecteplase group and 51% in the alteplase group being male. Participants had an average age of 70.4 years in the tenecteplase group and slightly higher at 71.9 years in the alteplase group. The distribution of stroke causes was comparable, with 21% in the tenecteplase group and 18% in the alteplase group experiencing large-artery occlusion. Cardioembolic occlusion was more frequent in the alteplase group (54%) compared to the tenecteplase group (46%). The median time from stroke onset to the initiation of IV thrombolysis was 125 minutes in the tenecteplase group and 134 minutes in the alteplase group. Although tenecteplase had a shorter delay, between group differences were not statistically significant. The primary outcome occurred in 22% of the tenecteplase group and 10% of the alteplase group. The incidence difference was 12 percentage points (95% CI: 2 to 21), meeting the noninferiority margin (not crossing -2.3 percentage points). The adjusted incidence ratio was 2.2 (95% CI: 1.1–4.4, p=0.03). Secondary outcome of mRS score at 90 days was statistically significant. The tenecteplase group had better function than the alteplase group, with a median score of 2 versus 3 (common odds ratio: 1.7, 95% CI: 1.0 to 2.8, P = 0.04). There were no significant differences in safety outcomes, except for less deaths in the tenecteplase group (10% vs. 18%) with an adjusted odds ratio of 0.4 (95% CI: 0.2–1.1, p=0.08). These results indicate that tenecteplase showed noninferiority with alteplase in achieving substantial reperfusion and improved functional outcomes in patients with ischemic stroke that undergo endovascular intervention.⁴

Despite clinical effectiveness shown in previous randomized controlled trials and endorsement by national practice guidelines, the strength of recommendation for tenecteplase's off-label use remained low. Previous trials had explored different dosages of tenecteplase, showing varied results in terms of safety and functional outcomes. The study aimed to fill this gap by conducting TRACE-2. TRACE-2 was a phase 3, multicenter, prospective, open-label, blinded-endpoint, randomized controlled, non-inferiority trial across 53 centers in China that aimed to understand the efficacy and safety of tenecteplase in patients without thrombectomy.⁷ The study enrolled 1430 participants who were randomly assigned to receive either tenecteplase (n=716) or alteplase (n=714). Of these, six participants in the tenecteplase group and seven in the alteplase group did not receive the study product. Additionally, five participants in the tenecteplase group and 11 in the alteplase group were lost to follow-up at 90 days. The study included adult patients who were eligible for IV thrombolytics within 4.5 hours of ischemic stroke, mRS score of 0-1, and had a disabling ischemic stroke with a NIHSS score between 5-25. Patients who received or intended to proceed to endovascular thrombectomy were excluded. Subjects were primarily older (mean age 66 years), male (69%), and Chinese (100%) with a median baseline NIHSS score of 7. The primary outcome was the proportion of subjects with an excellent functional outcome, defined as an mRS score of 0-1 at 90 days. Secondary outcomes included proportion of subjects with mRS score of 0-2 at 3 months, mRS score at 90 days, and improvement on NIHSS of ≥ 4 points or a score ≤ 1 at 24 hours. At the end of the study, an mRS score of 0-1 was achieved in 62% of the tenecteplase group and 58% of the alteplase group (RR 1.07, 95% CI 0.98 to 1.16). The study found no significant differences in other secondary outcomes between the two groups. Assessing safety, symptomatic intracranial hemorrhage occurred in 2% of the tenecteplase group (n=15) and 2% of the alteplase group (n=13), however these results were not statistically significant. Overall, similar rates of adverse events and serious adverse events were observed between the two groups.⁷

  In conclusion, the management of acute ischemic stroke remains a time-sensitive endeavor, and the choice of thrombolytic therapy plays a pivotal role in determining patient outcomes. While alteplase has been the gold standard for many years, recent trials have shed light on the advantages of tenecteplase, positioning it as a preferable alternative. The EXTEND-IA TNK trial and the TRACE-2 trial have significantly contributed to our understanding of the benefits associated with tenecteplase over alteplase. These trials have not only demonstrated the non-inferiority of tenecteplase but have highlighted its potential superiority in specific contexts. EXTEND-IA TNK emphasized tenecteplase's efficacy in large-vessel occlusion stroke patients undergoing mechanical thrombectomy, offering improved reperfusion rates and better functional outcomes. TRACE-2 expanded the investigation to a broader population without thrombectomy, affirming the comparable efficacy and safety of tenecteplase and alteplase. Tenecteplase's unique attributes, including its higher fibrin specificity, simplified administration as a single bolus, and cost-effectiveness, emphasize its suitability for acute ischemic stroke treatment. Moreover, its consistent performance across diverse subgroups enhances its generalizability and applicability in real-world clinical settings. These trials collectively advocate for the incorporation of tenecteplase into acute ischemic stroke protocols. Pharmacists, as integral members of the healthcare team, play a crucial role in the adoption of tenecteplase. Their expertise in medication management, dosage calculation, and understanding of pharmacokinetics are pivotal in ensuring safe and effective administration. By staying informed about the evolving landscape of thrombolytic therapy, pharmacists can provide evidence-based recommendations, optimizing patient care and outcomes.

References

1. Feigin VL, Nguyen G, Cercy K, et al. Global, regional, and country-specific lifetime risks of stroke, 1990 and 2016. N Engl J Med. 2018; 379(25):2429-37.
   
2. Go S. Stroke Syndromes. In: Tintinalli JE, Ma O, Yealy DM, Meckler GD, Stapczynski J, Cline DM, Thomas SH. eds. Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 9e New York, NY: McGraw Hill; 
   http://accessmedicine.mhmedical.com.proxy.libraries.rutgers.edu/content.aspx?bookid=2353§ionid=220293532. Accessed May 06, 2020.
3. Potla N, Ganti L. Tenecteplase vs. alteplase for acute ischemic stroke: a systematic review. Int J Emerg Med. 2022;15:1.
   doi.org/10.1186/s12245-021-00399-w
   
4. Campbell BCV, Mitchell PJ, Churilov L, et al. Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke. N Engl J Med. 2018;378(17):1573-82.
   
5. Nelson A, Kelly G, Byyny R, Dionne C, Preslaski C, Kaucher K. Tenecteplase utility in acute ischemic stroke patients: A clinical review of current evidence. Am J Emerg Med. 2019;37(2):344-8.
   
6. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2019;50(12):e344-418.
   
7. Wang Y, Li S, Pan Y, et al. Tenecteplase versus alteplase in acute ischaemic cerebrovascular events (TRACE-2): a phase 3, multicentre, open-label, randomised controlled, non-inferiority trial [published correction appears in Lancet. 2023 Apr 1;401(10382):1078]. Lancet. 2023;401(10377):645-54.

Are you a pharmacy student and PSHP member that is interested in publishing and building your CV? Then check out our student newsletter submission process and get published in the PSHP newsletter! See our link below for past articles and feel free to reach out to David Zimmerman, PharmD, BCCCP, BCEMP, FASHP (zimmerm6@duq.edu) for more information!

https://www.pshp.org/news/default.asp?id=11964

Students

What is a Poster Presentation?

Midyear’s student poster presentations provide the presenter with an opportunity to share their research with other students and attendees through visual aids and a brief verbal explanation of their content. Student presenters are able to answer questions about their research and receive timely feedback on their posters.

Residents and Fellows

What is a Poster Presentation?

Midyear’s residents and fellows showcase their project work through poster presentations. Poster presentations provide a wonderful opportunity for networking with other residents and fellows as well as other attendees interested in similar research topics.

Poster Submission Process

To increase the chances of your abstract being selected for presentation, read the Poster Submission Instructions in its entirety. The poster submissions site opens August 15; the poster abstract submission deadline is October 1.

Submit an Abstract:   Submitter Login Page - Call for Posters - 2023 Midyear Clinical Meeting & Exhibition (abstractscorecard.com)

Congratulations to all of the Student/Schools/Practitioners!

Residency Preparation Virtual Roundtable Series - Advice from New Practitioners

Hosted by the ASHP New Practitioners Forum: Membership & Outreach Advisory Group

Student pharmacists are invited to attend these virtual roundtables focused on residency preparation, career development, and successfully transitioning from student to new practitioner.

New practitioners will provide a presentation at the start of each roundtable to offer their insights and advice on the topic. Following the presentation, attendees can network with new practitioners informally and ask questions in smaller breakout sessions.

All roundtables will be held from 7:00 - 8:00 p.m. E.T.

The next Roundtable will be held: 

March 16, 2023 – Phase II Match Preparation: Click here for more information and to register.

May 16, 2023 - APPE Rotations & Residency Preparation (targeted towards P1-P3 students) - Click here for more information and to register.

Tom Kraus, Vice President of ASHP Office of Government Relations, discusses with current members of the Advancement of Professional Practice Advisory Group how and why students should get involved with state and federal advocacy efforts, as well as how local SSHP chapters can help their members to advocate for the profession.

Listen to the podcast here.