How the FDA Manages Drug Safety with Black Box Warnings, Use Restrictions, and Drug Removal, with Attention to Gastrointestinal Medications

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How the FDA Manages Drug Safety With Black Box Warnings, Use Restrictions, and Drug Removal, With Attention to Gastrointestinal Medications

Eli D. Ehrenpreis, MD1, Arthur A. Ciociola, PhD2, Prasad M. Kulkarni, MD, FACG3 and the FDA-Related Matters Committee of the American College of Gastroenterology

Am J Gastroenterol 2012;107:501–504; doi:10.1038/ajg.2011.449

Introduction the FDA developed additional activities to ies to define and clarify adverse events. A Physicians play a key role in helping the enhance medical product safety (4). common strategy involves requiring man- Food and Drug Administration (FDA) The FDA evaluates all medical products ufacturers to change drug labeling, also monitor the safety of medical products. before and after approval. During product known as “prescribing information” or the Physicians follow the principle of Hip- development, the manufacturer performs “package insert.” A black box warning on pocrates, primum non nocere (“first, do in vitro, animal, and human studies. Pre- a drug—the most serious type of label- no harm”). Some adverse drug reac- market testing takes place in a sequential ing change—is designed to call attention tions (ADRs) are expected due to known fashion. Typically, testing begins with nor- to serious or life-threatening risk. While mechanisms of action. Others may be mal volunteers and then proceeds to stud- the FDA is considering labeling changes idiosyncratic or not previously identified ies to define the lowest effective dose, then for a drug, it may release an Early Com- and therefore may not be preventable. The to define patient populations with the opti- munication About an Ongoing Safety FDA’s post-approval safety surveillance mal risk–benefit profile. However, because Review. After the review is completed, the activities are an attempt to control these the total number of subjects evaluated is FDA may issue a Public Health Advisory unexpected ADRs. relatively small (<10,000), rare ADRs may providing updated drug safety informa- not be detected before approval. The num- tion. The FDA may also require the drug Background ber of patients with comorbid conditions manufacturer to send a “Dear Healthcare The FDA is responsible for assuring the for whom safety data are collected is usu- Professional” letter outlining safety issues safety, efficacy, and security of human ally insufficient to allow for a robust risk with advice for corrective action. A medi- and veterinary drugs, biological prod- evaluation. As a result, safety information cation guide, an instruction sheet provided ucts, medical devices, foods, cosmetics, collected in the postmarketing period is of to the patient by the pharmacist, may be and radiation-emitting products (1–5). In considerable importance (13). The FDA used. If these educational strategies are 1938, Congress passed the Federal Food, launched the MedWatch Safety Informa- inadequate, additional management tools Drug, and Cosmetic Act after elixir of tion and Adverse Event Reporting System are required. These Risk Evaluation and sulfanilamide (containing ethylene gly- (AERS) in 1993 to stimulate voluntary Minimization Strategies are designed to col) caused 107 deaths (5–8). The act reporting of ADRs by health-care profes- ensure that the benefits of the product out- required companies to prove a product’s sionals and patients. weigh patient risk (4). They may also limit safety (2,9,10). Phocomelia and other birth who prescribes or dispenses drugs and defects were observed following maternal How the FDA manages the safety of a require physician training, laboratory test- use of thalidomide, prompting passage of drug ing, or registration and tracking of patients the Kefauver–Harris Amendment in 1962. If the FDA identifies a previously unrec- receiving the drug. This required pharmaceutical manufac- ognized safety issue, a variety of tools are At times, further restriction or removal turers to report all ADRs directly to the available to keep effective drugs and devices of a product from the market will be man- FDA (11,12). In 2007, following a series on the market while reducing risk of harm. dated. However, if it is determined that a of highly publicized drug withdrawals, The FDA may request further clinical stud- drug is longer safe to remain on the mar-

1Gastroenterology and Endoscopy, Highland Park Hospital, NorthShore University Health System, Chicago, Illinois, USA; 2Pharmaceutical Regulatory Strategy, Process, and Policy, Bausch+Lomb, Madison, New Jersey, USA; 3University of South Florida Physician’s Group, Tampa, Florida, USA. Correspondence: Eli D. Ehrenpreis, MD, Highland Park Hospital, NorthShore University HealthSystem, 777 Park Avenue, West Highland Park, Illinois 60035, USA. E-mail: ehrenpreis@ gipharm.net

ket, the FDA will request that the product is tions for gastrointestinal conditions that Tegaserod withdrawn. The FDA has the legal author- have undergone safety alerts. Tegaserod is a 5-HT4 receptor partial ago- ity to immediately withdraw authorization nist manufactured by Novartis under the to market a drug in the United States. In Metoclopramide name Zelnorm. Activated 5-HT4 recep-

extreme situations, products may be seized Metoclopramide is a dopamine D2 receptors in the gastrointestinal tract stimulate to prohibit further sales. Withdrawal of a tor antagonist in the chemoreceptor intestinal peristalsis and secretion and drug is communicated to the public by the trigger zone as well as a mixed 5-HT3 inhibit visceral sensitivity. Tegaserod was manufacturer using normal media chan- receptor antagonist/5-HT4 receptor ago- approved for the management of abdomi- nels. The Recalls, Market Withdrawals, nist and cholinomimetic. Metoclopramide nal discomfort, bloating and constipa- and Safety Alerts website (http://www.fda. increases antral contractions and small- tion associated with IBS (July 2002), and gov/Safety/Recalls/default.htm) also gives bowel peristalsis and is a treatment for chronic idiopathic constipation (August information about withdrawn drug prod- nausea and vomiting. It has also been used 2004). In March 2007, the FDA suspended ucts. The FDA also provides MedWatch as a prokinetic agent. Although a variety marketing and sales of tegaserod because Safety Alerts and Drug Safety Podcasts and of ADRs are associated with metoclo- a safety analysis found increased myocar- publishes a Drug Safety Newsletter. Pre- pramide, the development of tardive dys- dial infarction, stroke (cerebrovascular scribing information is available on Dai- kinesia (TD) prompted an FDA black box accident), and unstable angina in patients lyMed of the National Library of Medicine warning in February 2009 (14). Chronic treated with tegaserod compared with pla- (http://dailymed.nlm.nih.gov/dailymed/ treatment with metoclopramide can cause cebo. Subsequent observational studies about.cfm). TD, characterized by involuntary move- did not concur (18). In July 2007, the FDA These regulatory actions are based on the ments of the extremities, lips, tongue, and permitted the restricted use of tegaserod evaluation of postmarketing ADRs. Data face and eyes. TD is associated with cen- under a treatment–investigational new are obtained from a number of sources, trally acting dopamine blockers, includ- drug (T-IND) protocol for IBS with con- including the mandatory safety reporting ing phenothiazines (e.g., thorazine and stipation and chronic idiopathic constipa- from the manufacturer, the AERS, pub- prochlorperazine). Development of TD is tion in women younger than 55. Novartis lished literature, and clinical and non- related to the duration of metoclopramide subsequently abandoned this T-IND. Zel- clinical studies. Unfortunately, fewer than use and its cumulative dose. TD has no norm may be available in emergency situa- 10% of all adverse safety events with medi- known treatment and is often irreversible. tions that are immediately life-threatening cal products are reported to the FDA (13). The elderly, especially women, are at high- or that qualify for hospitalization. Physi- The AERS system has also been publicly est risk. The black box warning states that cians with patients who may qualify for criticized for taking years to understand prolonged treatment with metoclopramide emergency treatment with Zelnorm may the risk profile of a drug and delaying (longer than 12 weeks) should be avoided contact the FDA’s Division of Drug Infor- removal of products from the market. In in all but rare cases in which the therapeu- mation at [email protected]. an effort to improve the postmarketing tic benefit outweighs the risks of develop- surveillance, the FDA has mandated that ing TD. Cisapride drug advertisements encourage patients Cisapride, a serotonin-4 (5-HT4) receptor to report ADRs. In addition, the FDA has Alosetron agonist (and partial 5-HT3 antagonist), now made the reporting form simpler and Alosetron is an antagonist of serotonergic promotes gastric motility by enhancing more accessible to patients and health-care 5-HT3 receptors of the enteric nervous release of acetylcholine at the myenteric providers. The FDA also initiated devel- system. Alosetron diminishes gastro- plexus. Cisapride (marketed as Propulsid) opment of the Sentinel System in 2008, a intestinal motility, decreases noxious was used between 1993 and 1999 for the nationwide electronic system for postmar- sensations, slows colonic motility, and symptomatic treatment of adult patients keting tracking of drugs, biologics, and enhances colonic water reabsorption. It with nocturnal heartburn due to gastro- medical devices. The Sentinel System will was approved as Lotronex in February esophageal reflux disease. It was prescribed enable the FDA to query a diverse group of 2000 for women with diarrhea-predom- off-label as a prokinetic agent for gastropa- health-care databases, including electronic inant irritable bowel syndrome (IBS). In resis and other motility disorders. QT pro- health record systems, insurance claims November 2000, alosetron was withdrawn longation and serious cardiac arrhythmias databases, and medical registries. Cur- from the market after reports of ischemic including ventricular tachycardia, ven- rently, the FDA is evaluating a Mini-Senti- colitis and severe constipation resulting in tricular fibrillation, and torsade de pointes nel program that took two years to develop hospitalization, surgery, and death (15,16). were reported with cisapride use. and includes 17 US databases encom- It was reintroduced in June 2002 under Depletion of serum electrolytes further passing records for nearly 100,000,000 the approval of a supplemental new drug increases cardiac risk (19). Combined patients. The results from the Mini-Sen- application (sNDA) with restricted mar- use of cisapride with a number of drugs, tinel will guide the FDA in designing the keting for women with severe diarrhea- including those causing QT prolongation final Sentinel System to improve the speed predominant IBS. The sNDA includes a (tricyclics, certain antipsychotic agents) of ADR reporting. Table 1 shows medica- risk management program (17). and CYP-4503A4 inhibitors (fluconazole,

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Table 1. Prescribed gastrointestinal drugs, including those that have undergone status ketoconazole, itraconazole), was contrain- changes by the US Food and Drug Administration dicated. This drug was withdrawn from the market in 2000. Name Black box warning Medication guide

Adalimumab Yes Yes Domperidone Alosetron Yes Yes Domperidone, a peripheral dopamine D2 Atropine No No receptor antagonist, has not been approved Atropine/diphenoxylate No No by the FDA. Unlike metoclopramide, only Azathioprine Yes No a small percentage of this drug crosses the Balsalazide No No blood–brain barrier. As with cisapride, QT interval prolongation and ventricular Calcium acetate No No tachyarrhythmias have been reported with Certolizumab Yes Yes the use of domperidone. Domperidone Cholestyramine No No causes prolongation of cardiac repolariza- Cimetidine No No tion by blocking the cardiac potassium cur- Cisapride Not applicable (discontinued) No rent (IKr). This is similar to the therapeutic Cyclosporine Yes Yes effects of type III antiarrhythmic agents. Dicyclomine No No Infliximab, adalimumab, certolizumab Dronabinol No No pegol, and natalizumab Famotidine No No The monoclonal antibodies infliximab, Glycopyrrolate No No adalimumab, certolizumab pegol, and Granisetron No No natalizumab vary in their composi- Hyoscyamine Not applicable Not applicable tion and target. Infliximab is a chimeric (mouse–human) anti–tumor necrosis fac- Hyoscyamine extended-release Not applicable Not applicable tor-a (anti-TNF-a) monoclonal antibody. Infliximab Yes Yes Adalimumab is a fully human anti-TNF-a Interferon Yes Yes monoclonal antibody, and certolizumab is Lactulose No No a PEGylated Fabʹ fragment of a humanized Lansoprazole No No anti-TNF-a monoclonal antibody. Natali- Loperamide No No zumab is a humanized monoclonal antibody against the cellular adhesion molecule Meclizine No No a -integrin. Mesalamine enema No No 4 Because of potent immunomodulating Methylprednisolone No No effects, including reduction of immune sur- Metoclopramide Yes Yes veillance, these biologics have the potential Misoprostol Yes Yes to predispose to infection and to enhance Nizatidine No No development of malignancy. Latent and Octreotide No No new tuberculosis infections (frequently disseminated or extrapulmonary), invasive Omeprazole delayed-release No No fungal infections, and other, sometimes Ondansetron No No fatal opportunistic infections have been Pantoprazole delayed-release No No reported. Lymphoma and other malignan- Polyethylene glycol 3350 No No cies have also been described. Hepatosplenic Prochlorperazine No No T-cell lymphoma in patients receiving bio- Promethazine Yes Yes logic agents with or without other immune modulators has been reported (20,21). A Ranitidine No No review of the AERS database in 2005 indi- Ribavirin Yes Yes cated that infliximab was the seventh most Sodium phosphate Yes Yes commonly reported drug associated with Sucralfate No No death and the third most common drug Sulfasalazine No No associated with a disability or serious out- Tegaserod No No come (13). Infliximab and similar biologic agents have a black box warning regarding a Ursodiol No No variety of infections and malignancies.

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