Dianne L. Kennedy

Antibiotic Use in Pregnancy and Lactation What Is and Is Not Known About Teratogenic and Toxic Risks

OBJECTIVE: Over ten million women are either pregnant or lactating in the United States at any time. The risks of medication use for these women are unique. In addition to normal physiologic changes that alter the pharmacokinetics of drugs, there is the concern of possible teratogenic and toxic effects on the developing fetus and newborn. This article reviews the risks and pharmacokinetic considerations for 11 broad-spectrum antibiotics that can be used to treat routine and life-threatening infections during pregnancy and lactation. DATA SOURCES: Information from the U.S. Food and Drug Administration (FDA) product labels, the Teratogen Information Service, REPROTOX, Shepards Catalog of Teratogenic Agents, Clinical Pharmacology, and the peer-reviewed medical literature was reviewed concerning the use of 11 antibiotics in pregnant and lactating women. The PubMed search engine was used with the search terms “[antibiotic name] and pregnancy,” “[antibiotic name] and lactation,” and “[antibiotic name] and breastfeeding” from January 1940 to November 2005, as well as standard reference tracing. METHODS OF STUDY SELECTION: One hundred twenty-four references had sufficient information concerning numbers of subjects, methods, and findings to be included. TABULATION, INTEGRATION, AND RESULTS: The teratogenic potential in humans ranged from “none” (penicillin G and VK) to “unlikely” (amoxicillin, chloramphenicol, ciprofloxacin, doxycycline, levofloxacin, and rifampin) to “undetermined” (clindamycin, gentamicin, and vancomycin). Assessments were based on “good data” (penicillin G and VK), “fair data” (amoxicillin, chloramphenicol, ciprofloxacin, doxycycline, levofloxacin, and rifampin), “limited data” (clindamycin and gentamicin), and “very limited data” (vancomycin). Significant pharmacokinetic changes occurred during pregnancy for the penicillins, fluoroquinolones and gentamicin, indicating that dosage adjustments for these drugs may be necessary. With the exception of chloramphenicol, all of these antibiotics are considered compatible with breastfeeding. CONCLUSION: Health care professionals should consider the teratogenic and toxic risk profiles of antibiotics to assist in making prescribing decisions for pregnant and lactating women. These may become especially important if anti-infective countermeasures are required to protect the health, safety, and survival of individuals exposed to pathogenic bacteriologic agents that may occur from bioterrorist acts.

Prescription drug use in 1984 and changes over time.

More than 1.5 billion prescriptions were dispensed from retail pharmacies in 1984 at a consumer cost of

Patient-Reported Outcomes Supporting Anticancer Product Approvals

18.4 billion. The number of prescriptions dispensed in 1984 equaled the previous record set in 1973. Over 40% of 1984 prescriptions were for four therapeutic classes: cardiovascular drugs, anti-infectives, psychotherapeutic drugs, and diuretics. Prescriptions for cardiovascular drugs and diuretics increased substantially from 1975 to 1984, while prescriptions for psychotherapeutic drugs decreased. Outpatient use of systemic antiinfectives remained fairly stable over the 10-year period. Trends in the use of specific drug categories within these broad therapeutic classes were variable, as were patient age and sex distributions.

Evolution of clinical trials for irritable bowel syndrome: issues in end points and study design.

In 2006, the US Food and Drug Administration (FDA) published draft guidance to provide recommendations for development, validation, implementation, and interpretation of patient-reported outcome (PRO) measures that can support treatment benefit claims in product labeling. Here, we summarize and discuss FDA approvals of anticancer products in the context of the draft guidance. We identified anticancer product approvals having efficacy claim(s) based at least in part on a PRO. In addition, we collated limitations of PRO instruments commonly submitted for regulatory review over the period from October 1, 2004 to September 30, 2006. From 1995 onward, nine indications were approved for seven anticancer products based at least in part on a PRO. In eight of nine approvals, PRO data supplemented other evidence of clinical benefit. In seven approvals, the PRO measured a single symptom or functional domain that was directly attributable to the treatment benefit observed in the disease. The FDAs draft PRO guidance describes principles that have been used in anticancer product approvals for more than a decade. PRO end points typically support treatment benefit claims that refer to a patients symptoms or ability to function. Single-item PROs may be acceptable. PRO data should be both internally consistent and aligned with other evidence of clinical benefit. The FDA encourages sponsors to consult with the FDA early in the process of PRO development.

Risk management strategies in the Physicians' Desk Reference product labels for pregnancy category X drugs

Irritable bowel syndrome (IBS) involves a broad range of physiological and psychological alterations that may affect brain–gut dysregulation, gut function, visceral perception, and mucosal integrity and function. Despite advances in our understanding of basic neuroenteric mechanisms and the role of effectors and transmitters in the brain–gut axis, a reliable biologic marker of IBS has yet to be identified (1, 2, 3, 4, 5, 6, 7, 8). IBS diagnosis and status depend entirely on an assessment of IBS signs and symptoms. This has made development of optimal end points and study design for evaluation of efficacy of IBS drugs a challenge. This article addresses three main topics: the evolution of primary end points for IBS clinical trials; a potential path forward for IBS end points in new clinical trials; and recommendations for the future development of patient-reported outcome (PRO) instruments for use in IBS clinical trials.

Trends in Use of Oral Hypoglycemic Agents 1964–1986

AbstractBackground: Drugs that carry a concern for teratogenicity are often classified as pregnancy category X in the drug label and contraindicated for use during pregnancy. Many drug labels can be found in the Physicians’ Desk Reference (PDR), a widely used source of drug information by American clinicians and patients. Objective: To review product labelling in the electronic PDR for the pregnancy category X products for pregnancy prevention risk management components in labelling. Methods: The electronic version of the 2001 and 2002 PDR was searched for ‘pregnancy category X’ products using the full text search feature. All product labels identified were retrieved and reviewed for trade name, generic name, manufacturer and indication. Product labels were manually searched for any pregnancy prevention risk management strategies included in labelling. Those labels that had specific pregnancy prevention risk management strategies were further evaluated. Results: One hundred and seventeen pregnancy category X products were obtained from 2249 products searched in the 2001 PDR database and 124 pregnancy category X products were obtained from the 2150 products in the 2002 PDR database. All pregnancy category X products identified were drug products. The label/package insert for each drug was reviewed to identify risk management strategies for pregnancy prevention. The majority of the labels include as the sole risk management strategy either a black box warning and/or a contraindication for use in women who are or may become pregnant. Only 13 drugs contained specific pregnancy prevention risk management strategies in the label directing the clinician and/or patient, e.g. frequency of pregnancy testing, number and type of contraception methods. Two drugs, bexarotene capsules and gel, were only included in the 2001 PDR. Three drugs, isotretinoin, acitretin, and thalidomide, have formal pregnancy prevention risk management programmes. Conclusion: This study demonstrates the varied risk management approaches in labelling for pregnancy prevention for pregnancy category X drugs. There is a need for consistency in the classification of pregnancy category X products and the pregnancy prevention risk management strategies utilised in the labelling for them.

Maternal use of prescribed drugs associated with recognized fetal adverse drug reactions

Oral hypoglycemic (OH) agents have been available in the United States for the treatment of non-insulindependent diabetes mellitus (NIDDM) for almost 30 yr. During this time they have been subject to considerable controversy. In this article, we present pharmaceutical marketing research data that provide a review of several facets of OH use. The number of OH prescriptions dispensed peaked in 1973, decreased through 1980, and has been increasing since that year. In 1986, OH agents accounted for 21.5 million prescriptions: 1% of all prescriptions dispensed that year. Chlorpropamide is currently the most frequently ingested OH agent; it is used by 33% of the market. The two OH agents introduced in 1984, glyburide and glipizide, had acquired 41% of the OH market by the end of 1986. The rate of OH use per 1000 diabetes mellitus visits increases with patients age. Patients aged 60 yr and older received OH prescriptions at a rate of 478 per 1000 diabetes mellitus visits in 1986. Data estimating both the number of patients diagnosed with diabetes and the number of diabetic patients taking OH agents indicate that the percentage receiving OH treatment has increased over the past 5 yr, with ∼35% of all diabetic patients taking OH agents in 1986.

Patient-Reported Outcomes to Support Medical Product Labeling Claims: FDA Perspective

To quantitate the frequency of exposure in pregnancy to selected drugs listed by the American Medical Associations Department of Drugs as having known or suspected association with fetal adverse drug reactions, we examined the prescription records of 18,886 Michigan Medicaid recipients who delivered a liveborn infant between April 1, 1981, and March 31, 1983. Focusing only on specific trimesters considered risk periods for each drug-fetal occurrence of adverse drug reaction, the use of tetracyclines during the first trimester of pregnancy was the most prevalent (21.3 exposed women/1000) prescribed drug associated with known or suspected fetal adverse drug reactions. The second most prevalent was phenobarbital in the first trimester, with 10.8 women exposed/1000. Following a close third was the use of the sulfonamides in the second trimester, with 10.0 women exposed/1000. The prescribing of nitrofurantoin and the sulfonamides in the last trimester and tetracyclines throughout pregnancy appears excessive. There are few indications for the outpatient use of the tetracyclines during pregnancy. Practitioners caring for pregnant women need to carefully evaluate the need for these drugs and consider when risks may outweigh benefits.