9781451190823

A Reference Guide to Fetal and Neonatal Risk

Drugs in Pregnancy and Lactation, Tenth Edition

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A Reference Guide to Fetal and Neonatal Risk

Drugs in Pregnancy and Lactation, Tenth Edition Gerald G. Briggs, BPharm, FCCP

Pharmacist Clinical Specialist (Obstetrics) (Retired) MemorialCare Center for Women Miller Children’s Hospital Long Beach Memorial Medical Center Long Beach, California Clinical Professor of Pharmacy University of California, San Francisco Adjunct Professor of Pharmacy Practice University of Southern California, Los Angeles Adjunct Professor, Department of Pharmacotherapy Washington State University, Spokane, Washington

Roger K. Freeman, MD

MemorialCare Center for Women Miller Children’s Hospital Long Beach Memorial Medical Center Long Beach, California Director Mednax Medical Group Clinical Professor of Obstetrics and Gynecology University of California, Irvine

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Acquisitions Editor: Jamie M. Elfrank Marketing Manager: Stephanie Manzo Product Development Editor: Ashley Fischer Production Project Manager: Marian Bellus Senior Manufacturing Coordinator: Beth Welsh Design Coordinator: Doug Smock Production Service: Integra Software Services Pvt. Ltd. © 2015 Wolters Kluwer Health © 2011 by LIPPINCOTT WILLIAMS & WILKINS, a Wolters Kluwer business, © 2008, 2005, and 2002 by LIPPINCOTT WILLIAMS & WILKINS Two Commerce Square 2001 Market Street Philadelphia, PA 19103 All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any form or by any means, including photocopying, or utilizing by any information storage and retrieval system without written permission from the owner, except for brief quotations embodied in critical articles and reviews. To request permission, please contact Lippincott Williams & Wilkins at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at permissions@lww.com or via our website at lww.com (products and services).

Printed in China Library of Congress Cataloging-in-Publication Data Briggs, Gerald G., author.

Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk / Gerald G. Briggs, Roger K. Freeman, Sumner J. Yaffe. — Tenth edition. p. ; cm.

Includes bibliographical references.

ISBN 978-1-4511-9082-3 — ISBN 1-60831-708-0 I. Freeman, Roger K., 1935- author. II. Yaffe, Sumner J., 1923-2011, author. III. Title.

[DNLM: 1. Infant, Newborn, Diseases—chemically induced—Handbooks. 2. Drug-Related Side Effects and Adverse Reactions—Handbooks. 3. Lactation—drug effects—Handbooks. 4. Maternal-Fetal Exchange—drug effects—Handbooks.

5. Milk, Human—drug effects—Handbooks. 6. Pregnancy—drug effects—Handbooks. WS 39] RG627.6.D79 618.3'2—dc23 2014012988 Care has been taken to confirm the accuracy of the information presented and to describe generally accepted practices. However, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publication. Application of the information in a particular situation remains the professional responsibility of the practitioner.

The authors, editors, and publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accordance with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new or infrequently employed drug.

Some drugs and medical devices presented in the publication have Food and Drug Administration (FDA) clearance for limited use in restricted research settings. It is the responsibility of the health care provider to ascertain the FDA status of each drug or device planned for use in their clinical practice.

To purchase additional copies of this book, call our customer service department at (800) 638-3030 or fax orders to (301) 223-2320.

International customers should call (301) 223-2300. Visit Lippincott Williams & Wilkins on the Internet: at LWW.com. Lippincott Williams & Wilkins customer service representatives are available from 8:30 am to 6 pm, EST. 10 9 8 7 6 5 4 3 2 1

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In Memory Sumner J. Yaffe, M.D. May 9, 1923–August 10, 2011 On August 10, 2011, Dr. Sumner J. Yaffe, often regarded as the father of pediatric clinical pharmacology, passed away.

He had a long and distinguished career as a renowned researcher and expert in pediatric pharmacology.

Dr. Yaffe was our friend, colleague, and co-author for 31 years. In 1980, he enthusiastically accepted our offer to ­co-author this book. At that time, he was the Director of the Center for Research for Mothers and Children at the National Institute of Child Health and Human Development. Over the years, he authored and/or contributed to nearly 300 scientific articles and books, including ours. His comments on our reviews were always on target. Our readers and ourselves have reaped the benefits of his vast experience. We were indeed fortunate to have received his wise advice and counsel over three decades.

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Foreword

A

This book is now in its 10th edition and continues to enjoy great success with physicians and other professionals involved in the care of pregnant and lactating patients. Many of the reviews are exhaustive but pertinent to the management of pregnant and lactating patients who have already ingested a drug or who are in need of drug therapy where a cost–­ benefit analysis may be necessary for appropriate counseling.

There are seldom absolute answers to questions a woman may have when she ingests a drug when pregnant or nursing because human experience is usually, of necessity, somewhat anecdotal. Even with all the information in this publication, there are risks that are yet unknown that may apply to a small number of people making the dictum of not using drugs in pregnancy without good cause still important. The effect of drugs in animals, the importance of timing and dose, and the effect of environmental factors are all involved in the risks and benefits of drugs in pregnant and/or lactating women and their fetuses/neonates. These factors are considered when

data are available, but we must admit that in no individual case is the understanding of risks and benefits absolute.

Because many pregnant and lactating women take substances, both legal and illegal, without the knowledge of their caregivers, the challenge to understand the risks/benefits of any drug and its interactions with these substances is daunting. Today, we are just beginning to understand the specific genetic influences on the action, toxicity, and teratogenicity of drugs in an individual. I expect in the future there will be many identified genetic factors that will influence therapeutic decisions.

The contributions of Dr. Sumner J. Yaffe, who died after the last edition, will be greatly missed. His vast experience and expertise regarding the use of drugs in pregnancy and lactation were significant contributions to all editions of this book.

It is our hope that the 10th edition will continue to provide the practitioner appropriate assistance with questions regarding drugs in pregnancy and lactation.

Roger K. Freeman, MD MemorialCare Center for Women Miller Children’s Hospital Long Beach Memorial Medical Center Long Beach, California Director Mednax Medical Group Clinical Professor of Obstetrics and Gynecology University of California, Irvine

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Preface

In 2011, our co-author, Dr. Sumner J. Yaffe, MD, passed away.

Our tribute to this great man is shown on the In Memory page.

We have been writing this book for 34 years. The first edition was released in 1983, 31 years ago. With each new edition, we have tried to make improvements that would benefit our readers. The same is true for this edition.

Not only is the 10th edition in a print version, it is now completely online for those who prefer that method to acquire information. We have attempted to reduce the size of the book by removing 161 reviews of drugs no longer marketed. If information is needed for these agents, it can be obtained by referring to the 9th edition.

There are 124 new drugs in this edition. Unfortunately, the majority have no reported human pregnancy experience.

Consequently, to estimate the embryo–fetal risk, we had to rely on information from other drugs that had the same mechanism of action (if they had human data) and/or on animal data. Finally, 201 drug reviews have been revised with new information, but no new relevant data were found for an additional 300 drugs. However, the search for new data on all drugs in this edition is an ongoing process. Although new or revised drug reviews published in future quarterly Updates will not be in the print version of this edition, they will be available online. We believe this will be a significant benefit for our readers.

The revision focus has been on drugs with no human pregnancy data and those where new information would change our pregnancy or breastfeeding recommendation.

Nevertheless, there are still a large number of drugs that have little or no published human pregnancy experience, thus ­making the counseling function difficult.

As in previous editions, some drug reviews have toll-free telephone numbers for the use of health care professionals

or patients to enroll in observational studies. These studies are an important method for gathering prospective data on pregnancy exposures for high-risk drugs. In fact, such studies are often the only human pregnancy experience available for new drugs and pharmacologic drug classes. The data generated by these studies and registries can be valuable for the raising of hypotheses of major teratogenicity or providing some assurance that the agent is not a significant teratogen.

Because their importance is so high, health care professionals and patients are encouraged to call for information about patient enrollment.

We take great pleasure for the opportunity to thank the many individuals who have helped us. To those who have sent us references, know that your efforts are sincerely appreciated. We also appreciate those who have commented on our work because it identifies areas that may need modification or topics that we need to cover. In addition, the questions we received served to keep us informed of your information needs and often lead to the preparation of new reviews. On the following page, we have listed the names of those who have been particularly helpful in the preparation of this edition.

It also is a pleasure to announce that we have two new co-authors who will assist us in the next edition. Dr. Craig Towers, M.D., is a Maternal-Fetal Specialist and a professor at the University of Tennessee Medical Center, Knoxville. We have had the pleasure of working with Dr. Towers in the past and look forward to renewing that relationship. Dr. Alicia Forinash, Pharm.D, FCCP, BCPS, BCACP, is an Associate Professor, Saint Louis College of Pharmacy, and a Clinical Pharmacy Specialist in the Maternal-Fetal Care Clinic at Saint Mary’s Health Center in Saint Louis. We believe both will have a significant and beneficial impact on future editions of this book.

Gerald G. Briggs, BPharm, FCCP Pharmacist Clinical Specialist (Obstetrics) (Retired) MemorialCare Center for Women Miller Children’s Hospital Long Beach Memorial Medical Center Long Beach, California Clinical Professor of Pharmacy University of California, San Francisco Adjunct Professor of Pharmacy Practice University of Southern California, Los Angeles Adjunct Professor, Department of Pharmacotherapy Washington State University, Spokane, Washington

vii

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Acknowledgment

It is a pleasure to acknowledge the assistance of Dr. Christine Chambers, PhD, MPH, for her help in the preparation of several drug reviews. In addition, we want to thank Elizabeth Mason-Renteria, Parks Medical Library, Long Beach Memorial Medical Center, who retrieved numerous references for us during the preparation of this edition. Without her assistance, this edition would have been much harder to prepare.

We also are pleased to acknowledge the assistance of our former students in the preparation of some of the reviews contained in this edition. The students came from five schools of pharmacy. During their clerkship training in obstetrics/ gynecology, each researched and wrote two drug reviews. It was their first experience in how to assess the reproductive toxicity of drugs, and they did very well.

University of California, San Diego Samantha Luk, PharmD Natalie Nguyen, PharmD Esther Park, PharmD Teri Phan, PhD, PharmD Linda Tang, PharmD Caroline Wesemuller, PharmD University of California, San Francisco Sam Chung, PharmD Martha Prieto, MPH, PharmD Julia Zhu, PharmD University of Southern California, Los Angeles Rebecca Myung, PharmD Sherehan Salib, PharmD Chandra Smallwood, PharmD Midwestern University, Glendale, Arizona Tu Tran, PharmD University of Washington, Seattle Maridith Yoshida, PharmD

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Contents

Dedication..............................................................................................................................................................v Foreword............................................................................................................................................................... vi Preface................................................................................................................................................................. vii Acknowledgment.................................................................................................................................................. ix Introduction......................................................................................................................................................... xiii Instructions for Use of the Reference Guide.........................................................................................................xvii Monographs................................................................................................................................................. 1-1522 Appendix......................................................................................................................................................... 1523 Index............................................................................................................................................................... 1533

xi

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Introduction, 9th Edition Sumner J. Yaffe, MD

It is now generally accepted that the developing fetus may be adversely affected by exposure to drugs and environmental chemicals. The stage of development of the intrauterine host is a major determinant of the resultant effect as well as the nature and the concentration of the drug or chemical agent.

On a more positive side, fetal therapy (i.e., treatment of fetal disease in utero by administering the drug to the mother or directly to the fetus) has been recognized recently as a rational approach to treat fetal disease.

Forty years ago, the thalidomide catastrophe (limb defects) occurred when this drug was administered to pregnant women as an antianxiety and hypnotic agent during the 1st trimester. Thalidomide had been evaluated for safety in several animal species, had been given a clean bill of health, and had come to be regarded as a good pharmacologic agent (hypnotic/sedative). It is of interest that this drug is being reevaluated today for use in leprosy and approval for this use has been given by the FDA. It is important to note that, even though thalidomide produces a distinct cluster of anatomic defects that are virtually pathognomonic for this agent, it required several years of thalidomide use and the birth of many thousands of grossly malformed infants before the cause-and-effect relationship between thalidomide administration in early pregnancy and its harmful effects was recognized. This serves to emphasize the difficulties that exist in incriminating drugs and chemicals that are harmful when administered during pregnancy.

Hopefully, we will never have another drug prescribed for use during pregnancy whose teratogenicity is as potent as thalidomide (about one-third of women taking this agent during the 1st trimester gave birth to infants with birth defects).

Concern about the safety of foreign compounds administered to pregnant women has been increasingly evident since thalidomide. The direct response to this misadventure led to the promulgation of the drug regulations of 1962 in the United States. According to these regulations, a drug must be demonstrated to be safe and effective for the conditions of use prescribed in its labeling. The regulations concerning this requirement state that a drug should be investigated for the conditions of use specified in the labeling, including dosage levels and patient populations for whom the drug is intended. In addition, appropriate information must be provided in the labeling and be available when the drug is prescribed. The intent of the regulations is not only to ensure adequate labeling information for the safe and effective administration of the drug by the physician but also to ensure that marketed drugs have an acceptable benefit:risk ratio for their intended uses.

It is clear that any drug or chemical substance administered to the mother is able to cross the placenta to some extent unless it is destroyed or altered during passage, or its molecular size and low lipid solubility limit transplacental transfer.

Placental transport of maternal substrates to the fetus and of substances from the fetus to the mother is established at about the 5th week of embryo life. Substances of low molecular weight diffuse freely across the placenta, driven primarily by the concentration gradient. It is important to note, therefore, that almost every substance used for therapeutic purposes can and does pass from the mother to the fetus. Of greater importance is whether the rate and extent of transfer are sufficient to result in significant concentrations within the fetus. Today, the concept of a placental barrier must be discarded.

Experiments with animals have provided considerable information concerning the teratogenic effects of drugs.

Unfortunately, these experimental findings cannot be extrapolated with certainty from species to species, or even from strain to strain within the same species, much less from animals to humans. Research in this area and the prediction of toxicity in the human are further hampered by a lack of specificity between cause and effect.

Traditionally, teratogenic effects of drugs have been noted as anatomic malformations. It is clear that these are dose and time related and that the fetus is at greater risk during the first 3 months of gestation. However, it is possible for drugs and chemicals to exert their effects upon the fetus at other times during pregnancy. Functional and behavioral changes are much more difficult to identify as to cause and effect.

Consequently, they are rarely recognized. A heightened awareness on the part of health care providers and recipients will make this task easier.

The use of dietary supplements as well as complementary or alternative medicine products has been increasing markedly in the Western industrialized world. This use continues unabated during pregnancy and lactation. The efficacy of these compounds is generally unknown, with rare exception, and their safety poorly studied. In particular, little is known about the interaction between the use of a broad range of dietary supplements, alternative medicine products, and health outcomes in women, developing fetuses and nursing neonates. Such knowledge is essential to the evaluation of both the justification and safety of the use of these products during these critical periods of development. Until this occurs, women should be advised about current lack of knowledge and cautioned as to their use. A notable exception is folic acid supplementation during pregnancy to prevent neural tube defects.

It is crucial that concern also be given to events beyond the narrow limits of congenital anatomic malformations; evidence exist that intellectual, social, and functional development can also be adversely affected by drug administration during pregnancy. There are examples that toxic manifestations of intrauterine exposure to environmental agents may be subtle, unexpected, and delayed. Concern for the delayed xiii

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Introduction

effects of drugs, following intrauterine exposure, was first raised following the tragic discovery that female fetuses exposed to diethylstilbestrol (DES) are at an increased risk for adenocarcinoma of the vagina. This type of malignancy is not discovered until after puberty. Many of the drugs prescribed to pregnant women have been evaluated in the following pages as to their propensity to produce congenital anatomic malformations. During the past several decades, awareness that many of these compounds may act after the period of organogenesis, through birth and into lactation, has increased. We now realize that drugs considered safe (i.e., not producing anatomic malformations) can still produce more subtle yet permanent alterations in the physiology and biochemistry of the developing perinate. Furthermore, many of these subtle hitherto unrecognized defects are not present at birth and may be dormant and latent until years later after the time of administration. The teratogen appears to produce a programming or imprinting defect in the developing tissue or organ. This defect need not be expressed until adulthood, because the program may not be required until that time.

Consequently, in the absence of anatomical defects readily recognized, there is the danger that these late-onset dysfunctions will either be unrecognized or will be attributed to some other cause.

The purpose of the above paragraph is to raise the concept of a little known but potentially serious health hazard in children and adults. This refers to the ability of perinatally consumed drugs and food additives and nonprescription alternative agents to produce the subtle biochemical defects undetectable or unrecognized in the neonate but expressed years or even decades after birth. How serious a problem is the in utero exposure to drugs and chemicals to the delayed latent defect? The answer may in lie in the use of animals for these fetal origins of adult disease.

The physician is confronted with two imperatives in treating the pregnant woman: alleviate maternal suffering and do no harm to the fetus. Until now, the emphasis has been on the amelioration of suffering, but the time has come to concentrate on not harming the fetus. The simple equation to be applied here is to weigh the therapeutic benefits of the drug to the mother against its risk potential to the developing fetus. Since fetal ova may also be exposed to drugs given to the mother, effects may be evident in future generations.

When one considers that more than a billion drug prescriptions are written each year, that there is unlimited self-­administration of over-the-counter drugs, and that approximately 500 new pharmaceutical products are introduced annually, the need for prudence and caution in the administration of pharmaceuticals has reached a critical point.

Pregnancy is a symptom-producing event. Pregnancy has the potential of causing women to increase their intake of drugs and chemicals, with the potential being that the fetus will be nurtured in a sea of drugs.

In today’s society, the physician cannot stand alone in the therapeutic decision-making process. It has now become the responsibility of each woman of childbearing age to consider her use of drugs carefully. In a pregnant woman, the decision to administer a drug should be made only after a collaborative appraisal between the woman and her physician of the risk:benefit ratio.

BREASTFEEDING AND DRUGS Between 1930 and the late 1960s, there was a dramatic decline in the percentage of American mothers who breastfed their babies. This was also accompanied by a reduction in the length of breastfeeding for those who did nurse. The incidence of breastfeeding declined from approximately 80% of the children born between 1926 and 1930 to 49% of children born some 25 years later. For children born between 1966 and 1970, 28% were breastfed. Indeed, in 1972 only 20% of newborns were breastfed. As data have become available for the following years, it is clear the decline has been reversed. By 1975, the percentage of first-born babies who were breastfed rose to 37%. At the present time in the United States, a number of surveys indicate that more than 50% of babies discharged from the hospital are breastfed, and the number is increasing. Breastfeeding is difficult to contemplate, as more than 50% of mothers work and return to work soon after delivery. New solutions must be found by employers to encourage breastfeeding and develop the logistics to enable employees to breastfeed on the job.

Breast milk is known to possess nutritional and immunologic properties superior to those found in infant formulas. An American Academy of Pediatrics position paper emphasizes breastfeeding as the best nutritional mode for infants for the first 6 months of life. In addition to those qualities, studies also suggest significant psychologic benefits of breastfeeding for both the mother and the infant.

The upswing in breastfeeding, together with a markedly increased concern about health needs on the part of parents, has led to increased questioning of the physician, pharmacist, and other health professionals about the safety and potential toxicity of drugs and chemicals that may be excreted in breast milk. Answers to these questions are not very apparent. Our knowledge concerning the long- and short-term effects and safety of maternally ingested drugs on the suckling infant is meager. We know more now than Soranus did in 150 AD, when he admonished wet nurses to refrain from the use of drugs and alcohol, lest it have an adverse effect on the nursing infant. We must know more! The knowledge to be acquired should be specific with respect to dose administered to the mother, amount excreted in breast milk, and amount absorbed by the suckling infant. In addition, effects on the infant should be determined (both acute and chronic).

It would be easy to recommend that the medicated mother not nurse, but it is likely that this recommendation would be ignored by the mother and may offend many health providers, as well as their patients, on both psychosocial and physiologic grounds.

It must be emphasized that many of the investigations concerned with milk secretion and synthesis have been carried out in animals. The difficulty in studying human lactation using histologic techniques and the administration of radioactive isotopes is obvious. There are considerable differences in the composition of milk in different species. Some of these differences in composition would obviously bring about changes in drug elimination. Of great importance in this regard are the differences in the pH of human milk (pH usually >7.0) compared with the pH of cowâ&#x20AC;&#x2122;s milk (pH usually <6.8) where drug excretion has been extensively studied.

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Introduction

A number of reviews give tables of the concentration of drugs in breast milk. Often, these tables also give the milk:plasma ratio. Most of the values from which the tables are derived consist of a single measurement of the drug concentration. Important information, such as the maternal dose, the frequency of dose, the time from drug administration to sampling, the frequency of nursing, and the length of lactation, is not given.

The significance of these concentration tables only means that the drug is present in the milk, and they offer no advice to the physician. Because the drug in the nursing infantâ&#x20AC;&#x2122;s blood or urine is not measured, we have little information about the amount that is actually absorbed by the infant from the milk and, therefore, have no way of determining the possible pharmacologic effects on the infant. In fact, a critical examination of the tables that have been published reveals that much of the information was gathered decades ago when analytic methodology was not as sensitive as it is today. Because the discipline of pharmacokinetics was not developed until recently, many of the studies quoted in the tables of the review articles do not precisely look at the time relationship between drug administration and disposition.

Certain things are evident with regard to drugs administered during lactation. It is necessary that physicians become aware of the results of animal studies in this area and of the potential risk of maternal drug ingestion to the suckling infant. Many drugs prescribed to the lactating woman need to be studied more so that their safety during lactation can be assessed. It is clear that if the mother needs a drug that has a moderate-to-high potential to cause infant harm, then she should consider not nursing. The ultimate decision must be

individualized according to the specific illness and the therapeutic modality. Nursing should be avoided following the administration of radioactive pharmaceuticals that are usually given to the mother for diagnostic purposes.

CONCLUSIONS Two basic situations are dealt with throughout this book: (a) risk potential to the fetus of maternal drugs ingested during the course of pregnancy, and (b) risk potential to the infant of drugs taken by the mother while nursing.

The obvious solution to fetal and nursing infant risk avoidance is maternal abstinence. However, from a pragmatic standpoint, that would be impossible to implement. Another solution is to disseminate knowledge, in an authoritative manner, to all those involved in the pregnancy and breastfeeding processes: physician, mother, midwife, nurse, father, and pharmacist.

This book helps to fill a communication and information gap. We have carefully evaluated the research literature, animal and human, applied and clinical. Each of the more than 1180 drugs has a risk factor assigned by the manufacturer or ourselves in keeping with the FDA guidelines. We have also assigned our own recommendations for use of these drugs in pregnancy and lactation. We believe that this book will be helpful to all concerned parties in developing the risk:benefit decision.

This is but a beginning. It is our fervent hope that the information gained from the use of this book will cause the concerned parties to be more trenchant in their future decision-making, either before prescribing or before ingesting drugs during pregnancy and lactation.

xv

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Instructions for Use of the Reference Guide

The Reference Guide is arranged so that the user can quickly locate a monograph. If the American generic name is known, go directly to the monographs, which are listed in alphabetical order. If only the trade or foreign name is known, refer to the Index for the appropriate American generic name. Foreign trade names have been included in the Index. To the best of our knowledge, all trade and foreign generic names are correct as shown, but because these may change, the reader should check other reference sources if there is any question as to the identity of an individual drug. Some prescription combination products are listed in the Index. If not listed, the user should refer to the manufacturerâ&#x20AC;&#x2122;s product information for the specific ingredients, and then use the Reference Guide as for single entities.

Each monograph contains eight parts: Generic Name (United States) Pharmacologic Class Pregnancy Recommendation Breastfeeding Recommendation Pregnancy Summary Fetal Risk Summary Breastfeeding Summary References

PREGNANCY SUMMARY The Pregnancy Summary is intended as a brief overview of the reported data in pregnancy, both animal and human, whereas the Fetal Risk Summary provides the specific details of the data. Both the Pregnancy Summary and the Fetal Risk Summary support the Pregnancy Recommendation.

FETAL RISK SUMMARY The Fetal Risk Summary is an analysis of the literature concerning use of the drug in pregnancy. The intent is to provide clinicians and others with sufficient data to counsel patients and to arrive at conclusions as to the risk:benefit ratio a particular drug poses for the embryo, fetus, and newborn.

The molecular weight of most drugs has been included in the reviews because they help determine if a drug can reach the embryo or fetus, but this value, by itself, may not predict the amount crossing the placenta. The major determinant of the drug concentration in the embryo or fetus is the blood concentration of the drug in the mother. Other important factors include the elimination half-life, metabolism, placental blood flow, the placental surface area available for crossing (i.e., correlated to the gestational age), and the lipid solubility, protein binding, and the amount of ionization of the drug at physiologic pH. Because few absolutes are possible in the area of human teratology, the reader must carefully weigh the evidence, or

lack thereof, before utilizing any drug in a pregnant woman.

Readers who require more details than are presented should refer to the specific references listed at the end of the monograph. See Definitions for recommendations.

BREASTFEEDING SUMMARY The Breastfeeding Summary is a brief review of the literature concerning excretion of the drug into human breast milk and the effects, if any, on a nursing infant. Unfortunately, in many cases, there is no published information about use of the drug during lactation. Moreover, when studies do exist, infants often were not allowed to breastfeed. Readers should pay close attention to this distinction (i.e., excretion into milk vs. effects on the nursing infant) when using a Summary. Those who require more details than are presented should refer to the specific references listed at the end of the monograph.

See Definitions for recommendations.

PREGNANCY AND BREASTFEEDING RECOMMENDATIONS The pregnancy recommendations are intended to assist the reader in determining the level of risk of a specific drug. They only apply to the usual therapeutic dose of the drug in a typical patient. Because the genetic makeup of a specific patient may significantly alter the risk, the recommendations may not apply to the entire population. In addition to the animal reproduction data and known human pregnancy outcomes, the assessment of risk includes, when relevant, other major factors such as route of administration, metabolism to active metabolites, species differences, type of defects, pharmacokinetics, effects of other agents in the drug class, and the embryoâ&#x20AC;&#x201C;fetal effects of untreated or undertreated maternal disease. Moreover, drug exposures represent different levels of risk depending on the stage of pregnancy and, thus, timing of the exposure is critical in determining risk. Because short statements of risk may not always adequately assess the risk throughout the pregnancy, readers are encouraged to review the entire monograph before estimating the risk for a specific patient.

The risks also change during breastfeeding because nearly all reported adverse effects in nursing infants have occurred in infants <6 months of age. The neonate and very young infant are most at risk for toxic effects from drugs present in breast milk. The recommendations for breastfeeding are based on the known toxicity of the drug or similar drugs in adults or children (when known) and the amount of drug excreted into breast milk (if known). Although most drugs taken by the mother are probably present in milk, the milk concentrations are usually unknown. Fortunately, the amounts are usually too low to cause toxicity. However, the therapeutic dose for infants

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Instructions for Use of the Reference Guide

of most drugs is rarely known. Therefore, we used a proposal from the literature (Ito S. N Engl J Med 2000;343:118–28) to classify exposures as clinically insignificant if, in the absence of data suggesting otherwise, the estimated dose ingested by a nursing infant was no more than 10% of the mother’s weight-adjusted dose. In some cases, this classification may not be relevant. For example, the potential for neurotoxicity in a nursing infant from long-term maternal use of psychotropic medications continues to be a concern.

DEFINITIONS OF PREGNANCY RECOMMENDATIONS Compatible The human pregnancy experience, either for the drug itself or drugs in the same class or with similar mechanisms of action, is adequate to demonstrate that the embryo–fetal risk is very low or nonexistent. Animal reproduction data are not relevant.

No (Limited) Human Data—Probably Compatible There may or may not be human pregnancy experience, but the characteristics of the drug suggest that it does not represent a significant risk to the embryo–fetus. For example, other drugs in the same class or with similar mechanisms are compatible or the drug does not obtain significant systemic concentrations. Any animal reproduction data are not relevant.

Compatible—Maternal Benefit >> Embryo– Fetal Risk There may or may not be human pregnancy experience, but the potential maternal benefit far outweighs the known or unknown embryo–fetal risk. Animal reproduction data are not relevant.

Human Data Suggest Low Risk There is limited human pregnancy experience, either for the drug itself or drugs in the same class or with similar mechanisms of action, including the 1st trimester, suggesting that the drug does not represent a significant risk of developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death) at any time in pregnancy.

The limited human pregnancy data outweigh any animal reproduction data.

No (Limited) Human Data—Animal Data Suggest Low Risk Either there is no human pregnancy experience or the few pregnancy exposures have not been associated with developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death). The drug does not cause developmental toxicity (at doses that did not cause maternal toxicity) in all animal species studied at doses ≤10 times the human dose based on body surface area (BSA) or AUC*.

No (Limited) Human Data—Animal Data Suggest Moderate Risk Either there is no human pregnancy experience or the few pregnancy exposures have not been associated with developmental toxicity (growth restriction, structural anomalies, *AUC = area under the plasma concentration vs. time curve; a measure of the systemic exposure of a drug

functional/behavioral deficits, or death). The drug causes developmental toxicity (at doses that did not cause maternal toxicity) in one animal species at doses ≤10 times the human dose based on body surface area (BSA) or AUC*.

No (Limited) Human Data—Animal Data Suggest Risk Either there is no human pregnancy experience or the few pregnancy exposures have not been associated with developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death). The drug causes developmental toxicity (at doses that did not cause maternal toxicity) in two animal species at doses ≤10 times the human dose based on body surface area (BSA) or AUC*.

No (Limited) Human Data—Animal Data Suggest High Risk Either there is no human pregnancy experience or the few pregnancy exposures have not been associated with developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death). The drug causes developmental toxicity (at doses that did not cause maternal toxicity) in three or more animal species at doses ≤10 times the human dose based on body surface area (BSA) or AUC*.

Contraindicated—1st Trimester Human exposures in the 1st trimester, either to the drug itself or to drugs in the same class or with similar mechanisms of action, have been associated with developmental toxicity (growth restriction, structural anomalies, functional/­ behavioral deficits, or death). The drug should not be used in the 1st trimester.

Contraindicated—2nd and 3rd Trimesters Human exposures in the 2nd and 3rd trimesters, either to the drug itself or to drugs in the same class or with similar mechanisms of action, have been associated with developmental toxicity (growth restriction, structural anomalies, functional/ behavior deficits, or death). The drug should not be used in the 2nd and 3rd trimesters.

Contraindicated Human exposures at any time in pregnancy, either to the drug itself or to drugs in the same class or with similar mechanisms of action, have been associated with developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death). Animal reproduction data, if available, confirm the risk. The drug should not be used in pregnancy.

No (Limited) Human Data—No Relevant Animal Data There is no human pregnancy data or relevant data in animals, or the human pregnancy experience, that may or may not include the 1st trimester, is limited. The risk in pregnancy ­cannot be assessed.

Human Data Suggest Risk in 1st Trimester Evidence (for the drug or similar drugs) suggests that there may be an embryo–fetal risk for developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death) in the 1st trimester but not in the 2nd and 3rd trimesters. The human pregnancy data outweigh any ­animal reproduction data.

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Instructions for Use of the Reference Guide

Human Data Suggest Risk in 1st and 3rd Trimesters Evidence (for the drug or similar drugs) suggests that there may be an embryo–fetal risk for developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death) in the 1st and 3rd trimesters but not in the 2nd trimester. The human pregnancy data outweigh any animal reproduction data.

Human Data Suggest Risk in 2nd and 3rd Trimesters Evidence (for the drug or similar drugs) suggests that there may be a fetal risk for developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death) in the 2nd and 3rd trimesters but not in the 1st trimester. The human pregnancy data outweigh any animal reproduction data.

Human Data Suggest Risk in 3rd Trimester Evidence (for the drug or similar drugs) suggests that there may be a fetal risk for developmental toxicity (growth restriction, structural anomalies, functional/behavioral deficits, or death) in the 3rd trimester, or close to delivery but not in the 1st or 2nd trimesters. The human pregnancy data outweigh any animal reproduction data.

Human (and Animal) Data Suggest Risk The human data for the drug or drugs in the same class or with the same mechanism of action, and animal reproduction data if available, suggest there may be a risk for developmental toxicity (growth restriction, structural anomalies, functional/ behavioral deficits, or death) throughout pregnancy. Usually, pregnancy exposure should be avoided, but the risk may be acceptable if the maternal condition requires the drug.

DEFINITIONS OF BREASTFEEDING RECOMMENDATIONS Compatible Either the drug is not excreted in clinically significant amounts into human breast milk or its use during lactation does not, or is not expected to, cause toxicity in a nursing infant.

Hold Breastfeeding The drug may or may not be excreted into human breast milk, but the maternal benefit of therapy far outweighs the benefits of breast milk to an infant. Breastfeeding should be held until maternal therapy is completed and the drug has been eliminated (or reaches a low concentration) from her system.

No (Limited) Human Data—Probably Compatible Either there is no human data or the human data are limited.

The available data suggest that the drug does not represent a significant risk to a nursing infant.

No (Limited) Human Data—Potential Toxicity Either there is no human data or the human data are limited.

The characteristics of the drug suggest that it could represent a clinically significant risk to a nursing infant. Breastfeeding is not recommended.

Human Data Suggest Potential Toxicity Human data suggest a risk to a nursing infant. The drug is best avoided during breastfeeding. Depending on the drug, short-term use by the mother may be possible, but the infant should be closely monitored for potential adverse effects.

No (Limited) Human Data—Potential Toxicity (Mother) Either there is no human data or the human data are limited.

The characteristics of the drug suggest that breastfeeding could represent a clinically significant risk to the mother such as further loss of essential vitamins or nutrients. Breastfeeding is not recommended.

Contraindicated There may or may not be human experience, but the combined data suggest that the drug may cause severe toxicity in a nursing infant, or breastfeeding is contraindicated because of the maternal condition for which the drug is indicated.

Women should not breastfeed if they are taking the drug or have the condition.

Comparison of Agents within the Same Pharmacologic Class The Appendix arranges the drugs by their pharmacologic category. This allows the reader to identify all of the drugs that have been reviewed within a specific category, thus allowing, if desired, a comparison of the drugs. For example, the subsection Antihypertensives lists together those agents used for this purpose under the general heading Cardiovascular Drugs.

To assist the reader in locating an agent in the Appendix, page numbers (in parentheses) referring to the location in the Appendix have been added to the generic names (shown in bold) in the Index.

FDA Risk Categories Definitions Although the FDA risk categories have been excluded from this edition, readers wanting this information can obtain it from the manufacturer’s product information.

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K KANAMYCIN Antibiotic (Aminoglycoside) PREGNANCY RECOMMENDATION: Human Data Suggest Risk BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible

PREGNANCY SUMMARY Except for ototoxicity, no reports of congenital defects due to kanamycin have been located. Embryos were examined from five patients who aborted during the 11th and 12th weeks of pregnancy and who had been treated with kanamycin during the 6th and 8th weeks (1). No abnormalities in the embryos were found.

FETAL RISK SUMMARY Kanamycin is an aminoglycoside antibiotic. At term, the drug was detectable in cord serum 15 minutes after a 500-mg IM maternal dose (2). Mean cord serum levels at 3–6 hours were 6 mcg/mL. Amniotic fluid levels were undetectable during the first hour, and then rose during the next 6 hours to a mean value of 5.5 mcg/mL. No effects on the infants were mentioned.

Eighth cranial nerve damage has been reported following in utero exposure to kanamycin (1,3). In a retrospective survey of 391 mothers who received kanamycin, 50 mg/kg, for prolonged periods during pregnancy, 9 (2.3%) children were found to have hearing loss (1). Complete hearing loss in a mother and her infant was reported after the mother had been treated during pregnancy with IM kanamycin, 1 g/day for 4.5 days (3). Ethacrynic acid, an ototoxic diuretic, was also given to the mother during pregnancy.

BREASTFEEDING SUMMARY Kanamycin is excreted into breast milk. Milk:plasma ratios of 0.05–0.40 have been reported (4). A 1-g IM dose ­produced peak milk levels of 18.4 mcg/mL (5). No effects

were reported in the nursing infants. Because oral absorption of kanamycin is poor, ototoxicity would not be expected. However, three potential problems exist for the nursing infant: modification of bowel flora, direct effects on the infant, and interference with the interpretation of culture results if a fever workup is required. The American Academy of Pediatrics classifies kanamycin as compatible with breastfeeding (6).

References 1. Nishimura H, Tanimura T. Clinical Aspects of the Teratogenicity of Drugs.

New York, NY: American Elsevier, 1976:131.

2. Good R, Johnson G. The placental transfer of kanamycin during late pregnancy. Obstet Gynecol 1971;38:60–2.

3. Jones HC. Intrauterine ototoxicity. A case report and review of literature.

J Natl Med Assoc 1973;65:201–3.

4. Wilson JT. Milk/plasma ratios and contraindicated drugs. In: Wilson JT, ed.

Drugs in Breast Milk. Balgowlah, Australia: ADIS Press, 1981:79.

5. O’Brien T. Excretion of drugs in human milk. Am J Hosp Pharm 1974; 31:844–54.

6. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108: 776–89.

KAOLIN/PECTIN Antidiarrheal PREGNANCY RECOMMENDATION: No Human Data—Probably Compatible BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible

PREGNANCY SUMMARY No reports have related the use of the kaolin/pectin mixture in pregnancy with adverse fetal outcome. There have been reports of iron-deficiency anemia and hypokalemia secondary to the eating of clays (i.e., geophagia) containing kaolin (1–3).

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FETAL RISK SUMMARY

References

Kaolin is hydrated aluminum silicate clay used for its adsorbent properties in diarrhea, and pectin is a polysaccharide obtained from plant tissues that is used as a solidifying agent.

Neither agent is absorbed into the systemic c­ irculation.

The mechanism for iron deficiency anemia is thought to be either a reduction in the intake of foods containing absorbable iron or an interference with the absorption of iron. In humans, iron-deficiency anemia may significantly enhance the chance for a low-birth-weight infant and ­preterm delivery (4,5).

Rats fed a diet containing 20% kaolin became anemic and delivered pups with a significant decrease in birth weight (6).

When an iron supplement was added to the kaolin-fortified diet, no anemia or reduced birth weight was observed.

1. Mengel CE, Carter WA, Horton ES. Geophagia with iron deficiency and hypokalemia: Cachexia africana. Arch Intern Med 1964;114:470–4.

2. Talington KM, Gant NF Jr, Scott DE, Pritchard JA. Effect of ingestion of starch and some clays on iron absorption. Am J Obstet Gynecol 1970;108:262–7.

3. Roselle HA. Association of laundry starch and clay ingestion with anemia in New York City. Arch Intern Med 1970;125:57–61.

4. Scholl TO, Hediger ML, Fischer RL, Shearer JW. Anemia vs. iron deficiency: increased risk of preterm delivery in a prospective study. Am J Clin Nutr 1992;55:985–8.

5. Macgregor MW. Maternal anaemia as a factor in prematurity and perinatal mortality. Scott Med J 1963;8:134–40.

6. Patterson EC, Staszak DJ. Effects of geophagia (kaolin ingestion) on the maternal blood and embryonic development in the pregnant rat. J Nutr 1977;107:2020–5.

BREASTFEEDING SUMMARY Other than producing anemia in the mother after prolonged, chronic use, the kaolin/pectin mixture should have no effect on lactation or the nursing infant.

K

KETAMINE General Anesthetic PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible

PREGNANCY SUMMARY Although ketamine anesthesia close to delivery may induce dose-related, transient toxicity in the newborn, these effects are usually avoided with the use of lower maternal doses. No reports of malformations in humans (1) or in animals attributable to ketamine have been located, although experience with the anesthetic agent during human organogenesis apparently has not been published.

FETAL RISK SUMMARY Ketamine is a rapid-acting IV general anesthetic agent related in structure and action to phencyclidine. No teratogenic or other adverse fetal effects have been observed in reproduction studies during organogenesis and near delivery with rats, mice, rabbits, and dogs (2–6). In one study with pregnant rats, a dose of 120 mg/kg/day for 5 days during organogenesis resulted in no malformations or effect on fetal weight (5).

Ketamine rapidly crosses the placenta to the fetus in animals and humans (7,8). Pregnant ewes were given ­ 0.7 mg/kg IV, and 1 minute later the maternal and fetal ­concentrations of ketamine were 1230 ng/mL and 470 ng/ mL (ratio 0.38), respectively (7). Maternal effects were slight, transitory increases in mean arterial pressure and cardiac output; respiratory acidosis; and an increase in uterine tone without changes in uterine blood flow. In humans, the placental transfer of ketamine was documented in a study in which a dose of 250 mg IM was administered when the fetal head reached the perineum (8). The ketamine concentration

in cord venous plasma at the 0- to 10-minute dose-to-delivery interval was 0.61 mcg/mL, compared with 1.03 mcg/mL at the 10- to 30-minute interval, reflecting absorption following the IM route.

Pregnant monkeys were administered ketamine in IV doses of 2 mg/kg (N = 3) or 1 mg/kg (N = 2) in an investigation of the anesthetic’s effects on the fetus and newborn (9). No fetal effects were observed from either dose. The newborns from the mothers given 2 mg/kg, but not those exposed to lower doses, had profound respiratory depression.

The use of ketamine (C-581) for obstetric anesthesia was first described in 1966 (10). Since then, a large number of references have documented its use for this purpose (11–39).

Among the maternal and newborn complications reported with ketamine are oxytocic properties, an increase in maternal blood pressure, newborn depression, and an increased tone of newborn skeletal musculature. These adverse effects were usually related to higher IV doses (1.5–2.2 mg/kg) administered during early studies rather than to the lower IV doses (0.2–0.5 mg/kg) now commonly used.

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Ketamine usually demonstrates a dose-related oxytocic effect with an increase in uterine tone, and in frequency and intensity of uterine contractions (10–13,23,38), but one investigator reported weakened uterine contractions following a 250-mg IM dose administered when the fetal head reached the perineum (8). Uterine tetany was observed in one case (13). Low IV doses (0.275–1.1 mg/kg) of ketamine increased only uterine contractions, whereas a higher IV dose (2.2 mg/kg) resulted in a marked increase in uterine tone (23). Maximum effects were observed within 2–4 minutes of the dose. In one study, however, the effect on uterine contractions from an IV dose of 1 mg/kg, followed by succinylcholine 1 mg/kg, was no different from thiopental (15). No effect on intrauterine pressure was measured in 12 term patients treated with IV ketamine 2 mg/kg, in contrast to a marked uterine pressure increase in patients in early pregnancy undergoing termination (40).

Similarly, in 12 women given IV ketamine 2.2 mg/kg for termination of pregnancy at 8–19 weeks, uterine pressure and the intensity and frequency of contractions were increased (41).

Several investigators noted a marked increase in maternal blood pressure, up to 30%–40% in systolic and diastolic in some series, during ketamine induction (8,11,13,14,16,24,25). An increased maternal heart rate was usually observed. These effects are dose-related, with the greatest increases occurring when 2–2.2 mg/kg IV was administered, but smaller elevations of pressure and pulse were noted with lower IV doses.

Maternal ketamine anesthesia may cause depression of the newborn (8,13,16–19,22,24,27,33). As with the other complications, the use of higher IV doses (1.5–2.2 mg/kg) resulted in the highest incidence of low neonatal Apgar scores and requirements for newborn resuscitation. The induction-to-delivery (ID) interval is an important determinant for neonatal depression (8,22,33,35). In two studies, neonatal depression was markedly lower or absent if the ID interval was <10 minutes (8,33). In a third study, significant depression occurred with an ID interval of 9.2 minutes, but an IV dose of 2.1 mg/kg had been used (22).

The use of ketamine in low doses apparently has little effect on fetal cardiovascular status or acid–base balance as evidenced by neonatal blood gases (8,25,27,30,32–34). In one study, a ketamine dose of 25 mg IV administered with nitrous oxide and oxygen within 4 minutes of delivery did not adversely affect neonatal blood pressure (39).

Ketamine doses of 2 mg/kg IV have been associated with excessive neonatal muscle tone, sometimes with apnea (11,12,18). In some cases, the increased muscle tone made endotracheal intubation difficult. In contrast, lower doses (e.g., 0.25–1 mg/kg) have not been associated with this complication (25).

Neonatal neurobehavior, as measured by the Scanlon Group of Early Neonatal Neurobehavioral Tests during the first 2 days, is depressed following maternal ketamine (1 mg/kg IV) anesthesia but less than the effect measured after thiopental anesthesia (4 mg/kg IV) (42,43). In these studies, spinal anesthesia with 6–8 mg of tetracaine was associated with the best performance, general anesthesia with ketamine was intermediate, and that with thiopental was the poorest in performance.

BREASTFEEDING SUMMARY Because ketamine is a general anesthetic agent, breastfeeding would not be possible during use of the drug, and no reports have been located that measured the amount of the agent in milk. The elimination half-life of ketamine has been reported to be 2.17 hours in unpremedicated patients (32).

Thus, the drug should be undetectable in the mother’s plasma approximately 11 hours after a dose. Nursing after this time should not expose the infant to pharmacologically significant amounts of ketamine.

References 1. Friedman JM. Teratogen update: anesthetic agents. Teratology 1988;37: 69–77.

2. Nishimura H, Tanimura T. Clinical Aspects of the Teratogenicity of Drugs.

New York, NY: American Elsevier, 1976:178.

3. Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York, NY: Marcel Dekker, 1993:148.

4. Onnis A, Grella P. The Biochemical Effects of Drugs in Pregnancy. Vol. 1.

West Sussex, England: Ellis Norwood, 1984:18–9.

5. El-Karum AHA, Benny R. Embryotoxic and teratogenic action of ketamine.

Ain Shams Med J 1976;27:459–63.

6. Product information. Ketalar. Parke-Davis, 1993.

7. Craft JB Jr, Coaldrake LA, Yonekura ML, Dao SD, Co EG, Roizen MF, Mazel P, Gilman R, Shokes L, Trevor AJ. Ketamine, catecholamines, and uterine tone in pregnant ewes. Am J Obstet Gynecol 1983;146:429–34.

8. Nishijima M. Ketamine in obstetric anesthesia: special reference to placental transfer and its concentration in blood plasma. Acta Obstet Gynaecol Jpn 1972;19:80–93. As cited in Anonymous. Operative obstetrics and anesthesia. Obstet Gynecol Surv 1975;30:605–6.

9. Eng M, Bonica JJ, Akamatsu TJ, Berges PU, Ueland K. Respiratory depression in newborn monkeys at caesarean section following ketamine administration. Br J Anaesth 1975;47:917–21.

10. Chodoff P, Stella JG. Use of CI-581 a phencyclidine derivative for obstetric anesthesia. Anesth Analg 1966;45:527–30.

11. Bovill JG, Coppel DL, Dundee JW, Moore J. Current status of ketamine anaesthesia. Lancet 1971;1:1285–8.

12. Moore J, McNabb TG, Dundee JW. Preliminary report on ketamine in obstetrics. Br J Anaesth 1971;43:779–82.

13. Little B, Chang T, Chucot L, Dill WA, Enrile LL, Glazko AJ, Jassani M, Kretchmer H, Sweet AY. Study of ketamine as an obstetric anesthetic agent. Am J Obstet Gynecol 1972;113:247–60.

14. McDonald JS, Mateo CV, Reed EC. Modified nitrous oxide or ketamine hydrochloride for cesarean section. Anesth Analg 1972;51:975–83.

15. Peltz B, Sinclair DM. Induction agents for caesarean section. A comparison of thiopentone and ketamine. Anaesthesia 1973;28:37–42.

16. Meer FM, Downing JW, Coleman AJ. An intravenous method of anaesthesia for caesarean section. Part II: ketamine. Br J Anaesth 1973;45: 191–6.

17. Galbert MW, Gardner AE. Ketamine for obstetrical anesthesia. Anesth Analg 1973;52:926–30.

18. Corssen G. Ketamine in obstetric anesthesia. Clin Obstet Gynecol 1974;17:249–58.

19. Janeczko GF, El-Etr AA, Younes S. Low-dose ketamine anesthesia for obstetrical delivery. Anesth Analg 1974;53:828–31.

20. Akamatsu TJ, Bonica JJ, Rehmet R, Eng M, Ueland K. Experiences with the use of ketamine for parturition. I. Primary anesthetic for vaginal delivery.

Anesth Analg 1974;53:284–7.

21. Krantz ML. Ketamine in obstetrics: comparison with methoxyflurane.

Anesth Analg 1974;53:890–3.

22. Downing JW, Mahomedy MC, Jeal DE, Allen PJ. Anaesthesia for caesarean section with ketamine. Anaesthesia 1976;31:883–92.

23. Galloon S. Ketamine for obstetric delivery. Anesthesiology 1976;44:522–4.

24. Ellingson A, Haram K, Sagen N. Ketamine and diazepam as anaesthesia for forceps delivery. A comparative study. Acta Anaesth Scand 1977;21:37–40.

25. Maduska AL, Hajghassemali M. Arterial blood gases in mothers and infants during ketamine anesthesia for vaginal delivery. Anesth Analg 1978;57:121–3.

26. Dich-Nielsen J, Holasek J. Ketamine as induction agent for caesarean section.

Acta Anaesth Scand 1982;26:139–42.

K

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27. White PF, Way WL, Trevor AJ. Ketamine—its pharmacology and therapeutic uses. Anesthesiology 1982;56:119–36.

28. Hill CR, Schultetus RR, Dharamraj CM, Banner TE, Berman LS. Wakefulness during cesarean section with thiopental, ketamine, or thiopental–ketamine combination (abstract). Anesthesiology 1993;59:A419.

29. Schultetus RR, Paulus DA, Spohr GL. Haemodynamic effects of ketamine and thiopentone during anaesthetic induction for caesarean section. Can Anaesth Soc J 1985;32:592–6.

30. Bernstein K, Gisselsson L, Jacobsson L, Ohrlander S. Influence of two different anaesthetic agents on the newborn and the correlation between foetal oxygenation and induction-delivery time in elective caesarean section. Acta Anaesthesiol Scand 1985;29:157–60.

31. Schultetus RR, Hill CR, Dharamraj CM, Banner TE, Berman LS. Wakefulness during cesarean section after anesthetic induction with ketamine, thiopental, or ketamine and thiopental combined. Anesth Analg 1986;65:723–8.

32. Reich DL, Silvay G. Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth 1989;36:186–97.

33. Baraka A, Louis F, Dalleh R. Maternal awareness and neonatal outcome after ketamine induction of anaesthesia for caesarean section. Can J Anaesth 1990;37:641–4.

34. Rowbottom SJ, Gin T, Cheung LP. General anaesthesia for caesarean section in a patient with uncorrected complex cyanotic heart disease. Anaesth Intens Care 1994;22:74–8.

35. Krissel J, Dick WF, Leyser KH, Gervais H, Brockerhoff P, Schranz D. Thiopentone, thiopentone/ketamine, and ketamine for induction of ­anaesthesia in caesarean section. Eur J Anaesthesiol 1994;11:115–22.

36. Conway JB, Posner M. Anaesthesia for caesarean section in a patient with Watson’s syndrome. Can J Anaesth 1994;41:1113–6.

37. Maleck W. Ketamine and thiopentone in caesarean section. Eur J Anaesthesiol 1995;12:533.

38. Marx GF, Hwang HS, Chandra P. Postpartum uterine pressures with different doses of ketamine. Anesthesiology 1979;50:163–6.

39. Marx GF, Cabe CM, Kim YI, Eidelman AI. Neonatal blood pressures.

Anaesthesist 1976;25:318–22.

40. Oats JN, Vasey DP, Waldron BA. Effects of ketamine on the pregnant uterus. Br J Anaesth 1979;51:1163–6.

41. Galloon S. Ketamine and the pregnant uterus. Can Anaesth Soc J 1973;20:141–5.

42. Hodgkinson R, Marx GF, Kim SS, Miclat NM. Neonatal neurobehavioral tests following vaginal delivery under ketamine, thiopental, and extradural anesthesia. Anesth Analg 1977;56:548–53.

43. Hodgkinson R, Bhatt M, Kim SS, Grewal G, Marx GF. Neonatal neurobehavioral tests following cesarean section under general and spinal anesthesia.

Am J Obstet Gynecol 1978;132:670–4.

KETOCONAZOLE

K

Antifungal PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk (Oral) No Human Data—Probably Compatible (Topical) BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible

PREGNANCY SUMMARY Ketoconazole is a synthetic, broad-spectrum antifungal agent. It has been used, apparently without fetal harm, for the treatment of vaginal candidiasis occurring during pregnancy (1).

FETAL RISK SUMMARY Ketoconazole is in the same antifungal class of imidazole derivatives as butoconazole, clotrimazole, econazole, miconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole.

Ketoconazole is embryotoxic and teratogenic in rats, producing syndactyly and oligodactyly at a dose 10 times the maximum recommended human dose (weight basis) (2,3).

However, the dose caused maternal toxicity.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 20 newborns had been exposed to oral ketoconazole during the 1st trimester (F. Rosa, personal communication, FDA, 1993). No major birth defects were observed (one expected). Since this study, the FDA has received six reports of limb defects (F. Rosa, personal communication, FDA, 1996).

Limb malformations were reported in a 1985 abstract (4). A Turkish woman had used ketoconazole, 200 mg daily, during the first 7 weeks of gestation. Hydrops fetalis was diagnosed at 29 weeks’ gestation and she delivered a female infant at 30.5 weeks’. The infant, with a normal karyotype (46,XX), had multiple anomalies of the limbs (further details not specified).

Women infected with HIV frequently have vaginal candidiasis. Maternal symptoms, such as pruritus, may require treatment; in these cases, therapeutic and prophylactic ketoconazole regimens are recommended, even though the fungal infection has little perinatal significance (5).

Ketoconazole inhibits steroidogenesis in fungal cells. In humans, high doses, such as those >400 mg/day, impair testosterone and cortisol synthesis (6–9). Because of this effect, ketoconazole has been used in the treatment of hypercortisolism (10). A review summarizing the treatment of 67 cases of Cushing’s syndrome occurring during pregnancy did not find any cases treated with ketoconazole (10). A 1990 report, however, described a ketoconazole-treated 36-year-old pregnant woman with Cushing’s syndrome (11). The pregnancy, in addition to Cushing’s syndrome, was complicated by hypertension, diabetes mellitus diagnosed at 9 weeks’ gestation, and intrauterine growth restriction. Ketoconazole, 200 mg every 8 hours, was started at 32 weeks’ gestation and continued for 5 weeks because of maternal clinical deterioration resulting from the sustained hypercortisolism. Rapid clinical improvement was noted in the mother after therapy was begun. A growth-restricted, 2080-g, but otherwise normal,

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female infant was delivered by elective cesarean section at 37 weeks. The Apgar scores were 9 and 9 at 1 and 5 minutes, respectively. No clinical or biochemical evidence of adrenal insufficiency was found in the newborn. The infant’s basal cortisol and adrenocorticotropic hormone levels, 306 nmol/L and 8.1 pmol/L, respectively, were normal. The child was growing normally at 18 months of age.

BREASTFEEDING SUMMARY Ketoconazole is excreted into breast milk (12). A 41-year-old, 82-kg woman took 200 mg/day for 10 days while nursing her 1-month-old infant. Five manually expressed milk samples were collected over a 24-hour interval (1.75–24 hours postdose) on day 10. The maximum milk concentration (0.22 mcg/mL) was measured at 3.25 hours postdose. Ketoconazole was undetectable (detection limit 0.005 mcg/mL) at 24 hours postdose. The mean milk concentration, based on AUC for 0–24 hours, was 0.068 mcg/mL. The level corresponded to an estimated infant dose (based on 150 mL/kg/day) of 0.01 mg/kg/day (maximum estimated dose 0.033 mg/kg/day). The dose was about 0.4% of the mother’s weight-adjusted dose. No adverse effects were observed in the infant (12).

The effects on the nursing infant from exposure to drug in the milk are unknown, but the exposure in the above case does not appear to be clinically significant. The American Academy of Pediatrics classifies ketoconazole as compatible with breastfeeding (13).

References 1. Luscher KP, Schneitter J, Vogt HP. Incidence of Candida infections during pregnancy and their treatment with ketoconazole ovula. Schweiz Rundsch Med Prax 1987;76:1285–7.

2. Product information. Nizoral. Janssen Pharmaceutics, 1997.

3. Nishikawa S, Hara T, Miyazaki H, Ohguro Y. Reproduction studies of KW-1414 in rats and rabbits. Clin Rep 1984;18:1433–88. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: The Johns Hopkins University Press, 1989:1075.

4. Lind J. Limb malformations in a case of hydrops fetalis with ketoconazole use during pregnancy (abstract). Arch Gynecol 1985;237(Suppl):398.

5. Minkoff HL. Care of pregnant women infected with human immunodeficiency virus. JAMA 1987;258:2714–7.

6. Hobbs ER. Coccidioidomycosis. Dermatol Clin 1989;7:227–39.

7. Pont A, Williams PL, Loose DS, Feldman D, Reitz RE, Bochra C, Stevens DA. Ketoconazole blocks adrenal steroid synthesis. Ann Intern Med 1982;97:370–2.

8. Engelhardt D, Mann K, Hormann R, Braun S, Karl HJ. Ketoconazole inhibits cortisol secretion of an adrenal adenoma in vivo and in vitro. Klin Wochenschr 1983;61:373–5.

9. Divers MJ. Ketoconazole treatment of Cushing’s syndrome in pregnancy.

Am J Obstet Gynecol 1990;163:1101.

10. Aron DC, Schnall AM, Sheeler LR. Cushing’s syndrome and pregnancy. Am J Obstet Gynecol 1990;162:244–52.

11. Amado JA, Pesquera C, Gonzalez EM, Otero M, Freijanes J, Alvarez A. Successful treatment with ketoconazole of Cushing’s syndrome in pregnancy. Postgrad Med J 1990;66:221–3.

12. Moretti ME, Ito S, Koren G. Disposition of maternal ketoconazole in breast milk. Am J Obstet Gynecol 1995;173:1625–8.

13. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108: 776–89.

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KETOPROFEN Nonsteroidal Anti-inflammatory PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 1st and 3rd Trimesters BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible

PREGNANCY SUMMARY Constriction of the ductus arteriosus in utero is a pharmacologic consequence arising from the use of prostaglandin synthesis inhibitors during pregnancy (see also Indomethacin) (1). Persistent pulmonary hypertension of the newborn may occur if these agents are used in the 3rd trimester close to delivery (1,2). These drugs also have been shown to inhibit labor and prolong pregnancy, in both humans (3) (see also Indomethacin) and animals (4). Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including ketoprofen, because of the findings in a variety of animal models indicating that these agents block blastocyst implantation (5,6). As noted below, nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with spontaneous abortions (SABs) and congenital malformations (see also Ibuprofen), but the risk for these defects appears to be low.

FETAL RISK SUMMARY Ketoprofen is an NSAID that is indicated for the management of the signs and symptoms of rheumatoid arthritis and osteoarthritis. It is in the same subclass (propionic acids) as five other NSAIDs (fenoprofen, flurbiprofen, ibuprofen, naproxen, and oxaprozin). The drug undergoes metabolism to an inactive metabolite but can be converted back to the parent compound. Plasma protein binding, mainly to albumin, is high (>99%) and the elimination half-life is about 2 hours (7).

Reproductive studies in mice and rats at about 0.2 times the maximum recommended human dose based on BSA

revealed no teratogenic or embryotoxic effects (7). In rabbits, maternally toxic doses were embryotoxic but not teratogenic (7). Shepard (8) reviewed four animal studies that used mice, rats, and monkeys and found no adverse fetal effects or congenital malformations.

Consistent with the low molecular weight (about 254), ketoprofen crosses the human placenta. A 1998 study, using a human isolated perfused placenta, demonstrated transfer of the drug (9). The investigators had previously shown that the drug crosses to the fetus and is detectable in the newborn (10).

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KETOROLAC

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In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 112 newborns had been exposed to ketoprofen during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Three (2.7%) major birth defects were observed (five expected), including (expected/observed) 1/1 cardiovascular defect and 1/0.3 polydactyly. No anomalies were observed in four other categories of defects (oral clefts, spina bifida, limb reduction defects, and hypospadias) for which specific data were available.

A combined 2001 population-based, observational cohort study and a case–control study estimated the risk of adverse pregnancy outcome from the use of NSAIDs (11). The use of NSAIDs during pregnancy was not associated with congenital malformations, preterm delivery, or low birth weight, but a positive association was discovered with SABs. A similar study with NSAIDs found a significant association with cardiac defects and orofacial clefts (12). In addition, a 2003 study found a significant association between exposure to NSAIDs in early pregnancy and SABs (13). (See Ibuprofen for details on these three studies.)

A brief 2003 editorial on the potential for NSAID-induced developmental toxicity concluded that NSAIDs, and specifically those with greater cyclooxygenase 2 (COX-2) affinity, had a lower risk of this toxicity in humans than aspirin (14).

In a 2007 study, atosiban (an oxytocin inhibitor not available in the United States) was compared with ritodrine for the prevention of preterm labor (15). Ketoprofen was added to 51.1% of the atosiban group and 47.7% of the ritodrine group because the response to the single drug was unsatisfactory. The ketoprofen dose was 100 mg IV followed by 100–150 mg IV every 12 hours for a total duration up to 48 hours. Neonatal mortality and morbidity were unrelated to ketoprofen exposure (15).

BREASTFEEDING SUMMARY No reports describing the use of ketoprofen during breastfeeding have been located. However, in a 2007 report, 18 non-breastfeeding women immediately after delivery were given IV ketoprofen (100 mg every 12 hours) and nalbuphine (0.2 mg/kg every 4 hours) for postpartum pain (16).

The mean and maximum ketoprofen milk concentrations were 57 and 91 ng/mL, respectively. Assuming a milk volume of 150 mL/kg/day, the estimated mean and maximum infant doses were 8.5 and 13.6 mcg/kg/day, respectively. The relative infant dose as a percentage of the weight-adjusted maternal dose was 0.31% (16). (See Nalbuphine for additional data.)

The above data are consistent with the low molecular weight (about 254) of ketoprofen as well as the relatively short elimination half-life (about 2 hours) and the high plasma

protein binding (>99%). Although the amounts measured in the above are low, an abstract from France reported that ketoprofen use during breastfeeding was associated with adverse renal and gastrointestinal effects (17). Based on this information, maternal use of other agents should be considered, such as ibuprofen, which is classified as compatible with breastfeeding by the American Academy of Pediatrics (see Ibuprofen).

References 1. Levin DL. Effects of inhibition of prostaglandin synthesis on fetal development, oxygenation, and the fetal circulation. Semin Perinatol 1980;4: 35–44.

2. Van Marter LJ, Leviton A, Allred EN, Pagano M, Sullivan KF, Cohen A, Epstein MF. Persistent pulmonary hypertension of the newborn and smoking and aspirin and nonsteroidal antiinflammatory drug consumption during pregnancy. Pediatrics 1996;97:658–63.

3. Fuchs F. Prevention of prematurity. Am J Obstet Gynecol 1976;126: 809–20.

4. Powell JG, Cochrane RL. The effects of a number of non-steroidal anti-inflammatory compounds on parturition in the rat. Prostaglandins 1982;23:469–88.

5. Matt DW, Borzelleca JF. Toxic effects on the female reproductive system during pregnancy, parturition, and lactation. In: Witorsch RJ, ed.

Reproductive Toxicology. 2nd ed. New York, NY: Raven Press, 1995: 175–93.

6. Dawood MY. Nonsteroidal antiinflammatory drugs and reproduction. Am J Obstet Gynecol 1993;169:1255–65.

7. Product information. Ketoprofen. Mylan Pharmaceuticals, 2011.

8. Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: The Johns Hopkins University Press, 1989:364.

9. Lagrange F, Pehourcq F, Bannwarth B, Leng JJ, Saux MC. Passage of S-(+)- and R-(−)-ketoprofen across the human isolated perfused placenta.

Fundam Clin Pharmacol 1998;12:286–91.

10. Labat L, Llanas B, Demotes-Mainard F, Lagrange F, Demarquez JL, Bannwarth B. Accumulation of S-ketoprofen in neonates after maternal administration of the racemate. Fundam Clin Pharmacol 1995;9:62. As cited in Lagrange F, Pehourcq F, Bannwarth B, Leng JJ, Saux MC. Passage of S-(+)- and R-(−)-ketoprofen across the human isolated perfused placenta.

Fundam Clin Pharmacol 1998;12:286–91.

11. Nielsen GL, Sorensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population-based observational study and case-control study.

Br Med J 2001;322:266–70.

12. Ericson A, Kallen BAJ. Nonsteroidal anti-inflammatory drugs in early pregnancy. Reprod Toxicol 2001;15:371–5.

13. Li DK, Liu L, Odouli R. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population-based cohort study.

Br Med J 2003;327:368–71.

14. Tassinari MS, Cook JC, Hurtt ME. NSAIDs and developmental toxicity. Birth Defects Res B Dev Reprod Toxicol 2003;68:3–4.

15. Grignaffini A, Soncini E, Ronzoni E, Lo Cane F, Anfuso S, Nardelli GB. Clinical practice evaluation of combination of atosiban, ritodrine and ketoprofen for inhibiting preterm labor. Minerva Ginecol 2007;59:481–9.

16. Jacqz-Aigrain E, Serreau R, Boissinot C, Popon M, Sobel A, Michel J, Sibony O. Excretion of ketoprofen and nalbuphine in human milk during treatment of maternal pain after delivery. Ther Drug Monit 2007;29:815–8.

17. Lacroix I, Soussan C, Portolan G, Montastruc JL. Drug-induced adverse reactions via breastfeeding: a study in the French Pharmacovigilance Database (abstract 26-01). Fundam Clin Pharmacol 2013;27(Suppl 1): 42–3. doi:10.1111/fep.12025. As cited by National Library of Medicine LactMed Database. Ketoprofen, 2013.

KETOROLAC Nonsteroidal Anti-inflammatory PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 1st and 3rd Trimesters BREASTFEEDING RECOMMENDATION: Contraindicated

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KETOROLAC

PREGNANCY SUMMARY Because ketorolac is a prostaglandin synthesis inhibitor, constriction of the ductus arteriosus in utero and fetal renal impairment are potential complications when multiple doses of the drug are administered during the latter half of pregnancy (1) (see also Indomethacin). Premature closure of the ductus can result in primary pulmonary hypertension of the newborn that, in severe cases, may be fatal (1,2). Other complications that have been associated with nonsteroidal anti-inflammatory drugs (NSAIDs) are inhibition of labor and prolongation of pregnancy. Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including ketorolac, because of the findings in a variety of animal models indicating that these agents block blastocyst implantation (3,4). Moreover, as noted above, NSAIDs have been associated with spontaneous abortions (SABs) and congenital malformations (see also Ibuprofen). The risk for these defects, however, appears to be low.

In a “black box” warning, the FDA stated that ketorolac was contraindicated in labor and delivery because its prostaglandin synthesis inhibitory effect may adversely affect fetal circulation and inhibit uterine contractions.

FETAL RISK SUMMARY Ketorolac is an NSAID indicated for the short-term (≤5 days) treatment of pain. The drug is also available as a solution for ocular pain. Ketorolac is in an NSAID subclass (pyrrolizine carboxylic acid) with no other members.

Ketorolac was not teratogenic in rats (1.0 times the human AUC) and rabbits (0.37 times the human AUC) treated with daily oral doses of the drug during organogenesis. Oral dosing in rats at 0.14 times the human AUC after day 17 of gestation caused dystocia and decreased pup survivability (5).

In a study using chronically catheterized pregnant sheep, an infusion of ketorolac completely blocked the ritodrineinduced increase of prostaglandin F2α, a potent uterine stimulant, in the uterine venous plasma (6,7). The researchers speculated that ritodrine stimulation of prostaglandin synthesis in pregnant uterine tissue might contribute to the tachyphylaxis sometimes observed with the tocolytic agent.

It is not known if ketorolac crosses the human placenta.

The molecular weight (about 376) is low enough that passage to the embryo and fetus should be expected.

A combined 2001 population-based, observational cohort study and a case–control study estimated the risk of adverse pregnancy outcome from the use of NSAIDs (8). The use of NSAIDs during pregnancy was not associated with congenital malformations, preterm delivery, or low birth weight, but a positive association was discovered with SABs. A similar study, also published in 2001, failed to find a relationship, in general, between NSAIDs and congenital malformations, but did find a significant association with cardiac defects and orofacial clefts (9), In addition, a 2003 study found a significant association between exposure to NSAIDs in early pregnancy and SABs (10). (See Ibuprofen for details on these three studies.)

A brief 2003 editorial on the potential for NSAID-induced developmental toxicity concluded that NSAIDs, and specifically those with greater cyclooxygenase 2 (COX-2) affinity, had a lower risk of this toxicity in humans than aspirin (11).

A randomized, double-blind study published in 1992 compared single IM doses of ketorolac 10 mg, meperidine 50 mg, and meperidine 100 mg in multiparous women in labor (12). All patients also received a single dose of prochlorperazine (for nausea and vomiting) and ranitidine for acid reflux. Ineffective pain relief was observed in all three treatment groups, but both doses of meperidine were superior

to ketorolac. Duration of labor was similar among the three groups, as was the occurrence of adverse effects, including maternal blood loss. One-minute Apgar scores were significantly greater in the ketorolac group compared with the meperidine groups, most likely because of the lack of respiratory depressant effects of ketorolac, but this difference was not observed at 5 minutes (12).

A 1997 abstract and later full report described the use of ketorolac for acute tocolysis in preterm labor (13,14).

Women, at ≤32 weeks’ gestation, were randomized to receive either ketorolac (N = 45), 60 mg IM and then 30 mg IM every 4–6 hours, or magnesium sulfate (N = 43), 6 g IV and then 3–6 g/hour IV. Therapy was stopped if 48 hours lapsed, labor progressed (>4 cm), severe side effects occurred, or uterine quiescence was achieved. Ketorolac was significantly better than magnesium sulfate in the time required to stop uterine contractions (2.7 vs. 6.2 hours), but no difference was found between the two regimens for the other parameters (failed tocolysis, birth weight, gestational age at delivery, and neonatal morbidity). There was no difference in the incidence of maternal and neonatal adverse effects between the groups (13,14).

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BREASTFEEDING SUMMARY Ketorolac is excreted into breast milk (15). Ten women, 2–6 days postpartum, were given oral ketorolac, 10 mg four times daily for 2 days. Their infants were not allowed to breastfeed during the study. Four of the women had milk concentrations of the drug below the detection limit of the assay (<5 ng/mL) and were excluded from analysis. In the remaining six women, the mean milk:plasma ratios 2 hours after doses 1, 3, 5, and 7 ranged from 0.016 to 0.027, corresponding to mean milk concentrations ranging from 5.2 to 7.9 ng/mL. Based on a milk production of 400–1000 mL/day, the investigators estimated that the maximum amount of drug available to a nursing infant would range from 3.16 to 7.9 mcg/day (Note: The cited reference indicated 3.16–7.9 mg/day, but this appears to be an error), equivalent to 0.16%–0.40% of the mother’s dose on a weight-adjusted basis. These amounts were considered clinically insignificant (15).

The FDA has placed a “Black Box” warning on ketorolac, stating that drug is contraindicated during breastfeeding because of the potential adverse effects of prostaglandininhibiting drugs on neonates.

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KUDZU

References 1. Levin DL. Effects of inhibition of prostaglandin synthesis on fetal development, oxygenation, and the fetal circulation. Semin Perinatol 1980;4:35–44.

2. Van Marter LJ, Leviton A, Allred EN, Pagano M, Sullivan KF, Cohen A, Epstein MF. Persistent pulmonary hypertension of the newborn and smoking and aspirin and nonsteroidal antiinflammatory drug consumption during pregnancy. Pediatrics 1996;97:658–63.

3. Matt DW, Borzelleca JF. Toxic effects on the female reproductive system during pregnancy, parturition, and lactation. In: Witorsch RJ, ed. Reproductive Toxicology. 2nd ed. New York, NY: Raven Press, 1995:175–93.

4. Dawood MY. Nonsteroidal antiinflammatory drugs and reproduction. Am J Obstet Gynecol 1993;169:1255–65.

5. Product information. Toradol. Roche Laboratories, 2000.

6. Rauk PN, Laifer SA. Ketorolac blocks ritodrine-stimulated production of PGF2α in pregnant sheep (abstract). Am J Obstet Gynecol 1992;166:274.

7. Rauk PN, Laifer SA. The prostaglandin synthesis inhibitor ketorolac blocks ritodrine-stimulated production of prostaglandin F2α in pregnant sheep.

Obstet Gynecol 1993;81:323–6.

8. Nielsen GL, Sorensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory

drugs: population-based observational study and case-control study.

Br Med J 2001;322:266–70.

9. Ericson A, Kallen BAJ. Nonsteroidal anti-inflammatory drugs in early pregnancy. Reprod Toxicol 2001;15:371–5.

10. Li DK, Liu L, Odouli R. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population-based cohort study.

Br Med J 2003;327:368–71.

11. Tassinari MS, Cook JC, Hurtt ME. NSAIDs and developmental toxicity. Birth Defects Res (Part B) 2003;68:3–4.

12. Walker JJ, Johnston J, Fairlie FM, Lloyd J, Bullingham R. A comparative study of intramuscular ketorolac and pethidine in labour pain. Eur J Obstet Gynecol Reprod Biol 1992;46:87–94.

13. Schorr SJ, Ascarelli MH, Rust OA, Ross EL, Calfee EF, Perry KG Jr, Morrison JC. Ketorolac is a safe and effective drug for acute tocolysis (abstract). Am J Obstet Gynecol 1997;176:S7.

14. Schorr SJ, Ascarelli MH, Rust OA, Ross EL, Calfee EL, Perry KG Jr, Morrison JC. A comparative study of ketorolac (Toradol) and magnesium sulfate for arrest of preterm labor. South Med J 1998;91:1028–32.

15. Wischnik A, Manth SM, Lloyd J, Bullingham R, Thompson JS. The excretion of ketorolac tromethamine into breast milk after multiple oral dosing. Eur J Clin Pharmacol 1989;36:521–4.

KUDZU Herb

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PREGNANCY RECOMMENDATION: No Human Data—Probably Compatible BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible

PREGNANCY SUMMARY No studies describing the use of kudzu during animal or human pregnancy have been located. Because the herb has been used as a medicine for more than 2500 years, it is doubtful that it causes developmental toxicity. Moreover, many chemical constituents of kudzu can also be found in foods. Nevertheless, the safest course is to avoid high, frequent doses of the herb or its individual constituents during pregnancy.

FETAL RISK SUMMARY Kudzu, a fast-growing vine native to Japan, China, and Fiji, was introduced to the United States in the late 1800s to control soil erosion. It is well established in moist southern regions and is now considered an invasive pest. In China, kudzu has been used as a medicine since the 6th century BC as therapy for alcoholism, muscular pain, and treatment of measles. Treatment of alcohol hangover, drunkenness, and alcoholism is its primary indications. It also has been used for numerous other indications, none of which have been adequately studied. Kudzu also has been investigated for its antiproliferative activity in some cancers (breast, ovarian, and cervical), its cardiovascular activity for arrhythmia, ischemia, and angina pectoris, and for hepatic protection, hyperlipidemia, and osteogenic activity. Some constituents of kudzu are phytoestrogens and antioxidants (1,2).

The chemical constituents identified from the root, flowers, and leaves include flavonoids, isoflavonoids, and isoflavones. Specific constituents that have been identified include kudzu saponins, robinin, tectoridin, kakkalide, formononetin, biochanin A, plant sterols, and the isoflavones daidzein, daidzin, genistein, genistin, and puerarin. Many of these agents are found in food, such as daidzein and genistein from ­soybeans (1,2).

A long-term study in mice evaluated the fertility and reproductive toxicity of kudzu (3). Toxicity with high daily doses

(100 mg/kg) included prolonged estrous cycles, hyperplasia of the uterine endothelium, and a decrease in the number of growing ovarian follicles. This dose also resulted in a decrease in mating efficiency. The effects were attributed to decreases in the serum concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In contrast, a 10-mg/kg/ day dose induced no changes in the hypothalamic–pituitary– ovarian–uterine axis (3).

BREASTFEEDING SUMMARY No reports describing the use of kudzu during lactation have been located. Because the herb has been used as a medicine for more than 2500 years, it is doubtful that it causes harm during breastfeeding. Moreover, many chemical constituents of kudzu can also be found in foods. Nevertheless, nursing women should avoid high, frequent doses of the herb or its individual constituents.

References 1. Kudzu. In: The Review of Natural Products. St. Louis, MO: Wolters Kluwer Health, 2008.

2. Kudzu. In: Natural Medicines Comprehensive Database. 10th ed. Stockton, CA: Therapeutic Research Faculty, 2008:890–3.

3. Jaroenporn S, Malaivijitnond S, Wattanasirmkit K, Watanabe G, Taya K, Cherdshewasart W. Assessment of fertility and reproductive toxicity in adult female mice after long-term exposure to Pueraria mirifica herb. J Reprod Dev 2007;53:995–1005.

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KUNECATECHINS

KUNECATECHINS Dermatologic Agent PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Low Risk BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible

PREGNANCY SUMMARY No reports describing the use of kunecatechins ointment in human pregnancy have been located. The animal reproductive data suggest low risk, but the absence of human pregnancy experience prevents a complete assessment of the embryo– fetal risk. Kunecatechins is a water extract of green tea leaves. Moderate consumption of green tea during pregnancy is thought to be safe (1). If the recommended dose and directions are followed, the risk for an embryo or fetus appears to be low, if it exists at all.

FETAL RISK SUMMARY Kunecatechins is a partially purified fraction of the water extract of green tea leaves [Camellia sinensis (L.) O Kuntze].

It is a mixture of eight catechins (85%–95% of the total weight) and other green tea components (about 2.5% of the total weight) including gallic acid, caffeine, and theobromine. It is available as a 15% ointment that is applied three times daily for a maximum of 16 weeks. The systemic absorption of repeated topical administration of kunecatechins has not been adequately studied but is thought to be less than that obtained after a single oral intake of 400 mL of green tea. Kunecatechins is indicated for the topical treatment of external genital and perianal warts (Condylomata acuminata) in immunocompetent patients 18 years and older. Treatment of urethral, intravaginal, cervical, rectal or intra-anal human papilloma viral disease has not been evaluated and the ointment should not be used for these conditions (2).

Reproductive studies have been conducted in rats and rabbits. Comparisons, based on body weight, were made based on the maximum recommended human dose of the ointment (250 mg three times daily; 750 mg of the ointment or 125.5 mg kunecatechins per day) (MRHD). During organogenesis, daily oral doses in rats and rabbits of ≤86 and ≤173 times, respectively, the MRHD revealed no effects on embryo or fetal development or teratogenicity. In rabbits during organogenesis, daily SC doses that were about 2.1 and 6.3 times the MRHD caused maternal toxicity (marked local irritation at the injection site and decreased body weight and food consumption) and fetal toxicity (reduced body weights and delayed skeletal ossification). The no-effect dose for fetal toxicity was 0.7 times the MRHD. In a combined fertility/ embryo–fetal development test, female rats were given daily

vaginal doses of the ointment that were ≤8 times the MRHD from day 4 before mating through day 17 of gestation. No adverse effects on mating performance or fertility or on the embryo–fetus were observed (2).

Carcinogenicity studies were conducted in mice with daily doses ≤22 times the MRHD for 26 weeks. There was an increased incidence of either neoplastic or non-neoplastic lesions in the organs and tissues examined. In mutagenicity tests, four assays were negative and one was positive (2).

It is not known if the major components (i.e., catechins) of kunecatechins cross the human placenta. The molecular weights of the eight catechins are varied but are <500 and would be expected to cross the placenta. However, systemic concentration of kunecatechins is thought to be low.

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BREASTFEEDING SUMMARY No reports describing the use of kunecatechins ointment during lactation have been located. It is not known if the major components (i.e., catechins) of kunecatechins are excreted into breast milk. The molecular weights of the eight catechins are varied but are <500 and would be expected to pass into milk. However, systemic concentrations of kunecatechins are thought to be low. Moreover, kunecatechins is a water extract of green tea leaves. Moderate consumption of green tea during breastfeeding is thought to be safe (1). If the recommended dose and directions are followed, the risk for a nursing infant appears to be low, if it exists at all.

References 1. Green tea. In: Jellin JM, ed. Natural Medicines Comprehensive Database.

10th ed. Stockton, CA: Therapeutic Research Faculty, 2008:733–43.

2. Product information. Veregen. Doak Dermatologics, 2006.

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