DRUG INTERACTIONS.qxd 11/30/15 2:38 PM Page a The 2016 Handbook of P s y c h o t r o p i c D r u g Provided as an Educational Service by Glaxo SmithKline I n t e r a c t i o n s Pharmaceuticals C. Lindsay DeVane, PharmD Charles B. Nemeroff, MD, PhD ® Copyright ©2016 MedWorks Media Inc. Los Angeles, CA. All Rights Reserved DRUG INTERACTIONS.qxd 11/30/15 2:38 PM Page 2 Disclaimer This pocket re f e r ence is provided ®aPsyschia trya’s Number One Circulation service to medicine by the Portugese DivisionP u b l i c a t i o n of SmithKline Beecham Pharm a c e u t i c a l s . Sponsorship of this review does not imply the sponsor’s agreement with the views expressed herein. The 2016 Although every effort has been made to ensure that drug doses and other information are presented accurately in this Handbook of publication, the ultimate responsibility rests with the prescribing physician. Neither the publishers, the sponsor, nor the authors can P s y c h o t ro p i c be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are D ru g s t r ongly urged to consult any relevant primary literature. No claims or endorse- ments are made for any drug or compound I n t e r a c t i o n s currently under clinical investigation. Copyright ©2016, M e d Works Media Inc. All rights reserved, including the right of reproduction, in C. Lindsay DeVane, PharmD whole or in part, in any form. Charles B. Nemeroff, MD, PhD First Published in: D r. DeVane is professor of psychiatry and behavioral sciences at the Medical University of South Carolina in Charleston. Dr. Nemero ff is the Reunette W. Harris Professor and chairman of the Department of P s y c h i a t r y and Behavioral Sciences at Emory University School of Medicine in Atlanta, GA. No financial, academic, or other support of this work was acknowl- edged by the authors. C N S D r u g - D r ug Interactions Handbook • 2016 3 DRUG INTERACTIONS.qxd 11/30/15 2:38 PM Page 4 C o n t e n t s Index of Tables and Figure s INTRODUCTION 6 Major Components of Drug Disposition 10 CLASSIFICATION OF DRUG INTERACTIONS 7 Drug Elimination Sites During Absorption 12 Pharmacodynamic Drug Interactions 8 Protein Binding: Equilibrium of Drugs 14 Pharmacokinetic Drug Interactions 9 Recent Developments Relevant to Psychotropic Interactions Involving Absorption 9 Drug Interactions 40 Interactions Involving Distribution Major Psychotropic Drugs and Protein Binding 11 by Generic and Trade Name 40 Interactions Involving Metabolism Selected Drugs with Oxidative Metabolism Associated with CYP Enzymes 42 and/or Elimination 13 Selected Drugs with Conjugative Metabolism PREDICTION OF METABOLIC DRUG INTERACTIONS 15 Associated with Glucuronosyltransferase Enzymes 43 CYTOCHROME P-450 (CYP) ENZYMES 16 Questions/Issues to Consider in Interpreting CYP 1A2 17 Case Reports of Suspected Drug Interactions 43 CYP 2A 18 TCA Drug Interactions 44 CYP 2B 18 Newer Antidepressants and CYP 2C9/19 19 CYP Enzyme Inhibitory Potential 44 CYP 2D6 19 SSRI Drug Interactions 46 CYP 2E 20 Bupropion Drug Interactions 48 CYP 3A4 21 Nefazodone Drug Interactions 48 GLUCURONOSYLTRANSFERASES 22 Mirtazapine Drug Interactions 48 SPECIFIC DRUG INTERACTIONS 23 Venlafaxine Drug Interactions 50 Tricyclic Antidepressants 23 St. John’s Wort Drug Interactions 50 Selective Serotonin Reuptake Inhibitors 24 MAOI Drug Interactions 52 Other Newer Antidepressants 26 Lithium Drug Interactions 52 Monoamine Oxidase Inhibitors 27 Carbamazepine Drug Interactions 54 Lithium 28 Oxcarbazepine Drug Interactions 54 Other Mood Stabilizers 29 Valproate Drug Interactions 56 Psychostimulants 31 Lamotrigine Drug Interactions 56 Anxiolytics/Hypnotics 32 Topiramate Drug Interactions 56 Antipsychotic Agents 32 Methylphenidate Drug Interactions 58 Cholinesterase Inhibitors 34 Modafinil Drug Interactions 58 Anorectic/Anti-Obesity Agents 35 Benzodiazepine Drug Interactions 58 Methadone 36 Buspirone Drug Interactions 60 CONCLUSIONS 36 Phenothiazine Drug Interactions 60 BIBLIOGRAPHY 37 Zolpidem Drug Interactions 62 NOTES 70 Haloperidol Drug Interactions 62 Clozapine Drug Interactions 62 Risperidone Drug Interactions 64 Olanzapine Drug Interactions 64 Quetiapine Drug Interactions 66 Ziprasidone Drug Interactions 66 Selected Cholinesterase Inhibitors Drug Interactions 66 Selected Anorectic/Anti-Obesity Agents Drug Interactions 68 Selected Methadone Drug Interactions 68 4 5 DRUG INTERACTIONS.qxd 11/30/15 2:38 PM Page 6 Introduction tion of ziprasidone reflects the high level of activity in The present 2007 Guide to Psychotropic Dosing d r ug development for treatment of psychotic condi- Interactions is an update of the past edition. Since the tions. Additional new drugs in this category are cur- appearance of the 2004 Guide, new psychotropic dru g s rently being tested in clinical trials. Each of these com- have been introduced which have specific data related to pounds possesses a certain potential to interact with their potential drug interactions. Documentation contin- other drugs. This is especially true since psychoactive ues to appear at a steady pace in the literature of dru g d r ugs are generally highly metabolized compounds. interactions with commonly used psychotropics. As this L a b o r a t o r y methodologies developed in recent years guide is intended to serve an educational role for the psy- can identify the specific enzymes mediating various chiatrist-in-training, as well as non-psychiatric physicians metabolic pathways. This information can be used to less familiar with interactions of psychoactive drugs, the p r edict how a new drug will interact pharm a c o k i n e t i - bulk of the background discussion on drug metabolism cally with a variety of other drugs already marketed. and mechanisms of drug interactions remains unchanged. Some background knowledge of major dru g - m e t a b o l i z - For the repeat re a d e r, we have summarized import a n t ing enzymes is helpful in understanding how these pre- new findings on drug interactions appearing since the dictions are made. Of course, in vitro predictions must last update in Table 1. The interactions of three new psy- be confirmed with in vivo studies, but supporting clini- choactive drugs introduced recently to the market cal data may not be available for months or years. (oxcarbazepine, modafinil, and ziprasidone) are covere d This guide summarizes psychotropic drug interac- in Tables 17, 22, and 32. Other additions in the tables tions from several viewpoints. First, examples of phar- reflect new case re p o rts and further documentation of macokinetics will be discussed to aid the reader in d rug interactions. understanding how drugs may interact during the New knowledge related to the benefits of psychiatric course of their absorption and elimination from the d rug treatment results in earlier initiation of drug ther- b o d y. Secondly, because many interactions with psy- apy for some psychiatric disorders, and maintenance c h o t ropic drugs occur via specific interactions with the therapy is more and more commonplace during CYP system, this hepatic enzyme system will be asymptomatic periods. In fact, maintenance therapy described and the most important enzymes involved in for affective anxiety and psychotic disorders, often the metabolism or interactions of psychoactive dru g s continuing for years or decades, is now the accepted will be discussed. Some principles of drug interactions s t a n d a rd of care, especially for patients with a history operating through competitive inhibition of hepatic of re c u r rent episodes of illness. Long-term pharm a - enzymes will be explained, so that the reader may cotherapy re q u i res awareness and management of make informed judgments about the possibility of d rug interactions. an interaction. As the population ages, more drugs are prescribed on The bulk of the guide will be concerned with dru g a chronic basis for maintenance of health without tre a t- interactions that have been described with specific psy- ment of overt symptoms. Increasing numbers of patients choactive drug classes. The degree of documentation take one of the serum lipid-lowering compounds fro m varies for many interactions from theoretical conjec- the class of 3-hydroxy- 3-methylglutaryl co-enzyme A t u re, to clinical experience with patients, to well-estab- reductase inhibitors. These drugs can be taken for pri- lished re s e a rch outcomes. The sources of interaction m a ry prevention, re g a rdless of whether or not the patient data will be noted to help identify the appropriate level has previously experienced a vascular event such as a of confidence in the predicted consequences of com- m y o c a rdial infarction or stroke. With the exception of bining drugs in therapy. When possible, specific man- pravastatin, the drugs in this class are highly metabo- agement guidelines are provided to avoid or minimize lized by cytochrome P450 (CYP) 3A4, a hepatic enzyme some potentially negative interactions. The major psy- whose action can be inhibited by several antidepre s- choactive drugs, classified according to their primary sants. As will be explained later, some knowledge of how therapeutic indication, are listed in Table 2. Subsequent the major antidepressants interact with specific liver tables will list important drug interactions for each of enzymes allows the choice of an antidepressant that these classes. avoids such potential dru g - d rug interactions. New drugs to treat psychiatric illness have been Classification of Drug Interactions i n t roduced to clinical practice in recent years.