Drugs and Laboratory Parameters E-Book

Giuseppina Fava

• Herausgeber: SEEd Edizioni Scientifiche
• Kategorie: Fachliteratur
• Sprache: Englisch

Veröffentlichungsjahr: 2010

Beschreibung

Even if clinical and laboratory parameters can be considered as predictors for ADRs, the possibility of a drug-related variation of blood tests is seldom taken into consideration. Aim of this easy-to-read book is to help physicians in the routine interpretation of laboratory results, drawing their attention to the possibility that abnormal laboratory results may be drug-related. The book describes the most common variations (increase/decrease) of blood parameters that can be caused by drugs intake. Functions of each blood parameter are schematically reported, together with its standard blood concentration and a list of the most common disease for whose diagnosis that test is performed. Active principles are then listed, that can cause an increase or a decrease of that parameter.

Leseprobe

Drugs and Laboratory Parameters

Achille Patrizio Caputi, Giuseppina Fava

Colophon

© SEEd srl

Piazza Carlo Emanuele II, 19 – 10123 Torino – Italy Tel. [phone] – Fax [email protected]

Drugs and Laboratory Parameters

Title of original Italian edition “Farmaci e parametri chimico-clinici” by Achille Patrizio Caputi, Giuseppina Fava

First edition

September 2010

ISBN 978-88-8968-855-7

Although the information about medication given in this book has been carefully checked, the author and publisher accept no liability for the accuracy of this information. In every individual case the user must check such information by consulting the relevant literature.

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the Italian Copyright Law in its current version, and permission for use must always be obtained from SEEd Medical Publishers Srl. Violations are liable to prosecution under the Italian Copyright Law.

Preface to the English Edition

Adverse drug reactions (ADR) are inevitable consequences of pharmacotherapy. The identification of a possible adverse event is the first step in a diagnosis of ADR. It is simpler to identify visible and symptomatic events, such as those affecting skin, than asymptomatic ones, as are usually changes in laboratory values. In addition, while skin could be considered as a classic system affected by ADRs, laboratory value changes are intrinsically more ambiguous, and may be less easy to recognise as being related to a drug treatment.

Most marketed drugs may cause a wide range of modifications to laboratory values that are mostly non-specific, and these may also be associated to a complication of the treated disease (e.g. diuretic-induced nephropathy vs. hypertensive nephropathy). Certain ADRs, however, may be expected in view of the drug indication. This is the case of medication acting on coagulation, such as warfarin or other vitamin K antagonists, which are expected to cause changes in laboratory parameters that could become severe, symptomatic, and even fatal if not adequately monitored. Therefore anomalies have every chance to be identified and managed. On the other hand, most medications do not require monitoring via periodic laboratory tests, and the identification of anomalous values, as well as differential diagnosis with other non-pharmacological causes could be more difficult.

In daily practice, clinicians prescribing drugs have in mind efficacy before safety. Even for a clinical pharmacologist, it is impossible to remember all the ADRs associated with a single drug. For this reason, tools supporting the daily activities of clinicians are needed, and this book moves in this direction. Whereas most books on ADRs and drug dictionaries go from the drug to the symptom or ADR, this book may be used when faced with a laboratory test anomaly to rapidly identify what drugs may have or are known to be associated with this anomaly, thereby facilitating patient management. The inclusive nature of the information, collected from an overview of well-recognised data-sources concerning ADRs, and its layout make this book unique in terms of quality and, more importantly, utility for clinicians, helping them easily find information for the best management of their patients.

Dott. Francesco Salvo. Department of Pharmacology, University of Messina, Messina, Italy

Prof. Nicholas Moore. Department of Pharmacology, University of Bordeaux, Bordeaux, France

Foreword

During the last decade the importance of pharmacovigilance has increasingly grown. The word “pharmacovigilance” was proposed in the first half of the 1970s by a group of French pharmacologists and toxicologists to define all the activities aiming at promoting the “evaluation of the risk of adverse events potentially associated with drug administration.”

The first step of pharmacovigilance is signal generation, i.e., the process that can identify possible new adverse drug reactions (ADRs). After a signal has been identified, other steps are required to confirm or repudiate the signal:

hypothesis testing, i.e., processes that determine whether the signal does indeed indicate a new ADR, or whether it is false;hypothesis strengthening and preliminary evaluation of available data;evaluation, examination, and explanation of the signal.

Detection of ADRs is extremely important, since they represent a major health problem with many clinical consequences and high economic and social burdens. Unfortunately, in everyday practice there is a wide variation of potential risk factors associated with ADRs, and their recognition is still challenging. Signal detection based on spontaneous reporting is, in our opinion, absolutely essential, because it may generate rapid alerts and stimulate follow-up.

Even if ADRs are often associated with hypersensitivity reactions, clinical and laboratory parameters can also be considered as predictors for ADRs. A signal can therefore arise from abnormal results of diagnostic tests; these tests represent qualitative and quantitative descriptions of the physical-chemical state of the analysed system and its components, allowing diagnosis, follow-up, screening, and response to drug administration.

Nonetheless the possibility of a drug-related variations of blood tests is seldom taken into consideration. The aim of this easy-to-read book is to help physicians in their routine interpretation of laboratory results, drawing their attention to the possibility that abnormal results may be drug-related.

The book describes the most common variations (increase/decrease) of blood parameters that can be caused by drug intake; such variations are classified on the basis of diagnostic criteria (organ/disease). Data have been derived and adapted mainly from three reference books [Bonardi 1995, Burlina 1987, and Covelli 2001], which, despite their publication dates, still represent authoritative references in this field. Other books have been consulted [Fava 2005, Federici 2003, and Nespoli 1975], and all the data have been updated on the basis of findings in the literature (i.e., articles published on PubMed) and dedicated websites (e.g., www.farmacovigilanza.org, www.micromedex.com, and www.RxList.com).

The functions of each blood parameter are schematically reported, together with the standard blood concentration and a list of the most common diseases for whose diagnosis that test is performed. Active principles are then listed, which can cause an increase or a decrease in that parameter. Standard concentrations here reported are taken from the reference books previously cited; it is essential, however, to remember that each laboratory fixes its own standard concentrations, and that therefore they may not correspond exactly with those reported here. The book concludes with two indexes, allowing research on both parameters and drugs.

This text is not intended as an exhaustive reference; it is quite impossible to obtain a complete list of all the parameters and all the drugs potentially responsible for variations, because of objective difficulties in finding material about this topic. The book’s main purpose is to provide an overview of the most common drugs potentially responsible for unexpected laboratory results, giving clinicians an insight into the risk of drug interference in laboratory testing.

References

Bonardi R, Deambrogio V, Oliaro A (1995). Interpretazione dei dati di laboratorio. Turin: Minerva Medica.Burlina A (1987). Guida clinica all’esame di laboratorio. Turin: C.G. Edizioni Medico Scientifiche.Covelli I, Spandrio L, Zatti M, Lechi C, Nani E (2001). Medicina di laboratorio. Milan: Edizioni Sorbona.Fava G, Russo A (2005). Alterazioni dei parametri di laboratorio indotte da farmaci. Leghorn: Mb & Care.Federici G (ed.) (2003). Medicina di laboratorio. Milan: McGraw-Hill.Nespoli M (1975). Tabelle delle costanti chimico-fisiche e di diagnostica funzionale di laboratorio. Milan: Ferro.

Introduction

Drug Interference with Laboratory Tests

Biochemical laboratory activity can dramatically influence decision making: 60-70% of all critical decisions, such as admittance, discharge, and medication, are based on laboratory results [Forsman 1996]. As a consequence, the correct interpretation of laboratory data is extremely important [Plebani 2002]. A laboratory test is a qualitative, semiquantitative, or quantitative procedure that aims at detecting the presence or measuring the amount of a biochemical constituent in a biological material, performed to aid in the prevention, diagnosis, or therapy of a disease.

Qualitative tests can be divided into three classes, on the basis of their use [Poltronieri 2001]:

screening tests, usually used on a large level to point out the presence of a risk factor or a disease in the population;

diagnostic tests, used in the diagnosis of specific diseases, based on the presence of clinical findings;

confirmation tests, used to confirm screening or diagnostic tests previously performed.

The analytical process (from sample collection to results analysis) is complex and consists in a series of correlated steps, including different phases; each phase shows different variability characteristics and is potentially able to result in an error [Plebani 2006]. Particularly, three main phases can be identified: pre-, intra-, and postanalytical phases. The evaluation of the beginning and end of the cycle reveals that at the moment the pre- and postanalytical phases are the ones mainly associated with errors, compared to the intra-analytical one [Stroobants 2003].

Furthermore, in the preanalytical phase a pre-preanalytical phase can be identified, concerning procedures that are not performed in the clinical laboratory and that are not under the direct control of the laboratory staff. This step starts with the request for a test, followed by the patient’s identification; the collection, identification, and management of the sample; and eventually the transport of the sample to the laboratory. The results of many studies show the importance of this pre-preanalytical phase.

In almost all countries the incorrect use of the laboratory for inappropriate requests for diagnostic tests is submitted to serious evaluation for its impact on total costs and the increased risk of harm and errors. Very different estimates have been made about this misuse: from 5% of urine tests to 95% of microbiological tests, and from 17.4% of cardiac enzyme tests to 55% of exams of the thyroid [Silverstein 2003].

The continual introduction of new drugs in clinical practice creates dramatic problems, at the moment difficult to solve, because of the positive or negative influence of the drugs themselves. Besides the preanalytical causes (variables preceding sample collection that influence a test’s accuracy) there is pharmacologic interference [Covelli 2001]. In fact, the results of routine blood tests are influenced by the adverse reactions of many endocrine and exocrine components [Kazmierczak 2000]. For example, it has been estimated that in patients taking two or more drugs, test results are influenced by 7% and 16.6%, respectively [Kroll 1994].

Interferences can manifest themselves directly or indirectly at an analytical level. To begin with, they can not always be prevented, because of the great number of individual variables that can affect adsorption, metabolism, and elimination of the drug. Secondary toxic effects can be due both to overdose and to an unpredictable degree of binding of the drug to receptor sites in target organs or in metabolism and excretion districts which are functionally different depending on their integrity.

Adverse events are not well known for all the marketed drugs, nor are possible analytical interferences always analyzed and pointed out. Despite these trends and the results obtained currently, the adequate preparation of the patient prior to blood tests should include avoiding, for the longest period possible before the test, any pharmacologic treatment, with of course the exception of essential drugs (the so-called life-saving drugs).

For example, the prolonged administration of oral contraceptives can cause an increase of glycaemia, with changes in the glucose tolerance curve and subsequent increases of insulin, human growth hormone, cortisol, and thyroxine; oral contraceptives are also responsible for the increase of cholesterol and blood coagulation factors (I, VIII, IX, X), and of the decrease of antithrombin III [Covelli 2001].

Special attention should be paid as well to substance abusers (e.g., amphetamines, morphine, heroin, cannabis), that induce variations of many biological parameters. Intramuscular treatments, especially if repeated, can, independently from the injected drug, cause temporary but consistent increases of some enzymatic activities by the release of proteins from damaged muscular cells.

Pharmacologic interferences can have different causes:

biopharmacologic and metabolic causes;

physical causes; and

chemical (analytical) causes.

Biopharmacologic and metabolic causes implicate a complex mechanism, which often involves not only the drug itself, but also its metabolites. For example, diuretics and some steroids change the concentration of electrolytes in biological liquids; heparin decreases the secretion of aldosterone; phenotiazines and mono-amino oxidase inhibitors (I-MAO), and other drugs with hepatotoxic potential, cause a variation of alkaline phosphatase. Physical-chemical causes may result in an interference with the analytical process because the drug, or its metabolite, reacts with the analyte; or it may interfere with the chemical reactions involved in the analytical process.

Drug interference in the analytical process can be expressed through different mechanisms, such as drug-analyte interaction, drug-reagent interaction, or interaction between drug and techniques of measurement. The effect of this interference can consist in false-positive results (abnormally too high) or false-negative results. Pharmacologic interference should be distinguished from pharmacologic interaction. While the first occurs outside the organism, the second takes place inside the body.

Pharmacologic interactions can be divided into:

pharmacokinetics: which interact with absorption, distribution, metabolism, and excretion processes; and

pharmacodynamics: which arise from the mechanism of action of the drugs in their target site.

Interactions are extremely important, and given that their severity varies from one patient to another, they should be taken into account especially in at-risk patients, such as the elderly or patients with renal or hepatic failure. Drugs with a small therapeutic index (e.g., phenytoin) and those that need dosage monitoring (e.g., anticoagulants, antihypertensives, hypoglycemic agents) are often involved.

Drug-induced electrolyte abnormalities are very frequent and can involve both sodium and potassium; furthermore, herbal remedies, interacting with drugs, can cause changes in laboratory parameters. Such remedies can affect laboratory tests by three different mechanisms [Dasgupta 2006]:

direct assay interference, most commonly with the immunoassays, due to cross-reactivity of a component or components present in the preparation. For example, a falsely elevated digoxin level may be observed using the fluorescence polarization immunoassay (FPIA) for digoxin due to ingestion of the Chinese medicines Chan Su, Lu-Shen-Wan, or Dan Shen;

physiologic effects either through toxicity or enzyme induction due to an herbal product. For example, kava-kava causes liver toxicity; and elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin concentrations may be observed in healthy individuals taking kava-kava;

effects of contaminants, since an herbal product may contain undisclosed drugs; and an unexpected drug level (such as phenytoin in a patient who never took phenytoin but took a Chinese herb) may confuse the laboratory staff and the clinician.

It is essential to distinguish biochemical variations caused by drugs, from those caused by a pathological injury. To treat the former it could be sufficient to avoid some substances, while the others need a medical or a surgical treatment.

An Example: Drug-Induced Thrombocytopenia

One of the complications that can usually be connected to drug consumption is thrombocytopenia, defined as a platelet count greater than 150,000/mm3. In an article published in the New England Journal of Medicine, Aster and colleagues wrote: “Drug-induced thrombocytopenia can be caused by dozens, perhaps hundreds, of medications. Because thrombocytopenia can have many other causes, the diagnosis of drug-induced thrombocytopenia can easily be overlooked. On occasion, outpatients with drug-induced thrombocytopenia are treated for autoimmune thrombocytopenia and can have two or three recurrences before the drug causing the disorder is identified. In acutely ill, hospitalized patients, drug-induced thrombocytopenia can be overlooked because thrombocytopenia is attributed to sepsis, the effect of coronary-artery bypass surgery, or some other underlying condition. Although drug-induced thrombocytopenia is uncommon, it can have devastating, even fatal consequences that can usually be prevented simply by discontinuing the therapy. It is therefore essential that clinicians have a general knowledge of this disease and of the drugs that can cause it” [Aster 2007].

Even if heparin-induced thrombocytopenia is the most common cause of a decrease of platelet count associated with drug intake, it is often undertreated because of its complexity, and because thrombosis, and not thrombocytopenia, represents the main risk in those patients. Given that heparin is often prescribed in association with drugs that can cause thrombocytopenia (vancomycin and platelet inhibitors), it is important to distinguish between heparin-induced and drug-induced thrombocytopenia. Drug-induced platelet destruction is usually caused by a drug-induced antibody, but this is difficult to prove. Although platelets are antibodies’ favourite target, drugs can cause immune haemolytic anemia [Arndt 2005] and neutropenia [Stroncek 1993] following similar mechanisms.

Quinine, which is nowadays rarely used as an antimalaric agent, but is often prescribed for night muscle cramps, can still be an active agent. People of either sex and every age can be affected. Usually, a patient may take the inducing drug for a week, or discontinuously for a longer period, before showing haemorrhagic petechiae and ecchymosis, which are clear symptoms of thrombocytopenia. If the drug is discontinued, symptoms usually disappear in one or two days, and in less than a week platelet count is in the standard range.

Rare but convincing examples are described of thrombocytopenia induced by herbal remedies [Arnold 1998, Azuno 1999] and food [Lavy 1964]; and acute, severe thrombocytopenia has been seen many times after the administration of intravenous radiocontrast containing iodine [Warkentin 2005, George 1998]. It is unknown if immune mechanisms are involved.

Drug class

Drugs involved in more than 5 signallings

Other drugs

Heparins

Unfractionated heparins, low-molecular weight heparins

Cinchona alkaloids

Quinine, quinidine

Platelet inhibitors

Abciximab, eptifibatide, tirofiban

Antirheumatic agents

Gold salts

D-penicillamine

Antimicrobial agents

Linezolid, rifampicin, sulphonamides, vancomycin

Sedatives and anticonvulsants

Carbamazepine, phenytoin, valproic acid

Diazepam

Antagonists of histamine receptors

Cimetidine

Ranitidine

Diuretics

Chlorothiazide

Hydrochlorothiazide

Chemioterapy drugs and e immunosuppressant

Fludarabine, oxaliplatin

Ciclosporin, rituximab

Analgesics

Paracetamol, diclofenac, naproxen

Ibuprofen

Table I. Drugs causing thrombocytopenia [Iaccarino, 2008]

Some products, such as the antiepileptic agent valproic acid [Trannel 2001], the cardiovascular agent amrinone [Ross 1993], and the antibody linezolid [Attassi 2002] induce a low degree of thrombocytopenia in more than 30% of patients receiving long-term treatments; the mechanism of action is not fully understood. The decrease in platelet count is rarely so severe as to require treatment.

Although chemotherapy and immunosuppressive medications typically cause thrombocytopenia by hematopoiesis suppression, they can also induce immune-thrombocytopenia [Curtis 2006]. Drug-induced thrombocytopenia should be suspected, therefore, in patients treated with those drugs and is often neglected in severely ill conditions where it can be associated with other causes [Von Drygalski 2007].

Drug-induced thrombocytopenia, like many other hypersensitivity reactions, affects only a small percentage of the patients that consume the drugs that can cause this disease. Neither genetic nor environmental predispositions have been associated with it; animal models are not available. Drug-induced thrombocytopenia should be suspected in every patient with acute thrombocytopenia of unknown origin. In adults, severe thrombocytopenia (greater than 20,000 platelets/mm3) increases the probability of drug-induced thrombocytopenia, and this disease should be strongly suspected in every patient with a history of acute transitory thrombocytopenia. Because sometimes patients do not report drugs consumption, an adequate anamnesis is essential [Reddy 2004].

Many patients with drug-induced thrombocytopenia have only haemorrhagic petechiae and occasionally ecchymosis, and do not require specific treatments except for the discontinuation of the inducing drug. If the inducing drug is uncertain, equivalents should be substituted for all the prescribed drugs, depending on the patient’s needs.

Once diagnosed, the hypersensitivity to the drug persists indefinitely. Therefore, patients should be warned to permanently avoid that drug. Fortunately, drug-induced antibodies tend to be specific for the inducing drug [Christie 1984], and patients usually tolerate pharmacologic equivalents, especially those with similar structure.

References

Arndt PA, Garratty G (2005). The changing spectrum of drug-induced immune hemolytic anemia.

Semin Hematol

; 42: 137-44.

Arnold J, Ouwehand WH, Smith GA, Cohen H (1998). A young woman with petechiae.

Lancet

; 352: 618.

Aster RH, Bougie DW (2007). Drug-induced immune thrombocytopenia.

N Engl J Med

; 357: 580-7.

Attassi K, Hershberger E, Alam R, Zervos MJ (2002). Thrombocytopenia associated with linezolid therapy.

Clin Infect Dis

; 34: 695-8.

Azuno Y, Yaga K, Sasayama T, Kimoto K (1999). Thrombocytopenia induced by Jui, a traditional Chinese herbal medicine.

Lancet

; 354: 304-5.

Christie DJ, Weber RW, Mullen PC, Cook JM, Aster RH (1984). Structural features of the quinidine and quinine molecules necessary for binding of drug-induced antibodies to human platelets.

J Lab Clin Med

; 104: 730-40.

Covelli I, Spandrio L, Zatti M, Lechi C, Nani E (2001). Medicina di laboratorio. Milan: Edizioni Sorbona.

Curtis BR, Kaliszewski J, Marques MB, Saif MW, Nabelle L, Blank J et al (2006). Immune-mediated thrombocytopenia resulting from sensitivity to oxaliplatin.

Am J Hematol

; 81: 193-8.

Dasgupta A, Bernard DW (2006). Herbal remedies: effects on clinical laboratory tests.

Arch Pathol Lab Med

; 130: 521-8.

Forsman RW (1996). Why is the laboratory an afterthought for managed care organizations?

Clin Chem

; 42: 813-6.

George JN, Raskob GE, Shah SR, Rizvi MA, Hamilton SA, Osborne S et al (1998). Drug-induced thrombocytopenia: a systematic review of published case reports.

Ann Intern Med

; 129: 886-90.

Iaccarino P (2008). Farmaci che inducono piastrinopenia. Un esempio: l’eparina. Available at:

http://www.farmacovigilanza.org

.

Kazmierczak SC, Catrou PG (2000). Analytical interference-more than just a laboratory problem.

Am J Clin Pathol

; 113: 9-11.

Kroll MR, Elin RJ (1994). Interferences with clinical laboratory analysis.

Clin Chem

; 40: 1996-2005.

Lavy R (1964). Thrombocytopenic purpura due to lupinus termis bean.

J Allergy Clin Immunol

; 35: 386-9.

Plebani M (2002). Charting the course of medical laboratories in a changing environment.

Clin Chim Acta

; 319: 87-100.

Plebani M (2006). Errors in clinical laboratories or errors in laboratory medicine?

Clin Chem Lab Med

; 44: 750-9.

Poltronieri F (2001). La valutazione dei metodi di analisi qualitativi utilizzandole linee guida contenute nel documento NCCLS EP12-P “User protocol for evaluation of qualitative test performance; Proposed guideline.”

Riv Med Lab

; 2: S1.

Reddy JC, Shuman MA, Aster RH (2004). Quinine/quinidine-induced thrombocytopenia: a great imitator.

Arch Intern Med

; 164: 218-20.

Ross MP, Allen-Webb EM, Pappas JB, McGough EC (1993). Amrinone-associated thrombocytopenia: pharmacokinetic analysis.

Clin Pharmacol Ther

; 53: 661-7.

Silverstein MD (2003). An approach to medical errors and patient safety in laboratory services. A white paper. Atlanta: The Quality Institute Meeting.

Stroncek DF (1993). Drug-induced immune neutropenia.

Transfus Med Rev

; 7: 268-74.

Stroobants AK, Goldschmidt HM, Plebani M (2003). Error budget calculations in laboratory medicine: linking the concepts of biological variation and allowable medical errors.

Clin Chim Acta

; 333: 169-76.

Trannel TJ, Ahmed I, Goebert D (2001). Occurrence of thrombocytopenia in psychiatric patients taking valproate.

Am J Psychiatry

; 158: 128-30.

Von Drygalski A, Curtis BR, Bougie DW, McFarland JG, Ahl S, Limbu I et al (2007). Vancomycin-induced immune thrombocytopenia.

N Engl J Med

; 356: 904-10.

Warkentin TE (2005). Thrombocytopenia due to platelet destruction and hypersplenism. In: Hoffman R, Benz EJ Jr, Shattil SJ (ed.). Hematology: basic principles and practice. Philadelphia: Elsevier; pp. 2305-25.

Diagnostic Tests for Cardiovascular Diseases

Aldolase (ALD)

Aspartate aminotransferase (AST)

Creatine phosphokinase (CPK)

Fibrinogen

Glycaemia

Haptoglobin

HDL cholesterol

Insulin

Lactic dehydrogenase (LDH)

LDL cholesterol

Lipids (faeces)

Triglycerides

Aldolase (ALD)

Enzyme that can be found in a lot of tissues. Its function consists in the cleavage of fructose diphosphate in two triose phosphates.

Dosage required to confirm or suspect of

Acute hepatitis

Carcinoma

Dermatomyositis

Muscular dystrophy

Myocardial infarction

Myopathy

Standard concentrations

1.3-8.2 U/l

Variations

Concentration increased by

CortisolLabetalol

Concentration decreased by

—

Aspartate aminotransferase (AST)

Aspecific enzyme, present not only in the liver, but also in the myocardium, in the skeletal musculature, in renal tissues and in the red blood cells.

Dosage required to confirm or suspect of

Cholestatic icterus

Haemopathy

Hepatopathy

Infectious mononucleosis

Liver carcinoma

Liver cirrhosis

Liver metastases

Myocardial infarction

Myopathy

Pancreatitis

Right heart failure

Toxic-based liver necrosis

Viral hepatitis

Standard concentrations

9-25 U/l

Variations

Concentration increased by

AbacavirAceclofenacAcetylsalicylic acidAcitretinAcyclovirAdalimumabAldesleukinAlendronateAllopurinolAminoglutethimideAmiodaroneAmoxicillineAmphotericin BAmprenavirAnastrozoleAtazanavirAtorvastatinAtovaquoneAzithromycinAztreonamBalsalazideBarnidipineBexaroteneBezafibrateBisoprololBosentanBrivudineBromocriptineCalcitriolCandesartanCapecitabineCaptoprilCarboplatinCarvedilolCaspofunginCefalexinCefalotinCefamandoleCefatrizineCefazolinCefepimeCefiximeCefmetazoleCefodizimeCefonicidCefoperazoneCefotaximeCefoxitinCefpodoxime proxetilCefradineCeftazidimeCeftezolCeftibutenCeftizoximeCeftriaxoneCefuroximeCelecoxibChloroquinChlorpromazineCiclosporinCilazaprilCinoxacinCiprofloxacinCisplatinCitalopramClarithromycinClindamycinClofarabineClomifeneClotrimazoleClozapineCortisoneCytarabineDacarbazineDalteparinDanazolDarunavirDasatinibDelaprilDermatan sulphateDexrazoxaneDextranDiazepamDiazoxideDiclofenacDiltiazemDisopyramideDolasetronDoxazosinEfavirenzEletriptanEnoxacinErythromycinEscitalopramEsomeprazoleEstradiolEthacrynic acidEthambutolEtodolacEtoposideEtoricoxibFamotidineFelbamateFenofibrateFlucloxacillinFluconazoleFlucytosineFluvoxamineFosamprenavirFosinoprilGadobenic acidGanciclovirGemcitabineGemfibrozilGentamicinGlimepirideHeparinIdarubicinImatinibImipramineIndinavirIndometacinInterferon α-2bInterferon βIronIsoniazidIsotretinoinLabetalolLamivudineLansoprazoleLeflunomideLevodopaLincomycinLinezolidLisinoprilManidipineMebendazoleMefloquineMeloxicamMethotrexateMethyldopaMetoprololMexiletineMirtazapineMoexiprilMorniflumateNaltrexoneNaproxenNifedipineNimesulideNimodipineNorfloxacinOfloxacinOlanzapineOlmesartanOmeprazoleOrlistatParacetamolParecoxibParoxetinePenicillinPentamidinePioglitazonePiroxicamProgesteronePropoxyphenePyridoxineQuetiapineQuinupristin/dalfopristinRabeprazoleRamiprilRanitidineRisedronic acidRitodrineRitonavirSertraline hydrochlorideSibutramineSimvastatinSirolimusStreptokinaseSumatriptanTacrolimusTadalafilTelithromycinTenofovirThalidomideTiclopidineTioguanineTobramycinTretinoinTrospium chlorideValacyclovirValdecoxibValproic acidVardenafilVerapamil