VOL 22, NO 10 / www.pharmacygateway.ca OCTOBER 2006 / PHARMACY PRACTICE 27

Deborah M. Yoong, BScPhm, ACPR, is a clinical pharmacist in the HIV Program at St. Michael’s Hospital in Toronto, Ont. She handles HIV drug-related issues in patients who are admitted to hospital and in those who are cared for in the outpatient Positive Care Clinic.

The author gratefully acknowledges Tony Antoniou, Pharm.D., at St. Michael’s Hospital, for his review of this article.

COMBINATION THERAPY WITH AT LEAST THREE DIFFERENT ANTIRETROVIRAL

agents has become the standard of car

e for patients with chronic human

immunodeficiency virus (HIV) infectio

n, resulting in profound reductions in

HIV-related morbidity and mortality

.1 In addition to antiretroviral ag

ents,patients

with HIV often need medications to treat

or prevent opportunistic

infections

and/or manage antiretroviral si

de effects.P

atients with HIV are a

lso living longer

and therefore may require th

erapy for additional co-existing conditions, such as

diabetes and hyperten

sion.For these reasons, interac

tions between antiretroviral

agents and co-administered prescrip

tion medications present a c

ontinuing

challenge to clinician

s caring for HIV-positive

patients.2

-5 In addition to inter-

actions with prescr

iption drugs, patients may seek

alternative

therapy and use

interacting complementary or rec

reational drugs.6-9 Certain

drug interactions

can be beneficial, lead

ing to a simplifica

tion of dosing schedules or a reduction

in pill burden;10,11 however,other co

mbinations may be undesirable an

d lead to

therapeutic failure, in

creased side effe

cts or life-threate

ning consequences.12-17

ILLUSTRATION:© KEVIN GH

IGLIONE/i2iART.COM

When

collide

By Deborah M. Yoong, BScPhm, ACPR

28 PHARMACY PRACTICE / OCTOBER 2006 www.pharmacygateway.ca / VOL 22, NO 10

Computer software systems cannot berelied upon to detect all relevant druginteractions.18-20 Furthermore, studiesassessing the potential for interactionsbetween antiretrovirals and many con-comitant medications have not been con-ducted.Therefore, patients or cliniciansmay ask pharmacists to assess the poten-tial for an interaction, and an assessmentwill need to be made based on the knownmetabolic properties of the co-adminis-tered agents.This article aims to providean overview of the main principles and

mechanisms of antiretroviral drug inter-actions. It also suggests an approach thatpharmacists can take to help identify,pre-dict and manage clinically significant druginteractions. In addition, pharmacists aredirected to useful references and resourcesthat will help them keep abreast of newdrug interaction information.

Drug interaction mechanisms

DRUG INTERACTIONS CAN BE BROADLY

categorized as either pharmacoki-netic or pharmacodynamic in nature.Apharmacodynamic interaction changes thepharmacological effect of the drug with-out altering the drug’s disposition.Theoutcome may be additive, synergistic orantagonistic,with an increase or decreasein the efficacy and/or toxicity of thedrug. For example, while the combina-tion of didanosine and stavudine hasadditive or synergistic antiretroviral acti-vity, combined use is not recommendeddue to overlapping toxicities (e.g., peri-pheral neuropathy, lactic acidosis).21

In contrast,pharmacokinetic interactionsoccur when the concentration of one

SUBSTANCES THAT MAY DECREASENNRTI AND PI LEVELS THROUGHENZYME INDUCTION12,81-90

TABLE 2

• ascorbic acid (≥ 1g/day) • carbamazepine• dexamethasone • garlic supplements (Allium sativum)• oxcarbazepine • phenobarbital• phenytoin• primidone• rifampin• St. John’s wort

NNRTI = nonnucleoside reverse transcrip-tase inhibitor; PI = protease inhibitor

METABOLIC PATHWAYS OF ANTIRETROVIRALS34,40-50,76-80TABLE 1Antiretrovirals Substrates Inhibitors InducersNNRTIdelavirdine CYP3A4 CYP3A4, 2C9/19,

2D6

efavirenz CYP3A4, 2B6 CYP2B6, 3A4, CYP3A42C9/19

nevirapine CYP3A4 CYP3A4, 2B6

TMC125 (etravirine)a CYP3A4

PIdarunavir, indinavir, CYP3A4 CYP3A4saquinavir

tipranavir CYP3A4 (CYP3A4)b CYP3A4, GT

atazanavir CYP3A4 CYP3A4, 2C8, UGT1A1

fosamprenavir CYP3A4 CYP3A4, 2C19 CYP3A4

lopinavir/ritonavir CYP3A4 CYP3A4, 2D6 CYP2C9/19,1A2,GT

nelfinavir CYP3A4,2C19 CYP3A4, 2B6 2C9/19, GT

ritonavir CYP3A4 CYP3A4 > 2D6 >2C9 CYP1A2, 3A4, > 2C19 > 2A6 > 2E1; 2C9/19 GTCYP2B6

CCR5 antagonistsmaraviroca CYP3A4a investigational; b tipranavir may act as a CYP3A4 inhibitor when combined withcertain medications (e.g., atorvastatin); CCR5 = chemokine (CC motif) receptor 5;GT = glucuronosyltransferase; NNRTI = nonnucleoside reverse transcriptaseinhibitor; PI = protease inhibitor; UGT = UDP glucuronosyl transferase

ATTENTIONPHARMACY

TECHNICIANS

Brought to you by the publishers of:

Sponsored by:

PLUSComing in December.

The next issue of Tech Talk.

Featuring...• The winner of the Commitment

to Care Award for Pharmacy

Technician Initiatives

• A Q&A forum that answers your

most pressing questions

• Continuing Education: Under-

standing premenstrual syndrome

Don’t miss a single issue of Tech Talk. Download back

issues at www.novopharm.comor www.pharmacygateway.ca.

Online answering of over 20 Tech Talk CE lessons

is now available at

www.pharmacygateway.ca

Register online. It’s free, easy and you’ll get results right away.

Free CE now online

VOL 22, NO 10 / www.pharmacygateway.ca OCTOBER 2006 / PHARMACY PRACTICE 29

1OBTAIN A FULL MEDICATION HISTORY.Obtain a full medication history, including

the patient’s use of OTC, complementary andrecreational agents.

2FAMILIARIZE YOURSELF WITH THE CHARACTERISTICS OF THE DRUGS IN QUES-

TION, TO HELP PREDICT PHARMACODYNAMICAND PHARMACOKINETIC INTERACTIONS.The pharmacodynamic and pharmacokineticproperties that govern a drug’s behaviour in thebody can also be used to help predict possibledrug interactions.61 For example, does one drugalter gastric pH, while another drug’s absorp-tion is pH-dependent? Are the drugs substrates,inducers or inhibitors of the CYP450 enzymesystem? Understanding the potential mecha-nism of the drug interaction can help the phar-macist predict whether an interaction may leadto a favourable or detrimental pharmacokineticinteraction.

3CONSULT RESOURCES TO CONFIRM THEINTERACTION.

Evidence should be sought to confirm an interaction. Tables 4, 5, and 6 (available atwww.pharmacygateway.ca, Our publications, Pharmacy Practice, October 2006) summarizesome commonly encountered interactions withHIV drugs. Interactions between NNRTIs and PIs,and the dose adjustments required when dual PIsare used, are complex and beyond the scope ofthis article; information on managing such inter-actions can be found elsewhere.4,62,63 Pharmacistscan also refer to several reliable Internet sitesthat are updated frequently as new informationis presented at scientific conferences (Table 3).64

Review articles describing the potential for inter-actions between antiretrovirals and other classesof medications (e.g., antineoplastics, anticon-vulsants) can also be of assistance.5,9,65-72

4EVALUATE THE DATA AND CLINICAL SIGNIFICANCE.

The type of data reported, as well as its applic-ability, should be considered. For example,prospective pharmacokinetic trials with adequateexposure to the drug are more rigorous than ret-rospective data where adherence cannot be con-firmed. In addition, in vitro data may suggestthe potential for an interaction, although drugconcentrations used in these trials may greatly

exceed those used in clinical practice, therebylimiting their generalizability. Furthermore, phar-macokinetic studies where only a single dose ofa given medication was administered may notbe sufficient for ruling out the potential fordelayed interactions. Additional considerationsinclude the doses of drugs used (e.g., extent ofpossible interactions increases with increasingritonavir dose), patient body weight and drugformulation (e.g., didanosine buffered tablet vs.enteric coated capsule).73 Finally, it is worth not-ing whether clinical outcomes were measuredand correlated to drug levels. While pharmaco-kinetic drug interaction data may be available,data that specify the clinical outcome of theinteraction are undeniably more relevant.

5IN THE ABSENCE OF SPECIFIC DATA, USEPHARMACOKINETIC AND PHARMACODY-

NAMIC INFORMATION TO POSTULATE THEPOTENTIAL OUTCOME OF THE INTERACTION ANDDETERMINE WHAT ACTION MAY BE NECESSARY.If drug interaction data are limited for a specificcombination, it may be helpful to evaluate theother documented drug interactions with thedrug in question. Another interacting drug mayshare similar properties to the drug in question.Based on the pharmacological and pharmacoki-netic properties of the drugs (from Step 2), pos-tulations could be made and, most importantly,the potential outcomes should be considered. Ifthe interaction occurred as predicted, would itlead to severe toxicity or subtherapeutic levelsand failure of the drug regimen? Or would thepatient experience a side effect that is easilyreversible without significant morbidity?

6ASSESS WHETHER AN INTERVENTION ISREQUIRED AND CONSIDER ALTERNATIVES.

Once a drug interaction has been identified orpostulated, it may be necessary to intervene to minimize negative outcomes. Consult the literature to determine successful strategies,especially dose adjustments that may be necessary. Deciding among the various optionsprovided below requires careful consideration ofnumerous factors.

a) Do nothing and monitor.Predicting the time course of a drug interac-tion may help to determine an appropriatemonitoring schedule and anticipate when

interventions should be made to minimize anadverse event. If the interacting agent isbeing used short term, before a clinical inter-action occurs, no action may be required. Ifthe interacting drug has already been startedand the interaction was estimated to havealready occurred, no intervention may berequired if there does not appear to be anyadverse outcome. However, the potential fordelayed interactions with enzyme inducersshould be considered and anticipated, partic-ularly if antiretroviral treatment failure is apotential consequence.

b) Separate administration times.Many interactions that occur at the absorptionlevel may be overcome by separating the dos-ing times of the interacting drugs. However, thetimeframe of the interaction must be consideredto determine whether this strategy is a viablesolution. For example, separating the adminis-tration time of an antacid from atazanavir bytwo hours will minimize the absorption inter-action; however, this same approach is not ade-quate if a proton pump inhibitor that has anextended duration of acid suppression is usedrather than an antacid.74

c) Hold or discontinue one drug.It may be possible to reassess the need for cer-tain medications (e.g., proton pump inhibitors).Interruption of antiretroviral therapy is notencouraged, as this may promote the develop-ment of drug resistance.

d) Change the dose.Dosage adjustments can be considered to com-pensate for the effects of drug interactions;however, adjustments should generally be madewhere pharmacokinetic data are available to jus-tify such changes.

e) Change the drug.Therapeutic alternatives for the interactingdrugs should be reviewed. Pharmacists may beable to recommend alternative antiretroviralsthat do not interact with a patient’s currentmedications, as long as efficacy is not compromised. Alternatively, changes to thenon-antiretroviral medications can be consid-ered, if possible, to minimize to the potentialfor interactions.

SIDEBAR:

Step-by-step approach for assessing and predicting drug interactions60

drug is altered by another through inter-ference with the absorption,distribution,metabolism or elimination process.Phar-macokinetic interactions that result in sig-nificant reductions in antiretroviral drugexposure (AUC) or minimum concen-tration (Cmin) may lead to therapeuticfailure and the development of viral drugresistance.22-25 Conversely, clinical toxi-city may be associated with increases inan antiretroviral drug’s AUC, Cmin ormaximum concentration (Cmax).26-29

Antiretroviral pharmacokinetic inter-actions occur primarily at the level ofdrug absorption and metabolism and thisreview focuses mainly on interactionsinvolving these processes. Discussions ofthe impact of protein binding and inter-actions occurring at the level of the kid-ney have been published elsewhere.4,30,31

ABSORPTION INTERACTIONSClinically significant interactions involv-ing drug absorption result in a compro-mised ability to deliver a drug into thesystemic circulation, potentially decreas-ing its efficacy. Drugs that are most sen-sitive to these interactions include thosewhose absorption is dependent on themaintenance of an acidic gastric pH (e.g.,ketoconazole,32 itraconazole capsules,33

atazanavir34) and/or agents that are proneto chelation with cations found in nutri-tional supplements or antacids (e.g.,fluoroquinolones,35 tetracyclines). Sincedidanosine tablets are co-formulated withantacids, the potential for interactions andsubsequent negative treatment outcomeswith the aforementioned agents ishigh.34,36 Adjusting dosing times to avoidsimultaneous administration or using the

reformulated didanosine product (i.e.,capsules that contain enteric-coateddidanosine pellets) would avoid theseinteractions.37

METABOLISM AND ELIMINATION INTERACTIONSThe primary function of metabolism is toconvert drugs into water-soluble metabo-lites that are generally inactive productsthat can be readily removed.Occasionally,the end products of drug metabolism aremetabolites with more activity and/ortoxicity than the parent drug.

In general,drug metabolism is dividedinto two pathways: phase I and phase II.Phase I involves transformation reactions(oxidation, reduction or hydrolysis) cata-lyzed primarily by the cytochrome P450(CYP450) family of enzymes; phase IImetabolism consists of conjugation reac-tions mediated by transferases such as glu-curonosyl transferase.38 CYP450 enzymescan be classified (based on genetic simi-larity) into families and subfamilies,39 desi-gnated by a number and a letter (e.g.,CYP1A, CYP2D, CYP3A). Individualenzymes within a subfamily are identifiedwith an additional number (e.g.,CYP3A4, CYP2D6) and are referred toas isoenzymes of the CYP450 system.Many clinically important interactionsoccur as a result of antiretroviral-mediatedchanges in the activity of specific CYP450isoenzymes. Individual CYP450 isoen-zyme activity can be either inhibited orinduced by many currently available anti-retrovirals (Table 1).

All currently available proteaseinhibitors (PIs) (with the exception oftipranavir) and the nonnucleoside reverse

SELECTED INTERNET RESOURCES FOR INTERACTIONS WITHHIV THERAPYTABLE 3

Centers for Disease Control and Prevention, TB/HIV Drug Interactionswww.cdc.gov/nchstp/tb/tb_hiv_drugs/toc.htm

Clinical Care Options—HIV, Drug-Drug Interactions Tool http://clinicaloptions.com/HIV/Treatment%20Updates/Drug-Drug%20Interactions.aspx#{29DF8473-3349-4BF3-BF42-FD3EA2377FB4}

School of Medicine, Indiana University, Drug Interactions: Cytochrome P450 Systemwww.drug-interactions.com

Toronto General Hospital Immunodeficiency Clinicwww.tthhivclinic.com/interact_tables.html

University of California, San Francisco, HIVInSitewww.hivinsite.com/InSite.jsp?page=ar-00-02

University of Liverpoolwww.hiv-druginteractions.org

www.pharmacygateway.ca

Online answering and accreditation of Canada’s favourite

publication CCCEP-approved CE programs now available at

www.pharmacygateway.ca.

PHARMACY PRACTICE CEEpilepsy in women

Targeted drugs for cancer treatment

Bipolar disorder

NOVOPHARMCOMMUNICATIONS CENTRE CECommunication in a Multicultural Society

Communication in Pharmacy Practice

PHARMACY POST CEGinseng: Evaluating the Evidence

Promoting Protection:The broad spectrum of sun damage

PHARMACEUTICALMANUFACTURER CE

Single-Inhaler Maintenance and Reliever Therapy for Asthma Control

Acute Pain Management

Heart Failure Treatment and Diabetes Prevention

Topical anti-inflammatory treatment for management of atopic dermatitis

TECH TALK CEChronic Obstructive Pulmonary Disease

Smoking cessation

Investigating unfamiliar drugs

AND MANY MORE

CEs NOW ONLINE:

30 PHARMACY PRACTICE / OCTOBER 2006 www.pharmacygateway.ca / VOL 22, NO 10

VOL 22, NO 10 / www.pharmacygateway.ca OCTOBER 2006 / PHARMACY PRACTICE 31

transcriptase inhibitor (NNRTI) delavir-dine are inhibitors of the CYP3A4 isoen-zyme.34,40-48 Thus, co-administration of aPI or delavirdine with a drug metabolizedby CYP3A4 (i.e.,a substrate of CYP3A4)may result in accumulation of the substratedrug and thereby predispose patients toadverse events.For example,calcium chan-nel blockers and statins are CYP3A4 sub-strates; increased concentrations could leadto hypotension, bradycardia or rhab-domyolysis when combined with a PI ordelavirdine. Other CYP450 isoenzymescan also be inhibited by selected anti-retrovirals and, accordingly, can result inincreased or prolonged activity of therespective substrate. Since CYP450 inhi-bition is an acute process, the onset andoutcome of such interactions may be seenwithin a few days.38 Similarly, removal ofa CYP450 inhibitor usually results in aquick resolution of the interaction basedon the half-lives of both the inhibitor andthe substrate being inhibited.

In contrast, the NNRTIs efavirenzand nevirapine, as well as tipranavir, areinducers of the CYP3A4 system.49,50

Combined administration with CYP3A4substrates would therefore lead to anincrease in substrate metabolism, therebydecreasing substrate plasma levels andpotentially risking therapeutic failure. Insome cases, dosage adjustments may benecessary to compensate for the induc-ing effect of nevirapine and efavirenz.Unlike inhibition-based interactions, thetime to onset of enzyme induction isusually longer than one week, since newdrug metabolizing enzymes need to besynthesized.38Therefore, the outcome ofenzyme induction is generally not seenacutely. Similarly, once an enzymeinducer is discontinued, it may take sev-eral weeks for the newly synthesizedenzymes to decay and for drug metabo-lism activity to return to baseline levels.Dosage adjustments following the dis-continuation of an enzyme inducershould therefore be made according tothe time course of the interaction.

In addition to acting as inhibitors andinducers of the CYP3A4 system, PIs andNNRTIs are substrates of this isoenzyme.Therefore, their serum levels can beincreased or decreased with the concomi-tant administration of enzyme inhibitorsor enzyme inducers, respectively, includ-

ing other NNRTIs or PIs that may beincorporated into the HIV drug regimen.Although CYP3A4 inhibitor-mediatedincreases in PI and NNRTI levels maypredispose patients to adverse effects asso-ciated with these drugs, enzyme induc-tion, with a resultant decrease in anti-retroviral serum levels, may be of greaterclinical significance,given the ramificationssurrounding HIV treatment failure andthe emergence of drug resistance.Table 2provides a list of drugs that may compro-mise antiretroviral treatment.

Although most antiretroviral-medi-ated interactions involve modulation ofCYP isoenzymes, substrates that undergophase II glucuronidation (e.g., valproicacid, levothyroxine) may also be suscep-tible to fluctuations in drug levels as someantiretrovirals also modulate this path-way.51-54 Of note, nelfinavir, tipranavir,and ritonavir can induce the glu-curonidation of ethinyl estradiol, therebypotentially compromising the efficacy oforal contraceptives and necessitatingalternate means of contraception.41,43,44,55

The disposition of drugs may also beinfluenced by the presence of P-glyco-protein (Pgp). This efflux membranetransporter functions to limit drug expo-sure and its activity may be modulated byinducers and inhibitors.56 Most PIs aresubstrates and inhibitors of this proteinpump.57,58 While PIs may help increaseentry of other PIs into sanctuary sites,their inhibition of Pgp may also lead totoxicity from other Pgp substrates (e.g.,digoxin).59

The pharmacist’s role

AS NOVEL HIV THERAPIES CONTINUALLY

emerge, different drugs are beingcombined and new drug interactions(predicted and unexpected) are continu-ously being reported.To detect all docu-mented and potential drug interactions,pharmacists cannot rely on technologythat does not undergo daily updates.Aswell, data on multidrug interactions arescarce and pharmacists must consider allpotential interactions before making rec-ommendations.Thus, it is imperative thatpharmacists have a basic understanding ofclinical pharmacology and develop a sys-tematic approach for assessing and pre-dicting drug interactions.The sidebar out-lines a suggested approach.60

Summary

THE MANAGEMENT OF CHRONIC HIVrelies heavily on drug therapy that

modulates drug-metabolizing enzymes.In addition, the extended survival ofpatients with HIV has led to an increas-ing need for concomitant medications totreat co-existing conditions; therefore,drug interactions are now an inescapableaspect of HIV therapy. Such interactionscan result in positive or negative outcomesand it is crucial for pharmacists to recog-nize when interventions are required.75

An understanding of drug properties andmechanisms of interactions will enablepharmacists to predict interactions andrecommend safe and effective strategies tooptimize outcomes and minimize the riskof morbidity and mortality.

Tables 4, 5, 6 are available at www.pharmacygateway.ca.(Go to Our Publications, Pharmacy Practice, October2006.) References start on page 34.

The Pharmacy Group at Rogers Publishing is pleased to announce the appointment of Sonie Labrie as Bilingual Web Editor for www.pharmacygateway.ca andwww.monportailpharmacie.ca.

Ms. Labrie has widespread experience asa web editor, having worked for more thansix years for Rogers Communications Inc.,creating, editing and publishing documentsfor several online content management sys-tems. She graduated from Laval Universitywith a B.A. in Communications and alsocompleted a three-year French Editorial andCommunications program at the Universityof Sherbrooke.

Ms. Labrie is responsible for managingthe content of the two websites, whichoperate under the umbrella of PharmacyPractice, Pharmacy Post, L’actualite pharma-ceutique and Quebec Pharmacie.

APPOINTMENT

34 PHARMACY PRACTICE / OCTOBER 2006 www.pharmacygateway.ca / VOL 22, NO 10

Continued from page 31References

1. Palella FJJ, Delaney KM, Moorman AC, et al. Declining mor-bidity and mortality among patients with advanced human immun-odeficiency virus infection. N Engl J Med 1998;338:853-60.

2. van Cleef GF, Fisher EJ, Polk RE. Drug interaction poten-tial with inhibitors of HIV protease. Pharmacotherapy 1997;17:774-8.

3. Piscitelli SC, Gallicano KD. Interactions among drugs for HIVand opportunistic infections. N Engl J Med 2001;344:984-96.

4. Robertson SM, Penzak SR, Pau AK. Drug interactions inthe management of HIV infection. Expert Opin Pharmacother2005;6:233-53.

5. Fichtenbaum CJ, Gerber JG. Interactions between anti-retroviral drugs and drugs used for the therapy of the metaboliccomplications encountered during HIV infection. Clin Pharma-cokinet 2002;41: 1195-211.

6. Standish LJ, Greene KB, Bain S, et al. Alternative medi-cine use in HIV-positive men and women: demographics, uti-lization patterns and health status. AIDS Care 2001;13:197-208.

7. Mills E, Montori V, Perri D, et al. Natural health products-HIV drug interactions: a systematic review. Int J STD AIDS2005;16:181-6.

8. Patel J, Buddha B, Dey S, et al. In vitro interaction of theHIV protease inhibitor ritonavir with herbal constituents: changesin P-gp and CYP3A4 activity. Am J Ther 2004;11:262-77.

9. Antoniou T, Tseng AL. Interactions between recreationaldrugs and antiretroviral agents. Ann Pharmacother 2002;36:1598-613.

10. Gerber JG. Using pharmacokinetics to optimize anti-retroviral drug-drug interactions in the treatment of humanimmunodeficiency virus infection. Clin Infect Dis 2000;30:S123-S129.

11. King JR, Wynn H, Brundage R, et al. Pharmacokineticenhancement of protease inhibitor therapy. Clin Pharmacokinet2004;43:291-310.

12. Hugen PWH, Burger DM, Brinkman K, et al. Carba-mazepine-indinavir interaction causes antiretroviral therapy fail-ure. Ann Pharmacother 2000;34:465-70.

13. Harrington RD, Woodward JA, Hooton TM, et al. Life-threatening interactions between HIV-1 protease inhibitors andthe illicit drugs MDMA and γ-hydroxybutyrate. Arch Intern Med1999;159:2221-4.

14. Henry JA, Hill IR. Fatal interaction between ritonavirand MDMA. Lancet 1998;352:1751-2.

15. Foisy MM, Gough K, Quan CM, et al. Hospitalization dueto adverse drug reactions and drug interactions before and afterHAART. Can J Infect Dis 2000;11:193-201.

16. Preston SL, Postelnick M, Purdy BD, et al. Drug interac-tions in HIV-positive patients initiated on protease inhibitor ther-apy. AIDS 1998;12:228-30.

17. Antoniou T, Gough K, Yoong D, et al. Severe anemia sec-ondary to a probable drug interaction between zidovudine andvalproic acid. Clin Infect Dis 2004;38:e38-e40.

18. Cavuto NJ, Woosley RL, Sale M. Pharmacies and pre-vention of potentially fatal drug interactions. JAMA1996;275:1086-7.

19. Hazlet TK, Lee TA, Hansten PD, et al. Performance ofcommunity pharmacy drug interaction software. J Am PharmAssoc 2001;41:200-4.

20. Glassman PA, Simon B, Belperio P, et al. Improvingrecognition of drug interactions: benefits and barriers to usingautomated drug alerts. Med Care 2002;40:1161-71.

21. Department of Health and Human Services (DHHS).Guidelines for the use of antiretroviral agents in HIV-1-infectedadults and adolescents; May 4, 2006. http://aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7& ClassID=1 (accessed August 24, 2006).

22. Burger DM, Hoetelmans RM, Hugen PW, et al. Low plasmaconcentrations of indinavir are related to virological treatmentfailure in HIV-1-infected patients on indinavir-containing tripletherapy. Antivir Ther 1998;3:215-20.

23. Acosta EP, Henry K, Baken L, et al. Indinavir concen-trations and antiviral effect. Pharmacotherapy 1999;19:708-12.

24. Acosta EP, Kakuda TN, Brundage RC, et al. Pharmaco-dynamics of HIV-1 protease inhibitors. Clin Infect Dis 2000;30:S151-S159.

25. Durant J, Clevenbergh P, Garraffo R, et al. Importanceof protease inhibitor plasma levels in HIV-infected patientstreated with genotypic-guided therapy: pharmacological datafrom the VIRADAPT study. AIDS 2000;14:1333-9.

26. Dieleman JP, Gyssens IC, van der Ende ME, et al. Uro-

logical complaints in relation to indinavir plasma concentrationsin HIV-infected patients. AIDS 1999; 13:473-8.

27. Gatti G, Di Biagio A, Casazza R, et al. The relationshipbetween ritonavir plasma levels and side effects: implications fortherapeutic drug monitoring. AIDS 1999;13:2083-9.

28. Marzolini C, Telenti A, Decosterd LA, et al. Efavirenzplasma levels can predict treatment failure and central nervous sys-tem side effects in HIV-1-infected patients. AIDS 2001;15:71-5.

29. Barrios A, Rendon AL, Gallego O, et al. Predictors of viro-logical response to atazanavir in protease inhibitor-experiencedpatients. HIV Clin Trials 2004;5:201-5.

30. Boffito M, Back DJ, Blaschke TF, et al. Protein bindingin antiretroviral therapies. AIDS Res Hum Retroviruses 2003:19:825-35.

31. Izzedine H, Launay-Vacher V, Deray G. Renal tubular trans-porters and antiviral drugs: an update. AIDS 2005;19:455-62.

32. Piscitelli SC, Goss TF, Wilton JH, et al. Effects of rani-tidine and sucralfate on ketoconazole bioavailability. AntimicrobAgents Chemother 1991;35:1765-71.

33. Janssen-Ortho. Sporanox (itraconazole) capsules pre-scribing information. In: Repchinsky C, ed. Compendium of Phar-maceuticals and Specialties. Ottawa: Canadian Pharmacists Asso-ciation; 2005.

34. Bristol-Myers Squibb. Reyataz (atazanavir sulfate) pre-scribing information. Princeton, NJ: January, 2006.

35. Lehto P, Kivisto KT. Effect of sucralfate on absorption ofnorfloxacin and ofloxacin. Antimicrob Agents Chemother 1994;38:248-51.

36. Sahai J, Gallicanok, Olivera L, et al. Cations in thedidanosine tablet reduce ciprofloxacin bioavailability. Clin Phar-macol Ther 1993;53:292-7.

37. Damle DB, Mummaneni V, Kaul S, et al. Lack of effect ofsimultaneously administered didanosine encapsulated entericbead formulation (Videx EC) on oral absorption of indinavir, keto-conazole, or ciprofloxacin. Antimicrob Agents Chemother 2002;46:385-91.

38. Hansten PD, Horn JR. Pharmacokinetic drug interactionmechanisms and clinical characteristics. In: Drug interactions—analysis and management. Facts and comparisons. 2000 (Oct):PM1-20.

39. Nelson DR, Kamataki T, Waxman DJ, et al. The P450superfamily: update on new sequences, gene mapping, accessionnumbers, early trivial names of enzymes and nomenclature. DNACell Biol 1993;12:1-51.

40. GlaxoSmithKline. Telzir (fosamprenavir) product mono-graph. Mississauga, Ont.: January, 2006.

41. Abbott Laboratories. Kaletra (lopinavir/ritonavir) pre-scribing information. Montreal, Que.: March, 2001.

42. Abbott Laboratories. Norvir (ritonavir) condensed pre-scribing information. Montreal, Que.; January, 2000.

43. Boehringer-Ingelheim. Aptivus (tipranavir) productmonograph. Burlington, Ont.: November, 2005.

44. Pfizer. Viracept (nelfinavir mesylate) product monograph.Kirkland, Que.: September, 2004.

45. Merck Frosst. Crixivan (indinavir) product monograph.Kirkland, Que.: January, 2006.

46. Hoffmann-La Roche. Invirase (saquinavir mesylate) prod-uct monograph. Mississauga, Ont.: March, 2006.

47. Pfizer. Rescriptor (delavirdine mesylate) product mono-graph. Kirkland, Que.: September, 2003.

48. Janssen-Ortho. Prezista (darunavir) product monograph.Toronto, Ont.: July 27, 2006.

49. Bristol-Myers Squibb. Sustiva (efavirenz) prescribinginformation. Princeton, NJ: April, 2005.

50. Boehringer-Ingelheim. Viramune (nevirapine) prescrib-ing information. Burlington, Ont.: May, 2004.

51. Sheehan NL, Brouillette MJ, Delisle MS, et al. Possibleinteraction between lopinavir/ritonavir and valproic acid exac-erbates bipolar disorder. Ann Pharmacother 2006;40:147-50.

52. Touzot M, Le Beller C, Touzot F, et al. Dramatic interac-tion between levothyroxine and lopinavir/ritonavir in a HIV-infected patient. AIDS 2006;20:1210-2.

53. Tseng A, Fletcher D. Interaction between ritonavir andlevothyroxine. AIDS 1998;12:2235-6.

54. Lanzafame M, Trevenzoli M, Faggian F, et al. Interactionbetween levothyroxine and indinavir in a patient with HIV infec-tion. Infection 2002;30:54-5.

55. Ouellet D, Hsu A, Qian J, et al. Effect of ritonavir on thepharmacokinetics of ethinyl estradiol in healthy female volun-teers. Br J Clin Pharmacol 1998;46: 111-6.

Continued on page 34

38 PHARMACY PRACTICE / OCTOBER 2006 www.pharmacygateway.ca / VOL 22, NO 10

56. Matheny CJ, Lamb MW, Brouwer KLR, et al. Pharmaco-kinetic and pharmacodynamic implications of p-glycoproteinmodulation. Pharmacotherapy 2001;21: 778-96.

57. Lee CG, Gottesman MM, Cardarellies RM, et al. HIV pro-tease inhibitors are substrates for the MDR1 multidrug trans-porter. Biochemistry 1998;37:3594-601.

58. Gutmann H, Fricker G, Drewe J, et al. Interactions ofHIV protease inhibitors with ATP-dependent drug export proteins.Mol Pharmacol 1999;56:383-9.

59. Phillips EJ, Rachlis AR, Ito S. Digoxin toxicity and riton-avir: a drug interaction mediated through p-glycoprotein? AIDS2003;17:1577-8.

60. Tseng AL, Foisy MM. Management of drug interactionsin patients with HIV. Ann Pharmacother 1997; 31:1040-58.

61. Bertz RJ, Granneman GR. Use of in vitro and in vivo datato estimate the likelihood of metabolic pharmacokinetic inter-actions. Clin Pharmacokinet 1997;32:210-58.

62. Boffito M, Acosta E, Burger D, et al. Therapeutic drugmonitoring and drug-drug interactions involving antiretroviraldrugs. Antivir Ther 2005;10:469-77.

63. Boffito M, Moyle GJ. Pharmacokinetic considerations forcombining 2 protease inhibitors. AIDS Read 2004;14:110-21.

64. Sheehan NL, Kelly DV, Tseng AL, et al. Evaluation of HIVdrug interaction web sites. Ann Pharmacother 2003;37:1577-86.

65. Antoniou T, Tseng AL. Interactions between antiretro-virals and antineoplastic drug therapy. Clin Pharmacokinet2005;44:111-45.

66. Liedtke MD, Lockhart SM, Rathbun RC. Anticonvulsant andantiretroviral interactions. Ann Pharmacother 2004:38:482-9.

67. Tseng AL, Foisy MM. Significant interactions with newantiretrovirals and psychotropic drugs. Ann Pharmacother1999;33:461-73.

68. Wynn GH, Cozza KL, Zapor MJ, et al. Antiretrovirals, partIII: antiretrovirals and drugs of abuse. Psychosomatics 2005;46:79-87.

69. Khoo S, Back D, Winstanley P. The potential for inter-actions between antimalarial and antiretroviral drugs. AIDS2005;19:995-1005.

70. Bruce RD, Altice FL, Gourevitch MN, et al. Pharmacoki-netic drug interactions between opioid agonist therapy and anti-retroviral medications: implications and management for clinicalpractice. J Acquir Immune Defic Syndr 2006;41:563-72.

71. Fichenbaum C, Gerber J, Rosenkranz S, et al. Pharma-cokinetic interactions between protease inhibitors and statins inHIV-seronegative volunteers: ACTG Study A5047. AIDS2002;16:569-77.

72. Kumar GN, Dykstra J, Roberts EM, et al. Potent inhibitionof the cytochrome P-450 3A-mediated human liver microsomalmetabolism of a novel HIV protease inhibitor by ritonavir: a pos-itive drug-drug interaction. Drug Metab Dispos 1999;27:902-8.

73. Agarwala S, Gray K, Eley T, et al. Pharmacokinetic inter-action between atazanavir and omeprazole in healthy subjects(poster WePe3.3C08). 3rd International AIDS Society conference onHIV pathogenesis and treatment, Rio de Janeiro, July 24-27, 2005.

74. American Society of Health-System Pharmacists. ASHPstatement on the pharmacist’s role in the care of patients withHIV infection. Am J Health-Syst Pharm 2003;60:1998-2003.

76. Yeh RF, Gaver VE, Patterson KB, et al. Lopinavir/ riton-avir induces hepatic activity of cytochrome P450 enzymesCYP2C9, CYP2C19 and CYP1A2 but inhibits the hepatic andintestinal activity of CYP3A as measured by a phenotyping drugcocktail in healthy volunteers. J Acquir Immune Defic Syndr2006;42:52-60.

77. Hsu A, Granneman GR, Cao G, et al. Pharmacokineticinteractions between two human immunodeficiency virus pro-tease inhibitors, ritonavir and saquinavir. Clin Pharmacol Ther1998;63:453-64.

78. Fellay J, Marzolini C, Decosterd L, et al. Variations ofCYP3A activity induced by antiretroviral treatment in HIV-1infected patients. Curr J Clin Pharmacol 2005;60:865-73.

79. Aarnoutse RE, Keinnijenhuis J, Koopmans PP, et al.Effect of low-dose ritonavir (100 mg twice daily) on the activ-ity of cytochrome P450 2D6 in healthy volunteers. Clin Phar-macol Ther 2005;78:664-74.

80. Abel S, Russell D, Ridgway C, et al. Overview of the drug-drug interactions for maraviroc (UK-427,857, abstract 76). 6thInternational Workshop on Clinical Pharmacology of HIV Therapy,Quebec. April 28-30, 2005.

81. Slain D, Amsden JR, Khakoo RA, et al. Effect of high-dose vitamin C on the steady-state pharmacokinetics of the pro-tease inhibitor indinavir in healthy volunteers. Pharmacother-apy 2005;25:165-70.

82. Kaul S, Ji P, Xie J, et al. A 2-way pharmacokinetic inter-action between efavirenz and carbamazepine (abstract 575a). 13thConference on Retroviruses and Opportunistic Infections, Denver,CO. February 5-8, 2006.

83. Piscetelli SC, Burstein AH, Welden N, et al. The effectof garlic supplements on the pharmacokinetics of saquinavir. ClinInfect Dis 2002;34:234-8.

84. McCune JS, Hawke RL, LeCluyse EL, et al. In vivo and invitro induction of human cytochrome P450 3A4 by dexamethasone.Clin Pharmacol Ther 2000;68:356-66.

85. Robertson S, Penzak S, Lane J, et al. A potentially sig-nificant interaction between efavirenz and phenytoin: a case reportand review of the literature. Clin Infect Dis 2005;41:e15-e18.

86. Romanelli R, Pomeroy C. Concurrent use of antiretrovi-rals and anticonvulsants in human immunodeficiency virus (HIV)seropositive patients. Curr Pharm Des 2003;9;1433-9.

87. Lim ML, Min SS, Eron J, et al. A two-way drug interactionbetween lopinavir/ritonavir and phenytoin (poster T-52). 10th Con-ference on Retroviruses and Opportunistic Infections, Boston, MA.February 10-14, 2003.

88. CDC: Division of Tuberculosis Elimination. Updatedguidelines for the use of rifamycins for the treatment of tuber-culosis among HIV-infected patients taking protease inhibitorsor nonnucleoside reverse transcriptase inhibitors (Version1.20.04). www. cdc.gov/nchstp/tb/tb_hiv_drugs/PDF/tbhiv.pdf(accessed May 6, 2006).

89. Piscitelli SC, Burstein AH, Chaitt D, et al. Indinavir con-centrations and St. John’s wort. Lancet 2000; 355:547-8.

90. de Matt MMR, Hoetelmans RMW, Mathot RAA, et al. Druginteraction between St. John’s wort and nevirapine. AIDS 2001;15:420-1.

91. Samarasinghe YP, Boffito M, Di Perri G. Nucleo-side/nucleotide reverse transcriptase inhibitor drug interactions.J HIV Ther 2004;9:79-86.

92. Burger DM, Meenhorst PL, Koks CHW, et al. Drug inter-actions with zidovudine. AIDS 1993;7:445-60.

93. Hochster H, Dieterich D, Bozzette S, et al. Toxicity ofcombined ganciclovir and zidovudine for cytomegalovirus diseaseassociated with AIDS. Ann Intern Med 1990;114:111-7.

94. Perronne C. Antiviral hepatitis and antiretroviral druginteractions. J Hepatol 2006;44:S119-S125.

95. Hoggard PG, Kewn S, Barry MG, et al. Effects of drugson 2’,3’-dideoxy-2’,3’-didehydrothymidine phosphorylation invitro. Antimicrob Agents Chemother 1997;41:1231-6.

96. Foisy MM, Slayter KL, Hewitt RG, et al. Pancreatitis dur-ing intravenous pentamidine therapy in an AIDS patient with priorexposure to didanosine. Ann Pharmacother 1994;28:1025-8.

97. Ray AS, Olson L, Fridland A. Role of purine nucleosidephosphorylase in interactions between 2’,3’-dideoxyinosine andallopurinol, ganciclovir, or tenofovir. Antimicrob AgentsChemother 2004;48:1089-95.

98. Boelaert JR, Dom GM, Huitema AD, et al. The boostingof didanosine by allopurinol permits a halving of the didano-sine dosage. AIDS 2002;16:2221-3.

99. Taburet AM, Piketty C, Chazallon C, et al. Interactionsbetween atazanavir-ritonavir and tenofovir in heavily pretreatedhuman immunodeficiency virus-infected patients. AntimicrobAgents Chemother 2004; 48:2091-6.

100. Foisy M, Tseng A. Drug interactions with nucleoside reversetranscriptase inhibitors. www.tthhivclinic.com/pdf/RTI-INT.pdf(accessed April 30, 2006).

101. Indiana University, Division of Clinical Pharmacology.Drug interactions: cytochrome P450 system. http://medicine.iupui.edu/flockhart/table.htm (accessed April 25, 2006).

102. Tseng A. Drug interactions with non-nucleoside reversetranscriptase inhibitors. www.tthhivclinic.com/pdf/Nnrt-int.pdf(accessed April 30, 2006).

103. Almond L, Gibbons S, Davies G, et al. A retrospectivesurvey of the Liverpool TDM service: factors influencing efavirenzconcentrations in patients taking rifampicin (abstract 19). 6thInternational Workshop on the Clinical Pharmacology of HIV ther-apy, Quebec, Canada, April 28-30, 2005.

104. Altice FL, Friedland GH, Cooney EL. Nevirapine inducedopiate withdrawal among injection drug users with HIV infectionreceiving methadone. AIDS 1999;13:957-62.

105. Clarke SM, Mulcahy FM, Tjia J, et al. Pharmacokineticinteractions of nevirapine and methadone and guidelines for useof nevirapine to treat injection drug users. Clin Infect Dis2001;33:1595-7.

106. Cohn SE, Watts D, Lertora J, et al. An open-label, non-randomized study of the effect of depomedroxyprogesteroneacetate on the pharmacokinetics of selected protease inhibitorsand non-nucleoside reverse transcriptase inhibitor therapiesamong HIV-infected women. (abstract 82). 12th Conference on

Retroviruses and Opportunistic Infections, Boston, MA; February22-25, 2005.

107. Hesse LM, von Moltke LL, Shader RI, et al. Ritonavir,efavirenz, and nelfinavir inhibit CYP2B6 activity in vitro: poten-tial drug interactions with bupropion. Drug Metab Dispos 2001;29:100-2.

108. Park-Wyllie LY, Antoniou T. Concurrent use of bupro-pion with CYP2B6 inhibitors, nelfinavir, ritonavir and efavirenz:a case series. AIDS 2003;17:638-40.

109. Patel A, Patel K, Patel J, et al. Safety and antiretrovi-ral effectiveness of concomitant use of rifampicin and efavirenzfor antiretroviral-naïve patients in India who are coinfected withtuberculosis and HIV-1. J Acquir Immune Defic Syndr 2004;37:1166-9.

110. Ramachandran G, Hemanthkumar AK, SigamaniRajasekaran S, et al. Increasing nevirapine dose can overcomereduced bioavailability due to rifampicin coadministration. JAcquir Immune Defic Syndr 2006;41:1-6.

111. Tseng A, Nguyen ME, Cardella C, et al. Probable interac-tion between efavirenz and cyclosporine. AIDS 2002;16:505-6.

112. Tseng A. Antiretroviral interactions with transplant medi-cations. www.tthhivclinic.com/pdf/transplant-int.pdf (accessedApril 30, 2006).

113. Geel J, Pitt J, Orrell C, et al. The effect of fluconazoleon nevirapine pharmacokinetics (abstract weOrB1239). XV Inter-national AIDS conference, Bangkok, Thailand. July 11-16, 2004.

114. Mildvan D, Yarrish R, Marshak A, et al. Pharmacokineticinteraction between nevirapine and ethinyl estradiol/norethin-drone when administered concurrently to HIV-infected women.J Acquir Immune Defic Syndr 2002;29:471-7.

115. Gerber JG, Rosenkranz SL, Fichtenbaum CJ, et al. Effectof efavirenz on the pharmacokinetics of simvastatin, atorvas-tatin, and pravastatin: results of AIDS Clinical Trials Group 5108Study. J Acquir Immune Defic Syndr 2005;39:307-12.

116. Burman W, Orr L. Carbamazepine toxicity after startingcombination antiretroviral therapy including ritonavir andefavirenz. AIDS 2000;14:2793-4.

117. Mateu de Antonio J, Grau S, Gimeno-Bayon JL, et al.Ritonavir-induced carbamazepine toxicity. Ann Pharmacother2001;35:125-6.

118. Kato Y, Fujii T, Mizoguchi N, et al. Potential interac-tion between ritonavir and carbamazepine. Pharmacotherapy2000;20:851-4.

119. Honda M, Yasuoka A, Aoki M, et al. A generalizedseizure following initiation of nelfinavir in a patient with humanimmunodeficiency virus type I infection, suspected due to inter-action between nelfinavir and phenytoin. Intern Med 1999;38:302-3.

120. Van der Lee MJ, Dawood L, ter Hofstede H, et al.Lopinavir/ritonavir reduces lamotrigine plasma concentrations inhealthy subjects. Clin Pharmacol Ther 2006; 80(2):159-168.

121. Foisy M, Tseng A. Predicted interactions between psychotropics and protease inhibitors/non-nucleoside reversetranscriptase inhibitors. www.tthhivclinic.com/pdf/psych-int.pdf(accessed April 30, 2006).

122. Penzak SR, Chuck SK, Stajich GV. Safety and efficacy ofHMG-CoA reductase inhibitors for treatment of hyperlipidemia inpatients with HIV infection. Pharmacotherapy 2000;20:1066-71.

123. Van der Lee MJ, Schippers E, Koopmans P, et al. Phar-macokinetics of combined use of lopinavir/ ritonavir and rosu-vastatin in HIV-infected patients (abstract 25). 6th InternationalWorkshop on Clinical Pharmacology of HIV Therapy, Quebec,Canada; April 28-30, 2005.

124. Drommentuyn KML, Mulder JW, Sparidans RW, et al.Drug-drug interaction between itraconazole and the antiretro-viral drug lopinavir/ritonavir in an HIV-1-infected patient withdisseminated histoplasmosis. Clin Infect Dis 2004;38:e73-e75.

125. Samaras K, Pett S, Gowers A, et al. Iatrogenic Cush-ing’s syndrome with osteoporosis and secondary adrenal failurein human immunodeficiency virus-infected patients receivinginhaled corticosteroids and ritonavir-boosted protease inhibitors:six cases. J Clin Endocrinol Metab 2005:90:4394-8.

126. Clay PG, Adams MM. Pseudo-parkinson disease sec-ondary to ritonavir-buspirone interaction. Ann Pharmacother2003;37:202-5.

127. Van Heeswijk R, Sabo JP, Cooper C, et al. The phar-macokinetic interaction between tipranavir/ritonavir (500/200)bid and atorvastatin, antacid, and CYP3A4 in healthy adult vol-unteers (abstract 5.2). 5th International Workshop on ClinicalPharmacology of HIV Therapy, Rome, Italy; April 1-3, 2004.

128. Hall MC, Ahmad S. Interaction between sildenafil andHIV-1 combination therapy. Lancet 1999;353: 2071-2.

129. Pfizer Canada. Vfend (voriconazole) product mono-graph. Kirkland, Que.: May, 2006.

Continued from page 34

WEB444 PHARMACY PRACTICE / OCTOBER 2006 www.pharmacygateway.ca / VOL 22, NO 10

SELECTED DRUG INTERACTIONS WITH NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASEINHIBITORS17,33,34,36, 43, 45,47,60,91-101*TABLE 4

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)Class interactions: NRTIs are primarily renally eliminated and are not involved in the CYP450 enzyme system. They require intra-cellular phosphorylation to become active and may interact with agents that compete with, or modulate this process.

NRTI Interacting drug Potential consequence RecommendationGeneric name(code name)

zidovudine (AZT) amphotericin; anti- additive bone consider using alternate NRTI; add G-CSF neoplastics; flucytosine; marrow suppression or EPO if appropriatepyrimethamine; TMP/SMX (high dose); valganciclovir/ganciclovir

ribavirin additive risk for anemia consider using alternate NRTI

stavudine in vitro antagonism avoid combination

valproic acid ↑ zidovudine concentrations use with caution and monitor for leading to severe anemia zidovudine toxicity

stavudine (d4T) zidovudine in vitro antagonism avoid combination

didanosine; isoniazid; additive neurotoxicity monitor for neurotoxicity and consider vinca alkaloids alternative NRTI

intravenous pentamidine additive risk of pancreatitis avoid combination if possible

ribavirin potential for additive avoid combination if possiblemitochondrial toxicity

tenofovir (TDF) atazanavir ↓ atazanavir and ↑ tenofovir add ritonavir to overcome ↓ atazanavir concentrations concentration; monitor kidney function

routinely for toxicity

didanosine ↑ didanosine levels and avoid combination or consider reducing ↓ CD4 counts didanosine dose (i.e., didanosine EC

250 mg/day for pts > 60 kg, didanosine EC 200 mg/day for pts < 60kg)

lopinavir/ritonavir ↑ tenofovir concentration routinely monitor kidney function for and ↓ LPVr levels toxicity

didanosine (ddI) ribavirin ↑ didanosine levels avoid combination

allopurinol ↑ didanosine concentrations consider 50% dose reduction of didanosine

isoniazid; stavudine; additive neurotoxicity monitor for neurotoxicity and consider vinca alkaloids alternative NRTI

intravenous pentamidine additive risk of pancreatitis avoid combination if possible

tenofovir ↑ didanosine and ↓ CD4 avoid combination or consider reducing response didanosine dose (i.e., didanosine EC

250 mg/day for pts > 60 kg, didanosine EC 200 mg/day for pts < 60kg)

tipranavir ↓ tipranavir concentration separate administration times

ganciclovir ↑ didanosine concentration consider 50% dose reduction in didanosine or use alternate NRTI

didanosine atazanavir; delavirdine; decreased absorption of acid- separate administration times(buffered tablets indinavir (without ritonavir); dependent drugs and those only) itraconazole; ketoconazole; prone to chelation with cations

quinolones; tetracycline

lamivudine (3TC) emtricitabine similar resistance profile, thus avoid combinationno potential benefit

emtricitabine (FTC) lamivudine similar resistance profile, thus avoid combinationno potential benefit

abacavir (ABC) no significant drug interactions requiring dose adjustments identified

*Table summarizes commonly encountered interactions; it is not intended to be all inclusive.EC = enteric coated; EPO = epoetin; G-CSF = granulocyte colony stimulating factor; LPVr = lopinavir/low-dose ritonavir; NRTI = nucleoside reverse transcriptase inhibitor; pts = patients; TMP/SMX = trimethoprim/sulfamethoxazole

VOL 22, NO 10 / www.pharmacygateway.ca OCTOBER 2006 / PHARMACY PRACTICE WEB445

SELECTED POTENTIAL INTERACTIONS BETWEEN THE NNRTIs EFAVIRENZ (EFV) AND NEVIRAPINE (NVP)AND COMMONLY USED DRUGS49,50,88,102-116*TABLE 5

Drug class/drug Mechanism and result of interaction Recommendationbenzodiazepines

• alprazolam • possible ↓ zopiclone and benzodiazepine level • may require ↑ benzodiazepine dose to minimize • clonazepam resulting in loss of efficacy through CYP3A4 withdrawal symptoms or consider using alternatives:• diazepam induction by EFV or NVP - chloral hydrate• midazolam • competition for CYP3A4 by EFV may lead to - lorazepam• triazolam prolonged effect from midazolam or triazolam - oxazepam

other sedatives - temazepam• zopiclone • use of midazolam or triazolam is contraindicated

with EFV

antifungals

• fluconazole • ↓ ketoconazole levels and ↑ NVP concentrations; • due to potential risk of subtherapeutic antifungal • ketoconazole no data with EFV activity, consider fluconazole for serious fungal • itraconazole • ↑ NVP concentrations seen with fluconazole infections if appropriate; however, monitor NVP closely • voriconazole • ↓ voriconazole levels and ↑ EFV levels for signs of toxicity

• use of voriconazole contraindicated with EFV

antimycobacterials

• clarithromycin • ↓ clarithromycin and ↑ 14-OH metabolite • clinical significance unknown; may consider through CYP3A induction azithromycin as alternative macrolide

• rifampin • conflicting results when combined with EFV • consider ↑ EFV to 800 mg/day, especially for patients • ↓ NVP levels through CYP3A4 induction by > 60 kgrifampin; clinical significance unclear • may consider ↑ NVP to 300 mg BID or consider using

rifabutin as alternative

• rifabutin • ↓ rifabutin levels through CYP3A4 induction • no dose adjustment required when co-administered by EFV; no significant effect with NVP with NVP; increase dose to rifabutin 450 mg/day with

concomitant EFV

antidepressants

• citalopram • potential for ↓ levels of citalopram or • may require increased dose of antidepressant for • sertraline sertraline from CYP3A4 enzyme induction therapeutic efficacy

• bupropion • in vitro inhibition of bupropion metabolism • although no toxic effects (i.e., seizures) were seen in by CYP2B6 inhibition by EFV one case series, suggest monitoring closely for

• fluoxetine • potential for increased NVP levels through bupropion-related toxicityenzyme inhibition by norfluoxetine

HMG-CoA reductase inhibitors

• atorvastatin • potential for ↑ anti-lipid agent clearance • may require dose increase to achieve therapeutic • lovastatin through enzyme induction by EFV or NVP effect • pravastatin• simvastatin

immunosuppressants

• corticosteroids • potential for ↓ levels through EFV- or • monitor cyclosporine or tacrolimus levels closely and • cyclosporine NVP-induced CYP3A4 induction adjust dosage accordingly• tacrolimus

miscellaneous

ergot derivatives • competition for CYP3A4 by EFV may lead to • combination with EFV contraindicatedinhibition of ergot derivatives

methadone • possible ↓ methadone levels through CYP3A4 • monitor for signs of withdrawal and adjust dose and CYP2B6 induction accordingly

ethinyl estradiol • ↓ ethinyl estradiol levels by NVP • use additional or alternate method of contraception; • no interaction with EFV consider depot medroxyprogesterone

*Table summarizes commonly encountered interactions; it is not intended to be all inclusive.NNRTI = nonnucleoside reverse transcriptase inhibitor

WEB446 PHARMACY PRACTICE / OCTOBER 2006 www.pharmacygateway.ca / VOL 22, NO 10

SELECTED POTENTIAL INTERACTIONS BETWEEN PIs OR DELAVIRDINE AND COMMONLY USEDDRUGS5,9,34,40-47,48,51,59,66,71,86,88,102,109,113, 117-130*TABLE 6

antiarrhythmics• amiodarone • risk of ↑ levels of antiarrhythmics through • contraindicated with ritonavir-containing regimens; • encainide CYP enzyme inhibition otherwise, use with caution• flecainide• propafenone• quinidine• digoxin • potential ↑ digoxin levels due to Pgp monitor digoxin levels and adjust dose accordingly

inhibition by PIsanticonvulsants• carbamazepine • ↓ PI levels through enzyme induction by • consider alternative antiseizure medications:• phenytoin anticonvulsants - gabapentin

• in addition: risk of carbamazepine toxicity - lamotrigine (see below)through CYP3A4 inhibition - levetiracetam• potential for subtherapeutic phenytoin levels - valproic acid (see below)through CYP2C9/19 induction by nelfinavir and lopinavir/ritonavir

• lamotrigine • potential for subtherapeutic lamotrigine or • if combined with ritonavir or nelfinavir, increased • valproic acid valproic acid levels through glucuronidation doses of lamotrigine or valproic acid may be required.

induction by ritonavir or nelfinavirantidepressantsselective serotonin reuptake inhibitors (SSRIs):

• potential for ↑ SSRI levels due to various • monitor for SSRI side effects, including signs of enzyme inhibition serotonin syndrome, and lower dose accordingly

• citalopram • CYP3A4: citalopram, sertraline• fluoxetine • CYP2C19: citalopram• fluvoxamine • CYP2D6: fluoxetine, fluvoxamine, paroxetine• paroxetine • ↓ paroxetine and sertraline levels when • monitor for loss of SSRI effect and titrate dose • sertraline co-administered with darunavir accordingly

• ↓ paroxetine levels when co-administered with fosamprenavir/ritonavir• potential for ↑ PI or delavirdine levels from enzyme inhibition by norfluoxetine

tricyclic antidepressants (TCAs):• amitriptyline • potential for ↑ TCA concentrations from • monitor for TCA-related toxicities and consider lower • clomipramine CYP2D6 inhibition from ritonavir doses• desipramine• imipramine• nortriptylineother antidepressants:

• bupropion • in vitro inhibition of bupropion metabolism • although no toxic effects (i.e., seizures) were seenby CYP2B6 inhibition by ritonavir and nelfinavir in one case series, suggest monitoring closely for

bupropion-related toxicity• trazodone • ↑ trazodone levels through CYP3A4 inhibition • consider using lower doses of trazodone and monitor

and CYP2D6 (minor) closely• venlafaxine • potential for ↑ venlafaxine levels through • monitor for venlafaxine toxicity and adjust dose

CYP2D6 and CYP3A4 inhibition accordinglybenzodiazepines/other sedatives• alprazolam • possible ↑ benzodiazepine/anxiolytic con- • use of midazolam and triazolam is contraindicated• clonazepam centration resulting in prolonged sedation or with all PIs or delavirdine• diazepam Parkinson-like symptoms (buspirone) through • alprazolam, diazepam and flurazepam are contraindi-• midazolam CYP3A4 inhibition cated with ritonavir• triazolam • consider using alternatives:• buspirone - chloral hydrate• zopiclone - lorazepam

- oxazepam- temazepam

• (potential ↓ levels of lorazepam, oxazepam, and temazepam by nelfinavir or ritonavir through glucuronidation induction)

HMG-CoA reductase inhibitors • atorvastatin • ↑ concentration of statins by inhibition of • use of lovastatin and simvastatin contraindicated • lovastatin CYP3A4, increasing risk of myopathy or with delavirdine or PIs; atorvastatin may be used • simvastatin rhabdomyolysis cautiously at low doses• pravastatin • ↑ concentration of pravastatin by darunavir • consider using alternate statin:• rosuvastatin • ↑ concentration of rosuvastatin by lopinavir/ - fluvastatin

ritonavir - pravastatin (caution with darunavir)- rosuvastatin (monitor closely with lopinavir/ritonavir)

Drug class/drug Mechanism and result of interaction Recommendation

VOL 22, NO 10 / www.pharmacygateway.ca OCTOBER 2006 / PHARMACY PRACTICE WEB447

SELECTED POTENTIAL INTERACTIONS BETWEEN PIs OR DELAVIRDINE AND COMMONLY USEDDRUGS5,9,34,40-47,48,51,59,66,71,86,88,102,109,113, 117-130*TABLE 6

antifungals• fluconazole • potential for ↑ concentrations of ketoconazole • monitor closely for toxicity if > 200 mg/day of • ketoconazole and itraconazole via CYP3A4 inhibition ketoconazole or itraconazole needed• itraconazole• voriconazole • in vitro studies showed potential for inhibition • monitor closely for voriconazole toxicity

of voriconazole metabolismcalcium channel blockers• diltiazem • potential for ↑ levels of calcium channel • consider reducing dose of calcium channel blocker to • verapamil blockers from CYP3A4 inhibition minimize risk of hypotension or bradycardia• amlodipine• felodipineantimycobacterials• clarithromycin • ↑ clarithromycin through CYP3A4 inhibition • dose adjustment suggested for patients with renal

impairment; reduce clarithromycin dose by 50% if CrCl30–60 mL/min, 75% if CrCl < 30 mL/min• reduce clarithromycin dose by 50% if combined withatazanavir, or use azithromycin

• rifabutin • significantly ↑ levels of rifabutin by PIs • use rifabutin 150 mg q2d or 3x/week with all boosted • significant ↓ levels of delavirdine PIs or atazanavir

• may use rifabutin 150 mg/d with nelfinavir 1250 mg BID• avoid use with delavirdine

inhaled corticosteroids• fluticasone • potential for increased systemic steroid co-administration not recommended with any ritonavir-

exposure leading to adrenal suppression via boosted PI unless benefit outweighs risk; monitor for CYP3A4 inhibition Cushing's syndrome and other steroid-associated effects

acid-reducing agents• antacids • ↓ absorption of atazanavir, delavirdine, • separate administration times from antacids • H2-receptor unboosted indinavir, tipranavir/ritonavir • H2RAs: administer atazanavir 400 mg/day at least antagonists (H2RAs) 2 hours before and at least 10 hours after the H2RA,

or use atazanavir/ritonavir 300 mg/100 mg per day without need for separation; for patients receiving atazanavir/ritonavir 300 mg/100 mg per day, administer atazanavir at least 2 hours before and at least 10 hours

• proton pump after the H2RAinhibitors (PPIs) • avoid PPIs with unboosted or boosted atazanavirethinyl estradiol

• ↓ ethinyl estradiol concentrations by ritonavir, • use additional or alternate contraceptiontipranavir, nelfinavir and lopinavir/ritonavir through glucuronidation induction• ↑ ethinyl estradiol concentrations with • use low-dose estrogen products and monitor for atazanavir through inhibition of glucuronidation adverse effects if combined with atazanavir

methadone• ↓ methadone levels by induction of methadone • monitor for withdrawal symptoms and increase metabolism by ritonavir, lopinavir and nelfinavir methadone dose if needed

immunosuppressants• corticosteroids • ↑ risk of corticosteroid-related toxicity and • monitor for increased corticosteroid effects and • cyclosporine • ↑ cyclosporine and tacrolimus concentrations cyclosporine or tacrolimus levels for appropriate • tacrolimus through CYP3A4 inhibition adjustmentsphosphodiesterase type 5 (PDE5) inhibitors

• ↑ concentrations of PDE5 inhibitors via dose should not exceed:• sildenafil CYP3A4 inhibition • sildenafil 25 mg q48h• tadalafil • tadalafil 10 mg q72h• vardenafil • vardenafil 2.5mg q72hlevothyroxine

• ↓ levothyroxine concentration through • monitor thyroid hormone levels (e.g., TSH, free T4) or induction of glucuronyl transferase by ritonavir for signs of hypo- or hyperthyroidism depending on • potential ↑ levothyroxine levels through interacting agentinhibition of metabolism by indinavir

*Table summarizes commonly encountered interactions; it is not intended to be all inclusive.CrCl = creatinine clearance; NNRTIs = nonnucleoside reverse transcriptase inhibitors; NVP = nevirapine; Pgp = P-glycoprotein; PI = protease inhibitor; TSH = thyroid-stimulating hormone

Drug class/drug Mechanism and result of interaction Recommendation