HIV Postexposure Prophylaxis and
the Need for Drug Interaction Screening

Roger Cheng, Julie Greenall, Christine Koczmara, and Sylvia Hyland Contributions to this column are prepared by the Institute for Safe Medication Practices Canada (ISMPCanada), a key partner in the Canadian Medication Incident and Prevention System, and include, withpermission, material from the ISMP Canada Safety Bulletin. The present article is based on "Drug interaction incident with HIV post-exposure prophylaxis", ISMP Can Saf Bull 2008;8(3):1-2. From time totime, ISMP Canada invites others to share learning based on local initiatives. of postmortem examination and serum drug levels, the cause of death was determined to be fentanyl toxicity due to an Certain antiretroviral medications are known to be involved interaction with Kaletra. in numerous drug interactions through their inhibition of the cytochrome P450 system.1,2 One of the uses of antiretroviral medications is postexposure prophylaxis (PEP) against HIV, toreduce the risk of infection among people who may have been Failure to identify the clinically significant drug interac- tion between ritonavir and fentanyl was identified as possibly exposed to the virus, either through occupational exposure (e.g., contributing to the sentinel event described in the case report.
needlestick injuries) or non-occupational exposure (e.g., sexual Ritonavir is a potent inhibitor of the CYP 3A4 enzyme, assault).3,4 To maximize effectiveness in this situation, antiretroviral which is responsible for metabolizing fentanyl.6 In a study therapy must be started as soon as possible (preferably within evaluating the interaction between ritonavir and IV fentanyl,7 hours of exposure)3-5; therefore, if a person is deemed a suitable the authors found that fentanyl clearance was reduced to candidate for prophylaxis, an HIV PEP "starter kit" is often given one-third when ritonavir 200 mg, given 3 times per day, was to the patient in the emergency department or other ambulatory added to the drug regimen. The authors concluded that setting to ensure prompt initiation. When providing HIV PEP ritonavir treatment results in an approximately 3-fold increase in this setting, a systematic approach for identifying possible drug in fentanyl concentrations,7 an interaction of major clinical interactions may be lacking. As illustrated by the following case, significance.8 Administration of Kaletra for HIV PEP delivers a these interactions can have severe consequences if not promptly ritonavir dose of 100 mg twice per day (about one-third the identified and resolved. dose in the study by Olkkola and others7). Studies of the effecton fentanyl concentration as a result of an interaction with a CASE REPORT
lower dose of ritonavir (as in the HIV PEP protocol) have notbeen published. Of interest, product monographs for the A 46-year-old patient was given a "starter" medication kit fentanyl patch (e.g., Duragesic9) list ritonavir as an interacting for HIV PEP, containing Kaletra (lopinavir and ritonavir) and drug. However, the ritonavir product monographs (for Combivir (zidovudine and lamivudine), by a hospital emergency Kaletra,10 Norvir,11 and Norvir SEC11) do not include fentanyl department. The patient's regular medications were noted as in the list of interacting medications.
venlafaxine, amitriptyline, bupropion, hormone replacementtherapy, and fentanyl patch 100 mcg/h. About 4 days after SELECTED RECOMMENDATIONS OF HIGH
initiation of PEP, the patient was noted to be very drowsy and RELEVANCE TO PHARMACISTS
needed to be frequently wakened. The patient went to lie downand some time later that evening was found unresponsive.
Identification and resolution of drug interactions is an Resuscitation attempts were not successful. On the basis important component of pharmacists' patient care responsibil- C J H P – Vol. 61, No. 6 – November –December 2008 J C P H – Vol. 61, no 6 – novembre –décembre 2008 ities. The following recommendations highlight key areas 2. Lee LM, Henderson DK. Tolerability of postexposure antiretroviral where pharmacists can assist in the implementation of processes prophylaxis for occupational exposures to HIV. Drug Saf2001;24(8):587-597. to reduce the potential for harm due to drug interactions with 3. Panlilio AL, Cardo DM, Grohskopf LA, Heneine W, Ross CS. Updated U.S. Public Health Service guidelines for the management of • Develop and use a systematic approach (e.g., predefined occupational exposures to HIV and recommendations for postexposureprophylaxis. MMWR Recomm Rep 2005 [cited 2008 Apr 25]; electronic or printed order sets) for HIV PEP that includes 54(RR-9):1-17. Available from: documentation of any medications that patients are mmwrhtml/rr5409a1.htm currently taking. (This approach provides additional support 4. Smith DK, Grohskopf LA, Black RJ, Auerbach JD, Veronese F, Struble KA, et al. Antiretroviral postexposure prophylaxis after sexual, for medication reconciliation in the ambulatory setting.) injection-drug use, or other nonoccupational exposure to HIV in the • For patients taking any other medications, require an United States: recommendations from the U.S. Department of Health evaluation of the potential drug interactions using an and Human Services. MMWR Recomm Rep 2005 [cited 2008 Apr25];54(RR-2):1-20. Available from: electronic medication information database (e.g., pharmacy information system or Micromedex), preferably by a 5. Loutfy M. Medical guidelines for HIV post-exposure prophylaxis (HIV pharmacist. This evaluation should be done either before PEP) for sexual assault victims/survivors [Internet]. Rev. ed. Ontario Network of Sexual Assault/Domestic Violence Treatment Centres;2007 the HIV PEP medications are given to the patient or as soon Apr [cited 2008 Feb 1]. Available from: as possible after the first dose. • For treatment centres and clinics without access to an 6. Micromedex Healthcare Series. DRUGDEX evaluations: Kaletra.
Greenwood Village (CO): Thomson Scientific and Healthcare; c1974- on-site or on-call pharmacist, arrange a consultation service 2008 [cited 2007 Apr 28]. Available: with a local community pharmacy. products/hcs/. Subscription required to access content.
• If the concomitant use of ritonavir and transdermal fentanyl 7. Olkkola KT, Palkama VJ, Neuvonen PJ. Ritonavir's role in reducing fentanyl clearance and prolonging its half-life. Anesthesiology is required, reassess the fentanyl dosage, overall pain 1999;91(3):681-685. management, and monitoring.
8. Micromedex Healthcare Series. Micromedex drug interaction search.
• Counsel the patient regarding any potential adverse effects, Greenwood Village (CO): Thomson Scientific and Healthcare. c1974-2008 [cited 2007 Apr 28]. Available: including those that might arise from possible drug interac- products/hcs/. Subscription required to access content.
tions, and provide advice about when to seek immediate 9. Duragesic® product monograph. In: Compendium of pharmaceuticals medical attention. and specialties. Ottawa (ON): Canadian Pharmacists Association; 2008.
p.746-750. • Provide written information, including the complete 10. Kaletra® product monograph. In: Compendium of pharmaceuticals and medication list and HIV PEP prescribed, and advise the specialties. Ottawa (ON): Canadian Pharmacists Association; 2008.
patient to take this written information to the health care 11. Norvir®, Norvir SEC® product monograph. In: Compendium of provider(s) who will be seeing the patient in follow-up. pharmaceuticals and specialties. Ottawa (ON): Canadian PharmacistsAssociation; 2008. p.1552-1557. 12. Medication error prevention "toolbox". ISMP Med Saf Alert 1999 [cited 2008 Feb 1];4(11):1. Available from: With the ever-growing numbers of available drugs and potential drug interactions, an electronic check for drug Roger Cheng, RPh, BScPhm, Pharm D, is an Analyst with ISMP
interactions is an important safeguard. The provision of HIV Canada, Toronto, Ontario.
PEP medications directly to patients is an example of processes Julie Greenall, RPh, BScPhm, MHSc, FISMPC, is a Project Leader with
that may bypass drug-interaction screening. Since patients ISMP Canada, Toronto, Ontario.
receiving HIV PEP rarely need to be admitted to hospital, their Christine Koczmara, RN, BSc, is a Senior Analyst with ISMP Canada,
medications are not routinely entered into the hospital Toronto, Ontario.
pharmacy information system, which means there may be no Sylvia Hyland, RPh, BScPhm, MHSc, is Vice-President, ISMP Canada,
Toronto, Ontario.
opportunity for an automated check for drug interactions.
ISMP Canada homepage:
Although some treatment centres have developed their ownlists of important drug interactions involving HIV PEP, manual checks may be less reliable and are prone to humanerror.12 Given the high potential for clinically significant druginteractions associated with HIV PEP medications, Medication incidents (including near misses) can be reported pharmacists have an important role to play in ensuring to ISMP Canada in 1 of 2 ways: that processes for provision of HIV PEP include electronic • through the secure web portal at drug-interaction screening. err_report.htm References
• by telephone at 416.733.3131 or toll-free at 1. Cvetkovic RS, Goa KL. Lopinavir/ritonavir: a review of its use in the 1.866.544.7672 (1.866.54.ISMPC) management of HIV infection. Drugs 2003;63(8):769-802. C J H P – Vol. 61, No. 6 – November –December 2008 J C P H – Vol. 61, no 6 – novembre –décembre 2008



Antiviral Research 71 (2006) 154–163 Antiviral drugs for cytomegalovirus diseases Department of Clinical Virology, Division of Virology, GlaxoSmithKline Inc., RTP, NC, United States Received 15 March 2006; accepted 4 May 2006 Dedicated to Prof. Erik De Clercq on the occasion of reaching the status of Emeritus-Professor at the Katholieke Universiteit Leuven in September 2006


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