California Journal of HealtH-SyStem PHarmaCy

Perspective:Our Legacy of Volunteerism

Continuing Pharmacy Education (CPE):Some Thoughts on Opioid Use in Ante and Post Partum Women

Legislative Day 2010

Clinical Pearls:Think Inside the Box: The Black Box

Case Report:Interaction Between disulfiram and phenytoin

New Practitioner Profile Tech Talk:Medication Error Reduction and Safety

May/June 2010 Volume 22, Number 3

www.cshp.org

California Journal of HealtH-SyStem PHarmaCy

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CJHP-FullPage.pdf 9/9/2009 9:49:10 AM

California Journal of Health-System Pharmacy

Official Journal of the California Society of Health-System Pharmacists1314 H Street, Suite 200, Sacramento, CA 95814

(916) 447-1033 FAX (916) 447-2396 www.cshp.org E-Mail [email protected]

CJHP (ISSN 1097-6337) is published bimonthly by the California Society of Health-System Pharmacists, 1314 H Street, Suite 200, Sacramento, CA 95814, under the guidance of the Editorial Advisory Board. The CJHP is distributed as a regular membership service, paid through allocation of membership dues. Subscription rate for non-members is $75 per year; single copies are $15. Periodicals postage paid at Sacramento, CA. Postmaster: Send address change to California Society of Health-System Pharmacists, 1314 H Street, Suite 200, Sacramento, CA 95814 (email: [email protected]).

The views expressed by authors of contributions in the California Journal of Health-System Pharmacy do not necessarily reflect the policy of CSHP or the institution with which the author is affiliated, unless this is clearly specified. Policy statements and official positions of CSHP are clearly labeled as such. The editor and publisher assume no responsibility for material contained in articles and advertisements published, nor does publication necessarily constitute endorsement by them. Letters to the editor are encouraged. Publisher reserves the right to edit, reject or publish whole or part of manuscripts submitted. No portion of this magazine may be reproduced, in whole or in part, without written consent of CSHP. © 2010 by the California Society of Health-System Pharmacists. Payments to CSHP are not deductible as charitable contributions for federal income tax purposes; however, they may be deductible under other provisions of the Internal Revenue Code.

For display and employment advertising, please contact: C.J. Anderson, CSHP Development & Communications Manager, email at [email protected], or phone (916) 447-1033, ext. 102.

EditorDawn Benton

Managing EditorSara E. Freid

Contributing EditorJeanne Winnick Brennan

Design ConsultantHareLine Graphics

Editorial Advisory Board

CAlifOrniA SOCiEty Of HEAltH-SyStEM PHArMACiStS

Officers Nancy Korman (415) 221-4810President X3493Scott Takahashi (323) 783-1911 Chair, Board of DirectorsKelli Haase (209) 467-6369 Chair, House of DelegatesLisa Gunther Lum (323) 857-2140Treasurer

DirectorsChristine Antczak (609) 265-5955 Sylvia Banzon (916) 453-5797Julianna Burton (916) 734-1426 Sian Carr-Lopez (209) 946-7714 Daniel Dong (510) 625-6321Scott Goodrich (714) 299-9744Kenn Horowitz (323) 953-4507Kenneth Perrin (559) 244-3768Doreen Schneider (661) 398-3648

Directors-electBrian Kawahara (909) 825-7084 X6039Stacey Raff (415) 833-7102Victoria Serrano Adams (858) 626-7790

Student Section Executive Committee Ricky Martinez [email protected] Cynthia Gong [email protected]

Ex-OfficioDawn Benton (916) 447-1033Executive Vice President/CEO X109

Correction:Jan/Feb 2010 issue of CJHP, page 5, Section: Career Path and Service to the Profession, the first sentence should have read, “Nancy completed her pre-pharmacy training from UCLA and her doctor of pharmacy from UC San Francisco.”

Marcus Ravnan, ChairRon Floyd, Past-chairGary BesinqueAlexander CaoRochelle Castro

Kathy DalyCathlene RichmondDan RossCandy TsourounisDoris Wong

Vol. 22 no. 3May/June 2010

Perspective Our Legacy of Volunteerism ..........................................................................4

CSHP’s Seminar 2010 San francisco Seminar in the City .........................................................................................5

Continuing Pharmacy Education Some Thoughts on Opioid Use in Ante and Post Partum Women ....................6

CSHP legislative Day 2010 ..................................................................................17

Clinical Pearls Think Inside the Box: The Black Box ............................................................25

Case report Interaction Between disulfiram and phenytoin ..............................................30

new Practitioner Profile ......................................................................................33

tech talk Medication Error Reduction and Safety .........................................................34

Our legacy of Volunteerism Dawn Benton, MBA Executive Vice President and CEO

Perspective CaliforniaSocietyofHealth-SystemPharmacists

On the heels of our third successful Legislative Day - with images of over 80 CSHP members descending upon the Capitol and

University of the Pacific students conducting our first public health fair still fresh in my mind - I had the unique opportunity to sit down and talk with one of CSHP’s founders whose contributions have made our success possible today.

Norman Ashcraft, PharmD, who served as CSHP president in 1973, first started working with other devoted colleagues that included Kenn Horowitz, Ken Reifman, Joe Beckerman, and Alan Swartz to name a few. Together, they were part of the team that forged three regional chapters of hospital pharmacists (Northern California, Southern California, and San Diego) into our first statewide network in 1962 – the California Council of Hospital Pharmacists.

Norm, who is now retired, brought some important documents to our meeting and shared his valuable historical perspective. More importantly, as he described how they cobbled together those regional chapters, it was clear that what we enjoy today as a hallmark of our society – the keen spirit of volunteerism – has its roots in the collaborative style of our founders.

“A key to our success is that we were all close friends, and we met in each other’s hospitals monthly,” said Norm. “In the early 60s, mem-bers were also very involved with ASHP. We had an active executive committee, and each month we toured the host hospital, a speaker was always provided, and the deans of the pharmacy schools were in attendance at the annual meetings.”

Norm said the touring of each other’s hospitals was enlightening, and they shared many ideas and borrowed organizational concepts as a result. For those of you who have been involved in the collabor-ative-style of organizing our annual Seminar, the first group to blaze that trail held their Seminar October 10-12, 1969 in Stockton at the University of the Pacific and the nearby Holiday Inn. In those early years, Norm said they had some members on the California Board of Pharmacy, which was primarily involved with regulating the retail pharmacists. “They really didn’t know what to do with hospital phar-macists at that time,” he said.

As he toured our headquarters, he smiled in appreciation as he passed the display cases that now house Kenn Horowitz’s collection of antique and vintage pharmacy artifacts. Norm prefaced his com-

ments with a genuine appreciation for our interest in CSHP’s origins, and he was quick to point out that his recollections were only one viewpoint. At a time when CSHP has made recent important strides in legislative and political activism, professional partnerships with other statewide lobbying and regulatory groups, leadership forums, and the acquisition of our permanent headquarters building, it’s really impor-tant to appreciate the journey this organization has taken.

As a group of professionals who are guiding its growth today, we can all benefit by understanding where and how the voyage started. With the approach of CSHP’s 50th anniversary in 2012, the staff and I will share with you and the public in the coming months the informa-tion and stories we gather from our conversations with our leadership team and members; we’ll publish some stories here and on our web site. Our legacy of volunteerism with our peers is something to cel-ebrate. As Norm put it so well, “Friendship is what makes this group.”

My visit with Norm reminded me of the George Bernard Shaw quote that began my report to the 2009 House of Delegates last fall: “Life is no brief candle to me. It is a splendid torch which I have got to hold for the moment, and I want to make it burn as brightly as possible before handing it on to future generations.”

Norm Ashcraft, we thank you for your early efforts. I think I speak for all of us when I say we’re proud to pick up where you left off. u

4 cjhp: California Journal of Health-System Pharmacy May/June 2010

CSHP’s Seminar in the City San francisco 2010

What do the Golden Gate Bridge, Napa Valley, Union Square, networking pharmacy professionals, golfing and the Phun Run all have in common? It’s Seminar 2010 and it’s coming to San Francisco this October! “Seminar in the City” will be held October 21-24 at the Hilton Hotel located in the heart of San Francisco’s Union Square and you won’t want to miss it!

The 2010 Seminar Management Team presented a fashion show during Opening Session at Seminar 2009, featuring various high-lights of San Francisco from the iconic Golden Gate Bridge to scenic Chinatown and everything in between. It has been 17 years since Seminar was last in San Francisco and we hope that it will be one of the most successful events yet!

To start things off right we have landed a fantastic keynote speak-er – Edward H. O’Neil, PhD, MPA. Dr. O’Neil’s address, “Leadership Success in the Changing Health Care System” will explore the drivers of health care change, what will make for strategic success in this transition, and how hospital pharmacists can play an active leadership role.

Whether you’re a director of pharmacy, clinical pharmacist, pharmacy technician, resident pharmacist or student pharmacist, Seminar 2010 will provide you with a chance to network with other professionals and enhance your skills. As always, Seminar provides a wonderful opportunity to attend a wide variety of Continuing Pharmacy Education programs. There will be over 70 hours of CPE to choose from for pharmacists and technicians this year. Educational tracks will include Administrative/Management, Clinical, Professional Development, and Technicians.

CPE events are not the only opportunity to learn about the lat-est advances in the industry. This year’s Exhibit Hall will boast over 100 exhibitors, including Hospira, Octapharma USA, Pfizer, Inc., and Upsher-Smith Laboratories, showcasing the latest products and technologies that will appeal to all members in the pharmaceutical profession. In addition to the exhibit hall and CPE courses, attend-ees will have an opportunity to earn additional educational credit through our exhibitor theaters. This year Seminar will feature Zero Tolerance for HAI’s hosted by Vemco MedEd; Sedation Education Demonstrating Advances in the Intensive Care and Perioperative

Settings: 2010 CME Curriculum hosted by the France Foundation; and Managing Hyponatremia: Challenges and Opportunities for the Hospital Pharmacist hosted by the Illinois Council of Health-System Pharmacists/Missouri Society of Health-System Pharmacists. More events are in the works!

One of the most successful events at Seminar 2010 will no doubt be the Residency Showcase. With 8 schools of pharmacy graduating hundreds of students each year, there are many residency programs available. Seminar provides an excellent venue for students to meet current residents and program directors from all across the state. Other student programming highlights will include the Quiz Bowl, Clinical Skills Competition and of course the popular Student Mixer.

“Seminar in the City” will be in beautiful San Francisco so there will be plenty of wonderful sights in the city to take in or even in nearby Wine Country or Monterey. Just need a little break from Seminar? Union Square is home to hundreds of shops, art galleries, and wonderful restaurants within walking distance from the Hilton. Visit the Seminar 2010 website at http://seminar.cshp.org for all the “Hot Spots” around the city.

San Francisco is also known for its wonderful October weather, which should be perfect for the Golf Tournament that will be held at the Lincoln Park Golf Club in Golden Gate Park on October 21 and for the Phun Run event through the scenic sights of San Francisco on October 23. Don’t forget to sign-up for these events early – space is limited!

“Seminar in the City” is shaping up to be an exciting event this year! With the Seminar Management Team hard at work, you won’t want to miss out on all the wonderful events that are being planned for YOU! If you have never been to Seminar before, this year’s meet-ing is the perfect one for you to discover what the largest state run gathering of pharmacy professionals is all about and if you have been to Seminar in the past, we hope that the new programming and events make “Seminar in the City” one to never forget!

See you in San Francisco! u

CSHPSeminar2010

Shital Patel Kelshikar, PharmD Kali Sommer, PharmD Seminar Management Team 2010 Co-chairs

May/June 2010 cjhp: California Journal of Health-System Pharmacy 5

introductionThe writing of this article resulted from an earnest desire

to improve this pharmacist’s management of pain for patients in our women’s hospital. Specifically, for women who were suffering from poorly controlled pain and who were either pregnant, post-partum, or post-gynecologic surgery. Narrowing down, the control of pain during labor and imme-diately thereafter is with very rare exception, well managed by our anesthesiology staff, and thus, not our direct concern. Further, pain occuring in the great majority of our post-partum and post-surgery patients is adequately addressed by our institutional protocols. Rather, the focus of these efforts is upon a few, simple strategies for the use of opioid medi-cations for relieving moderate to severe, acute or sub-acute pain in women who are experiencing “uncontrollable” pain or who are demonstrating a need for administration of “exces-sive” amounts of opioids at “overly frequent” intervals.

This article covers selected material on the pharmacoki-netics, pharmacodynamics and pharmacogenetics of some common opioids, on the perception of pain relief by those opioids, and ends with a few suggestions for personalizing therapy. But first I present some background material helpful to understanding the unique physiological changes extant in the pregnant woman and their potential impact on medica-tion administration.

ContinuingPharmacyEducation

Some thoughts on opioid use in ante and Post Partum Women

Ronald A. Floyd, PharmD, MS, BCPS, FCCP PharmacistSpecialist SharpMaryBirchHospitalforWomenandNewborns 3003HealthCenterDrive SanDiego,CA92123

AssistantClinicalProfessor,Voluntary SkaggsSchoolofPharmacyandPharmaceuticalSciences UniversityofCalifornia,SanDiego

ClinicalAssistantProfessorofPharmacyPractice CollegeofPharmacy,WesternUniversityofHealthSciences Pomona,California [email protected]

Afterreadingthisarticle,thereadershouldbeableto:

1. Identify at least two physiological alterations associated with pregnancy that can change the pharmacokinetic behavior of an opioid analgesic.

2. Distinguish among common opioid analgesics with respect to their metabolic or elimination paths.

3. Identify the primary receptor with which common opioid analgesics interact, and other receptors that might modify its behavior.

4. Compare the pharmacokinetic and pharmacodynamic behaviors of selected common opioids.

5. Select from among opioids, the one that best resolves a specified clinical problem in pain management.

Continuing PharmacyEducation Learning Objectives:


CPE: Opioid Use in Ante and Post Partum Women

Physiological Changes in PregnancyIt bears pointing out that other factors affecting physiol-

ogy were sifted through to get to this point, for example, gender, ethnicity, age. These and other patient specific factors must be considered for the initial determination of the patient’s regimen. Physiological changes occurring in pregnancy can affect each of the basic processes of phar-macokinetics – absorption, distribution, metabolism and excretion. Absorption is affected by the slowing of gastroin-testineal motility that takes place during pregnancy. This can delay absorption of orally administered drugs, particularly delayed-release compounds; however, the effects on extent of absorption are variable. Slowed gastrointestineal transit times can allow for increased absorption of some drugs. Increased hepatic blood flow can result in an increased first pass effect, decreasing systemic bioavailability. Increased subcutaneous blood flow can result in increased rate of absorption of transdermally administered medications.

Distribution of drugs within the body is also affected by pregnancy through several changes, primarily cardiovascular. Both cardiac output and plasma volume increase during preg-nancy by up to 50% to accomodate the placenta and fetus. The placenta will receive almost 30% of cardiac output – about one sixth of maternal blood volume is within the uterus, placenta and fetus at any one time. Total body water increases by an average of 8 liters. While about 5 of these liters resides within the uterus, placenta and fetus, the remaining 3 liters is distributed within the vasculature and maternal tissues. One consequence is that plasma albumin decreases, resulting in a shift in the bound/unbound drug equilibrium. This can affect both distribution of the drug as well as the fraction of drug available for excretion and/or metabolism. Total body fat also increases by about 25%.

Together, the increases in body water and body fat lead to increases in distribution volume of both hydrophilic and lipo-philic substances. The change in distribution volume can be reflected in altered substance elimination, particularly when the elimination route is not limited by capacity. At the same time, renal blood flow increases to the extent that glomeru-lar filtration rate can increase up to 50%. Correspondingly, clearance of renally excreted substances can increase. This includes drugs, their metabolites, and endogenous substances such as BUN and creatinine. Thus the typical serum creati-nine during pregnancy can be much lower than usual for an adult female, for example, 0.3 mg/dl as opposed to 0.8 mg/dl.

The changes in pulmonary function also potentially affect urinary excretion of some medications. Pulmonary tidal volume, respiratory rate and pulmonary blood flow are all increased to produce increased oxygen intake and increased

carbon dioxide loss. Increased carbon dioxide loss (respira-tory alkalosis) is compensated with increased bicarbonate loss through the kidneys (metabolic acidoisis). The average urinary pH increases by about 0.5 units. This can affect the urinary excretion of drugs and metabolites having a pKa within the usual pH range of the urine. Metabolism can be affected by both the increase in hepatic blood flow and the increase in the free (unbound) fraction of the more tightly bound drugs. Further, the placenta has some metabolic abil-ity as it has both cytochrome p450 and conjugative enzymes, indeed as does the fetus later in term, although these are limited in type and capacity.

Selected Properties of Some Common OpioidsAs a part of our effort to better manage pain, we wish to

select from among the available opioids – those that will best suit our patients’ needs. Consideration of a review of the properties led us to first examine drug-receptor interactions.

Opioid receptors are located both in the central nervous system and the peripheral tissues. The three main opioid receptors are the mu (m), the kappa (k), and the delta (d). The subtypes of the mu receptor are the m1 and the m2. Mu recep-tors have also been called MOR or OP3 receptors. Analgesia is typically associated with stimulation of the mu receptor. Agonist stimulation of these transmembrane receptors causes intracellular activation of one of the G protein subfamilies, which then, depending on the type of cell, acts further on enzymes (for example, adenylate cyclase) or ion channels to bring about the end effect(s). Because the activation of the G protein can be measured, the potency and efficacy of vari-ous opioids can be assessed in vitro, purely at the receptor level, using, for example, human opioid transfected Chinese hamster ovary cells.1 In Figure 1, the efficacies of some com-monly available opioids are compared relative to morphine, which has been assigned a value of 1. In this model system, oxycodone was nearly as efficacious as morphine. Following in order of decreasing efficacy were oxymorphone, hydro-morphone, then more distantly, codeine and hydrocodone.

In Figure 2 the relative potencies are displayed, with mor-phine again being assigned a value of 1. Hydromorphone was found to be the most potent, followed by oxymorphone, then morphine. Nearly an order of magnitude lower in potency were oxycodone and hydrocodone, followed distantly by codeine. It is interesting that at the receptor level, the ratio of potency between hydromorphone and morphine is about the same as seen for their intravenous dosage forms, that is, hydromorphone being between 5 and 7.5 times more potent than morphine. Looking at Figure 3, the structures of these compounds, and Figure 2 again, one is immediately struck



by the association between the 3-OH compounds and their substantial potency as contrasted with their 3-MeOH cogen-ers and their lesser potency.

As the opioid molecules have a number of functional groups available for biotransformation, they are in general subject to both Phase 1 and Phase 2 alterations. While most of these have the intended result of inactivation and easier elimination, some alterations yield compounds with considerable activity. For example, oxycodone (see Figure 4) is metabolized by cytochrome p450 (CYP) 2D6 to oxymorphone by 3-O-demethylation, and by CYP3A4/5 (N-demethylation) to noroxycodone. Both oxymorphone and noroxycodone are nearly as efficacious as oxycodone at the receptor level but oxycodone and noroxycodone are 8 and 45 times, respectively, less potent than oxymorphone.2 The secondary metabolite, noroxymorphone, is also about as efficacious as oxycodone but is about 4 times less potent than oxymorphone. There are 7 secondary oxycodone metabo-lites and also tertiary ones, some of which are glucuronide conjugates. About 45% of a given oral dose is metabolized by the CYP3A4/5 path as opposed to only about 11% via CYP2D6. Finally, about 10% of an oral dose is excreted unchanged in the urine. Codeine is also extensively metabo-lized but primarily by CYP2D6 and also by glucuronidation.3 Codeine is essentially a prodrug for morphine; conversion to morphine is directly subject to the individual activity of CYP2D6. Between 7-10% of Caucasians are CYP2D6 poor metabolizers; in these, little to no morphine is formed, result-ing in failure of analgesia. Similarly in the nearly 7% of Caucasians who are CYP2D6 ultrafast metabolizers, much higher amounts of morphine are formed. In these individuals

one can expect higher rates of moderate to severe adverse effects and even frank toxicity.

Taken together, about 14% of Caucasians given codeine are at risk of failure of analgesia or adverse effects sufficient to halt codeine administration. Hydrocodone is metabolized somewhat similarly to oxycodone, via CYP2D6 and possibly CYP3A4. The O-demethylated metabolite is active and is also known as hydromorphone (Figure 3). Hydromorphone is subject to glucuronidation to hydromorphone-3-glucuronide. Evidence for establishing whether hydrocodone is active on its own or whether it functions as a prodrug for hydromorphone is lacking.4 Morphine (Figure 3) is primarily transformed via UGT2B7 to either morphine-3-glucuronide (M3G) or morphine-6-glucuronide (M6G – see Figure 5). At low to moderate daily doses a small fraction is also N-demethylated to normorphine while at daily doses exceeding 100 mg, hydromorphone may also be formed. M6G is active as an analgesic; with chronic administration of morphine, M6G can accumulate to the extent that it contributes to pain con-trol.5 In renal failure, M6G may accumulate to cause toxicity. M3G is devoid of analgesic activity but has been shown to have neuroexcitatory potential, similar in nature to that of hydromorphone-3-glucuronide6 but about one third to one half as potent.

Table 1 summarizes important parameters describing the pharmacokinetics and pharmacodynamics of some of the opioids. Some caveats about the values in the table should be mentioned first. The work cited spans nearly 30 years. The degree of sophistication in both laboratory ana-lytic techniques and in pharmacokinetic/pharmaodynamic methods increased rapidly during this time. Particularly of concern is the advance in the ability to reliably quantitate lower and lower serum opioid concentrations, thus enabling serum sampling to extend past a few hours to a day or more. This wider window allowed for the detection and improved Figure 1

Figure 2



Figure 3. Structures of Commonly Available Opioids Figure 4. Metabolic Pathways of Oxycodone (redrawn from reference 2).

Figure 5. Structure of Morphine-6-Glucuronide

characterization of longer terminal half lives and additional compartments. However, little or none of the earlier work has been repeated with the newer methods. Perhaps the reader would be wise to look at the table values more in relative terms than as being all equivalently accurate and precise. That being said, let us proceed.

In general these compounds are poorly orally bioavail-able, most being subject to extensive first pass effect. One exception to this is oxycodone. While still subject to first pass metabolism, the effect is only moderate such that oxy-codone’s overall bioavailabilty is higher than that of the other opioids. Another interesting exception is morphine-6-gluc-uronide. With an overall oral bioavailability of 4 to 11%, it seems a marvel that any drug gets through. Actually the serum concentration time profile of the drug shows 2 absorption peaks; the initial 1 demonstrates bioavailability of M6G of about 4% (1 to 12%). A second peak, about 4 hours after the first, brings overall bioavailibility up to 11% (6 to 15%). With the second peak, both morphine and M3G are also found. It is thought that M6G hydrolyzes in the gut to morphine and is then absorbed and re-glucuronidated during the morphine



first pass, a process that continues. Following administration of an oral solution, nearly as much M6G is absorbed between 12 and 24 hours after oral dosing as is absorbed during the first 12 hours. The transfer half times noted reflect both the time it takes to start to produce analgesia and the time it could take for the opioid to reach a steady state concentration at the site of action. Comparing these values, oxycodone can reach an effective concentration nearly as fast as fentanyl, and both more rapidly than hydromorphone, assuming that all are given intravenously. If unappreciated clinically, the prolonged times that it could take morphine, or more extreme, M6G, to achieve a steady state at the site of action, could manifest as pronounced and prolonged drug activity after repeated initial dosing. This is not of theoretical interest – this situation has resulted in mortality.13

Also of interest is the brain:plasma ratio of drug con-centration. Clearly oxycodone should pass more easily and actually concentrate within the brain as opposed to the other opioids listed, even when compared to its own very potent metabolite, oxymorphone. Unfortunately, information about the brain:plasma ratio of hydrocodone and hydromorphone could not be located. Such information would be useful for

understanding the impact of the 6-oxo as opposed to the 6-hydroxyl group of the molecules on potency and efficacy, as well as on their clinical effectiveness.

Genetic factors Affecting OpioidsGenetic factors affect pain management broadly, from

beginning to end. Lotsch et al14 has posited 5 key areas in which genetics can contribute to a particular patient’s par-ticipation in pain. These 5 areas include: 1. modulation of the probability of developing a pain-causing disease (e.g., migraine headaches) or its course or severity; 2. modulation of the individual’s perception of pain; 3. alteration of the indi-vidual’s pharmacokinetic handling of a drug, from systemic availability to drug presence at the site of action; 4. alteration of the individual’s pharmacodynamics with respect to the interaction of the drug with the target structure (i.e., gener-ally the receptor) and its signaling of pain intensity; and 5. factors influencing risk of side effects, including drug addic-tion. Because many, if not most of these genetic factors occur independently, the overall effect in an individual is really the summation of effects of each as they positively or negatively affect the perception of pain and its relief by specific medica-

Table 1. Important Parameters of Some Opioids (from references 2,4,5,7-12)

Drug Plasma T1/2 (hr) Distribution Volume Bioavailability % Brain:plasma ratio Transfer T1/2 (min) Molecular Weight

oxycodone 3.7 ± 2.3 2.6a ± 0.5 60 to 90 2.07 ± 0.62 11 315.36

oxymorphone 8.8 ± 4.4 10 0.23 ± 0.09 301.33

morphine 2 to 3.5 248b ± 40 11 to 45 0.23 ± 0.03 96 to 288 285.33

morphine-6-glucuronide 2.6 to 3.5 0.23a ± 0.3 4 to 11 372 to 492 461.45

hydromorphone 2.4 ± 0.6 2.9a ± 1.3 41.7 ± 23 18 to 38 285.33

hydrocodone 3.8 to 4.5 299.36

codeine 2.5 to 3.5 5.1a 42 to 71 0.99 ± 0.25 n/a 299.36

fentanyl 3 to 4, 8.9 5.4a ± 1.9 n/a 4.7 to 6.6 336.46

a--liters/kg, b--litersn/a--not applicable



tions. The discussion of the first and the last of these areas, i.e., modulation of pain disease and risk of drug addiction is beyond our current scope. Modulation of the individual’s perception of pain is not as profusely studied as have been genetically-controlled alterations of pharmacokinetics or pharmacodynamics. However, we will briefly mention some of the receptors associated with this topic next.

To date, many genetic variants have been identified as being potentially capable of affecting perception of pain. However, only a few of those occurring with frequencies greater than 10% in the population have been demon-strated to modulate pain. Opioid receptors are the target of the endogenous opioid transmitters, endorphin, enkephalin and dynorphin. The single nucleotide polymorphism (SNP), A118G, that occurs in the m-opioid receptor, has been shown to be associated with decreased perception of pressure pain and decreased pain-related cortical response after stimulation of nasal nociceptors. Individuals who are homozygous for GCH1 (guanosine triphosphate cyclohydrolase) variants have a decrease in GCH1 upregulation, which ultimately results in decreased neuropathic pain. Clinically, decreased report-ing of pain has been described in patients having variants of GCH1. This has included delay in the time that pain therapy needs to be initiated after diagnosis in cancer patients who were homozygous for GCH1 variants.

Individuals who carry the non-functional variant of the melanocortin-1 receptor (MC1R) have been shown to have increased tolerance to stimulation with electrical pain in one study. Clinical studies of this are limited to the observa-tions that this is sex-specific to women and limited to the individual’s benefit from pentazocine (a k-opioid receptor agonist). Interestingly, MC1R homozygotes have red hair and white skin, giving the clinician a useful sign. β-arrestin2 is a protein found intracellularly which, in the m-opioid recep-tor is thought to support desensitization and possibly the number of functional opioid receptors on the cell’s surface. Cancer patients who were homozygous for the C variant of the T8622C exon 11 allele of the β-arrestin2 gene were sig-nificantly more likely to respond to morphine and less likely to require switching to an alternative than those carrying at least one T allele. Non-switchers were significantly less likely to have intolerable side effects (primarily drowsiness), and had both lower average, and lower worst pain scores than switchers. Many other genetic variants in other recep-tors which might affect pain perception have been identified but have been sparsely studied: the d-opioid receptor, some members of subfamilies of the transient receptor potential cation channel (TRPV1, TRPM8, TRPA1), and fatty acid amide hydrolase (FAAH), the enzyme which degrades anandamide, the endogenous cannabinoid receptor agonist. Two genetic

variants, encoding for catechol-O-methyl transferase (COMT) and for P-glycoprotein (ATP-binding cassette B1, ABCB1, or multiple drug resistance 1, MDR1) will be discussed below.

As mentioned previously, the m-opioid receptor has at least one variant that appears to have clinical consequences. Actually, this understates the number of polymorphisms that have been identified for this receptor; approximately 1800 SNPs have been detected. Nearly all, however, are rare (allele frequency less than 1%). In Caucasians the frequency of the A118G polymorphism is typically about 10 to 14% which makes it of clinical relevance. In Asian populations, the frequency can range from 35 to 49%. This SNP is asso-ciated with a change in the amino acid sequence from an asparagine residue to an aspartate residue in the N-terminal, extracellular portion of the receptor. It is believed that this brings about the loss of a glycosylation site, with consequent changes in potency and affinity for opioid agonists. Of interest to our population, Landau et al15 examined the distribution of allelic frequency in an obstetric population consisting of self described white or Hispanic women. Women homozygous for the G variant constituted about 4%, heterozygotes, 29% and those homozygous for A118, 67%. In 2004, Klepstad et al16 in Caucasian cancer patients found the G variant frequency to be about 10%. Heterozygotes reported signifi-cantly greater average pain, despite having morphine titrated to provide the same degree of pain control. Further, those homozygous for 118G required over twice the daily dose of intravenous morphine to achieve a similar average pain score when compared to those homozygous for 118A. Serum mor-phine and M6G concentrations reflected the higher dose of morphine the 118G patients received.

In 2006, Chou et al17 examined the effect of the A118G SNP on intravenous morphine requirements in women post total abdominal hysterectomy in Taiwan. Homozygotes for the GG genotype comprised about 23% of the sample, and for the AA genotype, about 54%. Morphine was titrated to relief of pain – pain scores did not differ across the groups. Those in the GG genotype used significantly more morphine (albeit an average of about 4 mg/24 hrs more) than those with the AA genotype during the first 24 hours post operatively. Those in the AA and AG groups had the highest incidence of vomiting – about 3 times higher than the GG group. In 2008, Sia et al18 demonstrated similar findings in a group of women of Han Chinese descent who received intravenous PCA morphine after elective Cesarean delivery. In this group of 588 women, 46% were AA; 14% were GG. In this study, the AA group generally differed from both the AG and GG groups; both pain scores and amount of morphine used were significantly lower for the AA group compared to the others during the first 12 to 16 hours post operatively. The incidence



of vomiting was lower overall than in Chou’s study but again, the incidence was just over 3 times greater for the AA and AG groups when compared with the GG group. In 2009 Tan et al19 reported post-operative pain and morphine usage in 994 women who had undergone elective cesarean delivery and who were of either Chinese, Malay or Indian descent. Overall only 39% were AA and 17% were GG.

Again the results are similar to the foregoing studies, with those in the GG genotype group reporting higher average pain scores and higher average bodyweight-adjusted morphine use. Using multiple regression analysis to predict morphine usage, the most important factor was pain score, followed by ethnicity and then OPRM (genotype) status. Also, the average number of vomiting episodes of the AA group was about 4 times that of the GG group. In summation, it seems that in populations of women of varying ethnic backgrounds who are post gynecological or obstetrical surgery, the presence of the 118G allele is associated with greater pain reporting, greater use of morphine to attempt to alleviate pain, and lesser proclivity for vomiting. Other genetic variations have also been found to influence response to opioids.

The gene polymorphisms of catechol-O-methyl transferase (COMT) and ATP-binding cassette B1 (ABCB1), or multiple drug resistance 1 (MDR1), have been recently found20 to be associated with central side effects during pain therapy with morphine in patients with cancer. Why are these two genes of importance? COMT is an enzyme which metabo-lizes the CNS neurotransmitters, dopamine, epinephrine and nor-epinephrine. Opioid analgesia is known to be modified by descending adrenergic neurons. Alteration of dopamine concentration has been shown to interfere with endogenous opioid production as well as being linked with regulation of opioid receptor expression. The most widely studied variant of the highly polymorphic COMT gene is the V158M which is coded by the 472G>A SNP. The variant has a valine to methionine substitution; the resulting enzyme’s activity is decreased 3 to 4 times compared to wild type COMT. Rakvag et al21 found in 207 Caucasian cancer patients that higher oral morphine doses were required to maintain the same level of pain control in those who had the VV genotype (average = 155 mg/24 hrs), than those who were VM heterozygous (117 mg/24 hrs) or MM homozygous (95 mg/24 hrs). However, there are multiple SNPs across the gene which might form haplotypes of interest. Subsequently Rakvag et al22 con-structed haplotypes from 11 SNPs of the COMT gene and examined oral morphine requirements.

Six of the SNPs showed statistically significant or strong tendencies towards differences with median morphine doses. Their haplotype 1 (which contained the V158M SNP) was found

in about 35% of subjects and carriage of it was associated with a median morphine dose of 60 mg/24 hr as opposed to non-carriers who had a median dose of 100 mg/24 hr. This same group went on to then analyze their work23 by looking at the joint effect of variants of both the COMT and OPRM1 genes. As we saw previously, carriers of the OPRM1 GG genotype require more morphine as opposed to those who carry the AA genotype. And as we have just seen, carriers of the COMT VV genotype also require more morphine than those with the VM or MM genotypes. What of the joint effect? Reyes-Gibby et al23 reported that those subjects who carried both the OPRM1 AA and COMT MM genotypes required the lowest median daily dose of morphine (87 mg) and that this differed significantly from those who were not OPRM1 AA nor COMT MM (these required 147 mg/day). Multiple regression analysis showed that this held true even after controlling for patient and clinical variables. Remember, COMT appears to alter the ability of the OPRM1 receptor to influence pain perception. What of ABCB1/MDR1? This gene encodes for the transmembrane transporter, P-glycoprotein, which is expressed at the blood-brain barrier, as well as in the gastrointestinal tract, liver and kidneys.

At the blood-brain barrier it functions as an outward trans-porter, effecting the removal of many substrates (including opioids) from the brain. Impairment of P-glycoprotein drug transport could lead to increased concentrations of drugs in the extracellular fluid of the brain, as well as increased systemic bioavailability. The C3435T SNP that occurs within MDR1 has been shown to affect P-glycoprotein expression levels and activities. Campa et al24 have reported their find-ings in 137 Italian cancer patients, whom they genotyped for both the OPRM1 A118G SNP and the MDR1 C3435T SNP, and who were treated with twice daily oral extended release morphine tablets.

Those patients homozygous for OPRM1 AA had signifi-cantly greater decreases in pain scores than GG homozygotes (as we have previously seen above). OPRM1 SNP status accounted for about 23% of the variance in pain scores. In addition, those patients homozygous for MDR1 TT also had significantly greater decreases in their pain scores than those who were homozygous for CC. MDR1 SNP status accounted for 16% of the pain score variance. However, when both genotypes were analyzed together in a multivariate model, about 30% of pain score variance could be explained. Those patients homozygous for OPRM1 AA and MDR1 TT were the “best responders” having the greatest decrease in pain scores. Those who were OPRM1 AA and either MDR1 CC or CT had an adequate decrease in pain scores and were termed the “normal responders.” The poor or non-responder group included subjects with all other allele combinations. Using



these definitions, the investigators were able to classify their subjects into responders and non-responders with sensitivity of 75% and specificity of 72%.

So far we have looked at the effects of the variants of COMT and ABCB1/MDR1 when studied separately on morphine usage with regard to alleviation of pain. When studied togeth-er, what can they tell us about morphine side effects? Ross et al20 in 228 mostly (87%) Caucasian patients with cancer who were titrated with oral morphine to achieve their desired anal-gesic effect. Due to side effects this was not successful in 28% of patients who had to be switched to an alternative, usually finding success with oxycodone. Patients who were switched complained of experiencing significantly more intense drowsi-ness, confusion, drowsiness and confusion, nightmares, nausea and dry mouth than those who remained on morphine. The patients were also characterized for 13 COMT SNPs and 5 MDR1 SNPS. Associations between central side effects of morphine (drowsiness, confusion, hallucinations and night-mares), and certain SNPs were discovered. For MDR1, alleles 21/2677G and 12/1236C were significantly associated with a lack of “drowsiness/confusion/nightmares.” For COMT, a similar protective effect was significantly associated with allele

-4873G (note that this is not the same as the COMT V158M SNP discussed above that was associated with decreased morphine usage). Multivariate analysis demonstrated that MDR1 21/2677G and COMT -4873G were significantly and independently associated with this protective effect. The con-verse was also true; MDR1 21/2677T or A, and COMT -4873A were associated with the greatest proportions of patients with drowsiness and confusion.

Another way of looking at this is that the proportion of patients with moderate or severe central side effects was 55% among those with neither protective genotype, was about 17% among those having either genotype, and was only about 7% for those with both protective genotypes. Note that during the above discussion we moved from genotypes that could influence the perception of pain (or side effects) to one that could influence the concentration of drug at the site of action. Now we turn to one that influences how many of the opioids are metabolized.

As you have seen from the section on pharmacokinetics and metabolism, CYP2D6 is important to the biotrans-formation of several of our opioids. CYP2D6 is a highly polymorphic enzyme which has recently25 been reviewed for

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many drugs, although initially the enzyme was of great inter-est for its influence on psychotropic medications.26

Briefly, 74 allelic variants and a series of subvariants have been reported and more continue to be discovered. CYP2D6 activity spans a range from poor metabolizers, through intermediate metabolizers, to extensive metabolizers and ultrarapid metabolizers. Poor metabolizers result from alleles which confer reduced or non-functional activity. Gene duplication or multiduplication also occurs and is typically associated with ultrametabolizers. Enzyme activity in either case may be substrate-dependent. Clinical consequences of this wide variation of activity depend on whether the substrate of interest is active, is transformed to an active or inactive metabolite(s), with which species adverse effects are associated, the therapeutic index of the drug, and the overall contribution of the CYP2D6 pathway to removal of the drug from the body. The proportion of the various alleles and gene duplications varies among ethnic groups; alleles associated with reduced activity might be prominent in one group and not found in another. Not only must each drug be studied in relation to CYP2D6 but also the drug must be studied within the context of a particular population. Further there is an impressive array27 of drugs and substrates that can compete for activity, or inhibit or induce the enzyme.

In 2005, a commercial assay was introduced for detecting and identifying CYP2D6 (and also CYP2C19) variants, dele-tions and duplications for an individual. Knowledge of the individual’s CYP2D6 genotype might be helpful in some pain management situations.

A few, Simple StrategiesIn the Introduction, I noted that the focus of this article

would be on a few, simple strategies for the use of opi-oid medications for relieving moderate to severe, acute or sub-acute pain in women – women who are experiencing “uncontrollable” pain or who are demonstrating a need for administration of “excessive” amounts of opioids at “overly frequent” intervals. Some of these strategies fall within the application of clinical or “bedside” pharmacy, and some within interprofessional education. Remember, the near-term or immediately post partum woman has altered physiology--doesn’t absorb drugs as well perhaps, has increased drug clearance, an enlarged distribution volume. So you would like an oral drug with good oral bioavailability, that is potent at the OPRM1 receptor and that can readily reach high concentrations in the extracellular fluid of the brain and pref-erably one not subject to myriad drug interactions and the vagaries of genetic influence on its biotransformation.

Based on the available evidence, oxycodone fits these criteria reasonably well. Further, it is available as a single agent so that dosage escalation, if necessary, can be done without risk of toxicity from another drug that must “go along for the ride.” It is available in oral liquid, immediate release (IR) tablets and sustained release tablets. A simplified com-parison of analgesia following administration is presented in Figure 6. Note that for an equivalent milligram dose, the oral liquid peaks slightly higher and faster than the IR tablet. We have noticed that in pre-term women who have a source of intermittant but sharp pain, i.e., kidney stones, the oral liquid provides a faster onset of relief that is considerably more acceptable to most such women than the IR tablets. The sustained release tablets on the other hand, are use-ful for providing basal analgesia overnight or continuously for women who also have a continuous source of pain, in addition to their intermittant, sharp attacks. An example here might be the woman with moderately severe chronic low back pain and severe round ligament pain. Often the third trimester woman who presents with kidney stones is in excruciating pain. Breaking the hold of this pain and allowing the woman to rest will usually allow a subsequent lowering, often dramatic lowering, of opioid dose. The sharp pains of the kidney stone come on abruptly and sometimes disappear quickly. For this acute situation, an opioid that is quickly on and off can be useful. Intravenous fentanyl and hydromor-phone both come to mind. Administration of both of these by PCA has worked well for us. However, the dosing pattern differs somewhat from typical post-operative PCA, wherein the patient gives themselves multiple “mini” doses to keep ahead of relatively constant, perhaps mildly fluctuating pain.

Figure 6. Comparative Analgesia Curves After Various Oxycodone Dosage Forms


For kidney stones, relatively generous doses are used but with proportionately tighter hourly limits. This way the woman can respond to one or two sharp pain attacks that occur closely together, without exceeding a safe amount within an hour’s time. We often prefer hydromorphone for this as it provides a longer taper down for the sort of pain that peaks abruptly, then initially declines over a few minutes by 1 or possibly 2 pain score units, but then declines much more slowly.

For patients who are referred for “uncontrollable” pain, typically after transfer from the post anesthesia (“recovery”) unit to the post gynecologic surgery unit, it is important to both provide pain relief and to get an accurate estimate of the required dosage of the selected opioid as quickly as possible. Intravenous hydromorphone seems to be our most frequent choice for this as it gets to the site of action rea-sonably quickly, has less delay in accumulation there than morphine, and has a useful duration of action. Selecting an initial dose of hydromorphone guided by whatever previ-ous opioids were given (to which the patient had poor or no response) we proceed to give this IV push and repeat it (or perhaps half of it) every 10 to 15 minutes until the patient’s pain score decreases by 1.5 to 2 units (on the 0 to 10 scale), or until the patient is visibly showing signs of pain relief, e.g.,

relaxation, decreased anxiety, resolution of tachycardia. The pharmacist remains present during this procedure, usually continuing the intake interview and monitoring the respira-tory rate. A typical hydromorphone “challenge” might have an initial dose of 2 mg, followed by 2 to 3 repeat doses of 1 mg each. Discounting the total dose by the amount of drug presumed eliminated during the period gives a crude estimate of a dose necessary to relieve pain, while the patient remains in the same pain state. Patients rarely require more than 6 mg of hydromorphone. The goal is to use this information as a guide for fixing PCA pump parameters and to start PCA as soon as possible after the last challenge dose so that control of pain is not lost. Note that usual protocol PCA doses will probably be too small, they should be increased to provide the individually estimated pain relieving dose over an hour, assuming the patient can cooperate with PCA.

Longer lockout intervals may be necessary for safety – a basal rate may be necessary overnight so the patient does not awake in excruciating pain. The patient’s response must be monitored daily. As the natural rate of pain resolution takes place due to healing, the PCA parameters may have to be decreased. Because of previous poor experiences, many of these patients are distrustful or have a “prove it to me” attitude. Overlapping the PCA for a day with scheduled oral


Beginning with the July/August 2010 issue of CJHP, the Continuing

Pharmacy Education exams will no longer be printed in the Journal.

They will be available online at www.HealthSystemCE.org.

As a member of CSHP, you are entitled to free CPE on the Health

System CE website. Log in with your email address and password

and click on Journal CE to complete the exam. You will then

be able to print your statements of credit and will no longer be

required to mail or FAX exams to the CSHP office.

Non-members may still download the exams from www.cshp.org.

Attention



references

1. Thompson CM, Wojno H, Greiner E, et al. Activation of G-proteins by morphine and codeine congeners: insights to the relevance of O and N-demethylated metabolites at m- and d-opioid receptors. J Pharmacol Exp Ther 2004; 308(2):547-554.

2. Lalovic B, Kharasch E, Hoffer C, et al. Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites. Clin Pharmacol Ther 2006;79:461-79.

3. Vree TB, Verwey-van Wissen CP. Pharmacokinetics and metabolism of codeine in humans. Biopharm Drug Dispos 1992;13(6):445-60.

4. Trescot AM, Datta S, Lee M, et al. Opioid pharmacology. Pain Physician 2008;11:S133-S153.

5. Romberg R, Olofsen E, Sarton E, et al. Pharmacokinetic-pharmacodynamic modeling of morphine-6-glucuronide-induced analgesia in healthy volunteers: absence of sex differences Anesthesiology 2004;100:120-133.

6. Smith MT. Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol 2000;27(7):524-528.

7. Lotsch J, Skarke C, Schmidt H, et al. Pharmacokinetic modeling to predict morphine and morphine-6-glucuronide plasma concentrations in healthy young volunteers. Clin Pharmacol Ther 2002;72:151-162.

8. Skarke C, Schmidt H, Geisslinger G, et al. Pharmacokinetics of morphine are not altered in subjects with Gilbert’s syndrome. Br J Clin Pharmacol 2003;56:228-231.

9. Hoskin PJ, Hanks G, Aherne G, et al. The bioavailability and pharmacokinetics of morphine after intravenous, oral and buccal administration in healthy volunteers. Br J Clin Pharmacol 1989;27:499-505.

10. Penson R, Joel S, Roberts M, et al. The bioavailability and pharmacokinetics of subcutaneous, nebulized and oral morphine-6-glucuronide. Br J Clin Pharmacol 2002;53:347-354.

11. Rogers J, Findlay J, Hull J, et al. Codeine disposition in smokers and nonsmokers. Clin Pharmacol Ther 1982;32:218-227.

12. Poyhia R, Vainio A and Kalso, K. A review of oxycodone’s clinical pharmaokinetics and pharmacodynamics. J Pain Symptom Manage 1993;8:63-67.

13. Lotsch J, Dudziak R, Freynhagen R, et al. Fatal respiratory depression after multiple intravenous injections. Clin Pharmacokinet 2006;45:1051-1060.

14. Lotsch J, Geisslinger G and Tegeder I. Genetic modulation of the pharmacological treatment of pain. Pharmacol Ther 2009;124:168-184.

15. Landau R, Cahana A, Smiley RM et al. Genetic variability of µ-opioid receptor in an obstetric population. Anesthesiology 2004;100:1030-1033.

16. Klepstad P, Rakvag TT, Kaasa S et al. The 118 A>G polymorphism in the human µ-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anesthesiol Scand 2004; 48:1232-1239.

17. Chou WY, Wang CH, Liu PH et al. Human opioid receptor A11G polymorphism affects intravenous patient-controlled analgesia morphine consumption after total abdominal hysterectomy. Anesthesiology 2006;105:334-337.

18. Sia AT, Lim Y, Lim EC et al. A11G single nucleotide polymorphism of human µ-opioid receptor gene influences pain perception and patient-controlled intravenous morphine consumption after intrathecal morphine for postcesarean analgesia. Anesthesiology 2008;109:520-526.

19. Tan E, Lim EC, Teo Y et al. Ethnicity and OPRM variant independently predict pain perception and patient-controlled analgesia usage for post-operative pain. Molecular Pain; 2009;5:32-39.

20. Ross JR, Riley J, Taegetmeyer AB et al. Genetic variation and response to morphine in cancer patients: catechol-O-methyltransferase and multidrug resistance-1 gene polymorphisms are associated with central side effects. Cancer 2008;112:1390-1403.

21. Rakvag TT, Klepstad P, Baar C et al. The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain 2005;116:73-78.

22. Rakvag TT, Ross JR, Sato H et al. Genetic variation in the catechol-O-methyltransferase (COMT) gene and morphine requirements in cancer patients with pain. Molecular Pain 2008;4:64-75.

23. Reyes-Gibby C, Shete S, Rakvag T et al. Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain 2007;130:25-30.

24. Campa D, Gioia A, Tomei A et al. Association of ABCB1/MDR1 and OPRM1 gene poloymorphisms with morphine pain relief. Clin Pharmacol Ther 2008;83:559-566.

25. Zhow SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet 2009;48:689-723 and Part II. Clin Pharmacokinet 2009;48:761-804.

26. Bertilsson L, Dahl M, Dalen P et al. Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol 2002;53:111-122.

27. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). http://medicine.iupui.edu/clinpharm/ddis/table.asp. updated November 11, 2009, accessed March 2, 2010.

medication helps to ease the transition for the patient when switching to orals, and helps to maintain the patient’s confi-dence in the process. For the patient with continuing pain, when the PCA is weaned off, the scheduled oral therapy is continued and “as needed” doses of the same opioid are ordered for breakthrough or anticipatory pain.

Some patients requiring “excessive” doses simply have pre-existing chronic pain conditions for which they have been taking a regular opioid regimen. Continuing their previous regimen (or its equivalent) without change, as far as possible, generally meets their baseline needs. Adding the usual post operative therapy to this baseline regimen typically adequately addresses their need for alleviation of pain from the incision and operative intervention. The total opioid dose might seem excessive but when separated out into the baseline and “postop” parts, the “postop” part can be quite reasonable. The most common reason we’ve encountered for patients requiring “overly frequent” opioid administration is that the usual opioid duration of effect of 2.5 to 3.5 hours is ignored and the opioid has been ordered to be administered every 4 or 6 hours. The second most common reason for “overly frequent” need is that the select-ed dose is inappropriately small and consequently: a) it does not relieve pain, and/or b) the minimal pain relief it affords wears off faster than the prescriber expected. Occasionally one encounters a patient in whom the opioid is eliminated much faster than usual or who has a low threshold for per-

ceiving pain. The simple strategy for all of these is to listen to the patient. Order an adequate dose and then give the next dose before the first one fully wears off. You might have to experiment (oh! I mean titrate) with the dose and interval a bit but with the patient’s cooperation you will find a regi-men that works. Ordering the opioid on a scheduled basis (with appropriate hold parameters), rather than “as needed” or “if has pain,” for the first 24 hours, is sometimes all that is needed to keep a patient’s pain to a tolerable level and to keep that patient’s satisfaction high.

Remember, genetic variation of the opioid receptor, OPRM1 can influence the perception of increased pain and the need for higher opioid doses in 5 to 50% of patients; variation of COMT, in 65% of patients, and MDR1 in 70% of patients. Because so much of the patient’s perception of pain and response to opioids is under genetic control, one must really fit opioid selection and regimen to the patient. Be encouraged to participate in each of your patients’ journeys with pain; the more of these travails you undertake, the better guide you will become.

AcknowledgmentThe author wishes to thank especially Dan Parsoneault

and Blair Frater for their support, and his other pharmacy and nursing colleagues for helpful discussions and their collective wisdom, and the many patients, each of whom has been a pre-cious teacher, while sharing their journey with pain. u


CSHP’s 3rd Legislative day was held on Tuesday,

April 13.More than80CSHPmembersmetwith

legislatorsandtheirstaffandattendedcommitteehear-

ingsattheCapitol.

CSHP’s Legislative Advocate, Bryce Docherty, pre-

sentedacontinuingpharmacyeducationcourse,which

enabled participants to learn what motivates elected

officialsandhowtheymakedecisions;identifywaysto

promotetheprofessionofpharmacythroughgrassroots

activity; and attendees were also walked through the

legislativeandregulatoryprocesses.

Attendeesheardanoverviewoftheactivi-

tiesofCSHP’sGovernmentAffairsAdvisory

Committee, pending pharmacy-related

legislation, a Board of Pharmacy update

from Assistant Executive Officer Anne

Sodergren, and heard the keynote address

fromAssemblymanJoseSolario,theauthor

of CSHP’s sponsored legislation,Assembly

Bill 2077, Centralized Hospital Pharmacy

Packaging. Assemblyman Solario also

receivedtheLegislatoroftheYearAward.

ThedayculminatedinaPPC-PACrecep-

tionatCSHPheadquarters,whichallowed

everyoneachance tonetworkand reflect

ontheday’sactivities.

CSHP’s 3rd AnnuAl Health-System Pharmacy Legislative Day 2010

President-elect Maria Serpa with CSHP’s Legislator of the Year, Assemblyman Jose Solorio


1 President-elect Serpa, Sponsors from CSL Behring Bill Carroll and Kim Isenberg, and EVP/CEO Dawn Benton

2 President Nancy Korman and Directors Kenn Horowitz and Christine Antczak

3 San Gabriel President Daniel Kudo and President-elect Steven Dohi

4 CSHP Pacific Student Kim Diep provides a cholesterol screening during the health fair

5 Legislative Day 2010 attendees gather on the steps of the State Capitol

6 UCSD Students Fauzia Khan, Susan Cho, Christine Luu, Traci Bricker, and David Ha

7 CSHP Pacific Students (L-R) Simon Wong, Rory Okasaki Gutierrez, Marisa Smith, and Nweni Naing provide heartburn education

8 Sacramento Valley President Jim Walsh, Sponsor from AmerisourceBergen Sean Martin, and Sacramento Valley Past-president Allen Schaad

1

2

3

4 6

5


8

9

10

11

7

9 TDEC Members Jeanne Li, Paul Sabatini, and Kathy Daly

10 EVP/CEO Benton and Sacramento Valley President-elect Grant Lackey

11 UCSF President Linda Quan, Assembly Member Mary Hayashi, and SSEC Co-chair Richard Martinez

12 2010 Legislative Day attendees at Lucca Restaurant.

12


Don’t take a chance: You know the risks, but do your adolescent patients and their parents?

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Safety InformationThe most common local and systemic adverse reactions to Menactra vaccine include injection site pain, redness, and induration; headache, fatigue, and malaise. Other adverse reactions may occur. Menactra vaccine is contraindicated in persons with known hypersensitivity to any component of the vaccine or to latex, which is used in the vial stopper. Guillain-Barré syndrome (GBS) has been reported in temporal relationship following administration of Menactra vaccine. Persons previously diagnosed with GBS should not receive Menactra vaccine. Vaccination with Menactra vaccine may not protect all individuals. Before administering Menactra vaccine, please see brief summary of full Prescribing Information on following page.a ACIP = Advisory Committee on Immunization Practices.b CPT = Current Procedural Terminology is a registered trademark of the American Medical Association.

Menactra vaccine is manufactured and distributed by Sanofi Pasteur Inc.Reference: 1. Centers for Disease Control and Prevention. Notice to readers: revised recommendations of the Advisory Committee on Immunization Practices to vaccinate all persons aged 11–18 years with meningococcal conjugate vaccine. MMWR. 2007;56(31):794-795.

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FOR INTRAMUSCULAR INJECTIONBrief Summary: Please consult package insert for full prescribing information.

INDICATIONS AND USAGE Menactra vaccine is indicated for active immunization of individuals 2 through 55 years of age for the prevention of invasive meningococcal disease caused by N meningitidis serogroups A, C, Y and W-135.Menactra vaccine is not indicated for the prevention of meningitis caused by other microorganisms or for the prevention of invasive meningococcal disease caused by N meningitidis serogroup B. Menactra vaccine is not indicated for treatment ofmeningococcal infections. Menactra vaccine is not indicated for immunization against diphtheria. Menactra vaccine may not protect all individuals.

CONTRAINDICATIONS Known hypersensitivity to any component of Menactra vaccine including diphtheria toxoid, or a life-threatening reaction after previous administration of a vaccine containing similar components,1 are contraindications to vaccine administration. Known history of Guillain-Barré syndrome (see WARNINGS section) is a contraindication to vaccine administration. Known hypersensitivity to dry natural rubber latex (see WARNINGS section) is a contraindication to vaccine administration.

WARNINGS Guillain-Barré syndrome (GBS) has been reported in temporal relationship following administration ofMenactra vaccine. An evaluation of post-marketing adverse events suggests a potential for an increased risk of GBS following Menactra vaccination2 (see ADVERSE REACTIONS, Post-Marketing Reports section). Persons previously diagnosed with GBS should not receive Menactra vaccine. The stopper of the vial contains dry natural rubber latex, which may cause allergic reactions in latex-sensitive individuals. There is no latex in any component of the syringe. The ACIP has published guidelines for vaccination of persons with recent or acute illness (refer to www.cdc.gov).3

PRECAUTIONS General Before administration, all appropriate precautions should be taken to prevent adversereactions. This includes a review of the patient’s previous immunization history, the presence of any contraindications to immunization, the current health status, and history concerning possible sensitivity to the vaccine, similar vaccine, or to latex. As a precautionary measure, epinephrine injection (1:1000) and other appropriate agents and equipment must be immediately available in case of anaphylactic or serious allergic reactions. Special care should be taken to avoid injecting the vaccine subcutaneously since clinical studies have not been conducted to establish safety and efficacy of the vaccine using this route of administration. The immune response to Menactra vaccine administered to immunosuppressed persons has not been studied.

Information for Patients Prior to administration of Menactra vaccine, the health-care professional should inform the patient, parent, guardian, or other responsible adult of the potential benefits and risks to the patient (see ADVERSEREACTIONS and WARNINGS sections). Patients, parents or guardians should be instructed to report any suspectedadverse reactions to their health-care professional. Females of childbearing potential should be informed that Sanofi Pasteur Inc. maintains a pregnancy registry to monitor fetal outcomes of pregnant women exposed to Menactra vaccine. If they are pregnant or become aware they were pregnant at the time of Menactra vaccine immunization, they should contact their health-care professional or Sanofi Pasteur Inc. at 1-800-822-2463 (see PRECAUTIONS section).

Drug Interactions For information regarding concomitant administration of Menactra vaccine with other vaccines,refer to ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION sections. Immunosuppressive therapies, includingirradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses) may reduce the immune response to vaccines.

Carcinogenesis, Mutagenesis, Impairment of Fertility Menactra vaccine has not been evaluated in animals for its carcinogenic or mutagenic potentials or for impairment of fertility.

Pregnancy Category C Animal reproduction studies have not been conducted with Menactra vaccine. It is also not known whether Menactra vaccine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. There are no adequate and well controlled studies in pregnant women. Menactra vaccine should only be given to a pregnant woman if clearly needed. Assessment of the effects on animal reproduction has not been fully conducted with Menactra vaccine as effects on male fertility in animals has not been evaluated. The effect of Menactra vaccine on embryo-fetal and pre-weaning development was evaluated in one developmental toxicity study in mice. Animals were administered Menactra vaccine on Day 14 prior to gestation and during the period of organogenesis (gestation Day 6). The total dose given per time point was 0.1 mL/mouse via intramuscular injection (900 times the human dose, adjusted by body weight). There were no adverse effects on pregnancy, parturition, lactation or pre-weaning development noted in this study. Skeletal examinations revealed one fetus (1 of 234 examined) in the vaccine group with a cleft palate. None were observed in the concurrent control group (0 of 174 examined). There are no data that suggest that this isolated finding is vaccine related, and there were no vaccine related fetal malformations or other evidence of teratogenesis observed in this study. Health care providers are encouraged to register pregnant women who receive Menactra vaccine in Sanofi Pasteur Inc.’s vaccination pregnancy registry by calling 1-800-822-2463.

Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Menactra vaccine is administered to a nursing woman.

Pediatric Use Safety and effectiveness of Menactra vaccine in children below the age of 2 years have not been established.

Geriatric Use Safety and effectiveness of Menactra vaccine in adults older than 55 years have not been established.

ADVERSE REACTIONS The safety of Menactra vaccine was evaluated in 8 clinical studies that enrolled 10,057participants aged 2–55 years who received Menactra vaccine and 5266 participants who received Menomune–A/C/Y/W-135 vaccine. There were no substantive differences in demographic characteristics between the vaccine groups. Among Menactra vaccine recipients of all ages, 24.0%, 16.2%, 40.4% and 19.4% were in the 2–10 year age range, 11–14, 15–25 and 26–55-year age groups, respectively. Among Menomune–A/C/Y/W-135 vaccine recipients of all ages, 42.3%, 9.3%, 30.0% and 18.5% were in the 2–10 year age range, 11–14, 15–25 and 26–55 year age groups, respectively. The three primary safety studies were randomized, active-controlled trials that enrolled participants 2–10 years of age (Menactra vaccine, N=1713; Menomune-A/C/Y/W-135 vaccine, N=1519), 11–18 years of age (Menactra vaccine, N=2270; Menomune–A/C/Y/W-135 vaccine, N=972) and 18–55 years of age (Menactra vaccine, N=1384; Menomune–A/C/Y/W-135 vaccine, N=1170), respectively. As the route of administration differed for the two vaccines (Menactra vaccine given intramuscularly, Menomune–A/C/Y/W-135 given subcutaneously), study personnel collecting the safety data differed from personnel administering the vaccine. Solicited local and systemic reactions were monitored daily for 7 days post-vaccination using a diary card. Participants were monitored for 28 days for unsolicited adverse events and for 6 months post-vaccination for visits to an emergency room, unexpected visits to an office physician, and

serious adverse events. Unsolicited adverse event information was obtained either by telephone interview or at an interim clinic visit. Information regarding adverse events that occurred in the 6-month post-vaccination time period was obtained via a scripted telephone interview. At least 94% of participants from the three studies completed the 6-month follow-up evaluation. In the two concomitant vaccination studies with Menactra and either Typhim Vi or Td vaccines, local and systemic adverse events were monitored for 7 days post-vaccination using a diary card. Serious adverse events occurring within 1 month after each vaccination were reported and recorded.

Serious Adverse Events in All Safety Studies Serious adverse events reported within a 6-month time period following vaccination in children 2–10 years old occurred at the rate of 0.6% following Menactra vaccine and at a rate of 0.7% following Menomune-A/C/Y/W-135 vaccine. Serious adverse events reported within a 6-month time period following vaccination in adolescents and adults occurred at a rate of 1.0% following Menactra vaccine and at a rate of 1.3% following Menomune-A/C/Y/W-135 vaccine.

Solicited Adverse Events in the Primary Safety Studies The most frequently reported solicited local and systemic adverse reactions in US children aged 2–10 years (TABLE 1) were injection site pain and irritability. Diarrhea, drowsiness, and anorexia were also common. The most commonly reported solicited adverse reactions in adolescents, ages 11–18 years (TABLE 2), and adults, ages 18–55 years (TABLE 3), were local pain, headache and fatigue. Except for redness in adults, local reactions were more frequently reported after Menactra vaccination than after Menomune–A/C/Y/W-135 vaccination. The majority of local and systemic reactions following Menactra or Menomune–A/C/Y/W-135 vaccination were reported as mild in intensity. Between the vaccine groups, differences in rates of malaise, diarrhea, anorexia, vomiting, or rash, including urticaria, were not statistically significant.

Adverse Events in Concomitant Vaccine Studies Local and Systemic Reactions when Given with Td VaccineThe two vaccine groups reported similar frequencies of local pain, induration, redness and swelling at the Menactra injection site, as well as at the Td injection site. Pain was the most frequent local reaction reported at both the Menactra and Td injection sites. More participants experienced pain after Td vaccination than after Menactra vaccination (71% versus 53%). The majority (66%–77%) of local solicited reactions for both groups at either injection site were reported as mild and resolved within 3 days post-vaccination. The overall rate of systemic adverse events was higher when Menactra and Td vaccines were given concomitantly than when Menactra vaccine was administered 28 days after Td. In both groups, the most common reactions were headache (Menactra vaccine + Td, 36%; Td + Placebo, 34%; Menactra vaccine alone, 22%) and fatigue (Menactra vaccine + Td, 32%; Td + Placebo, 29%; Menactra vaccine alone,17%). Between the groups, differences in rates of malaise, diarrhea, anorexia, vomiting, or rash were not statistically significant. Fever ≥40.0ºC and seizures were not reported in either group.

TABLE 1: PERCENTAGE OF US PARTICIPANTS 2–10 YEARS OF AGE REPORTING SOLICITEDADVERSE REACTIONS WITHIN 7 DAYS FOLLOWING VACCINE ADMINISTRATION

Reaction Any Moderate Severe Any Moderate SevereRedness† 21.8 4.6 3.9 7.9 0.5 0.0Swelling† 17.4 3.9 1.9 2.8 0.3 0.0Induration† 18.9 3.4 1.4 4.2 0.6 0.0Pain‡ 45.0 4.9 0.3 26.1 2.5 0.0Drowsiness§ 10.8 2.7 0.3 11.2 2.5 0.5

Irritability|| 12.4 3.0 0.3 12.2 2.6 0.6Arthralgia¶ 6.8 0.5 0.2 5.3 0.7 0.0Diarrhea# 11.1 2.1 0.2 11.8 2.5 0.3Anorexia** 8.2 1.7 0.4 8.7 1.3 0.8Fever†† 5.2 1.7 0.3 5.2 1.7 0.2Vomiting‡‡ 3.0 0.7 0.3 2.7 0.7 0.6Rash§§ 3.4 3.0 Seizure§§ 0.0 0.0

Menactra vaccine*N=1157

Menomune–A/C/Y/W-135 vaccine*N=1027

*N = The total number of subjects reporting at least one solicited reaction. The median age of participants was 6 years in both vaccine groups.; † Moderate: 1.0–2.0 inches, Severe: >2.0 inches; ‡ Moderate: interferes with normal activities, Severe: disabling, unwilling to move arm; §Moderate: interferes with normal activities, Severe: disabling, unwilling to engage in play or interact with others; || Moderate: 1–3 hours duration, Severe: >3 hours duration; ¶ Moderate: Decreased range of motion due to pain or discomfort, Severe: unable to move major joints due to pain; #Moderate: 3–4 episodes, Severe: ≥5 episodes; ** Moderate: Skipped 2 meals, Severe: skipped ≥3 meals; †† Oral equivalent temperature; Moderate: 38.4–39.4°C, Severe: ≥39.5°C; ‡‡ Moderate: 2 episodes, Severe: ≥3 episodes; §§ These solicited adverse events were reported as present or absent only.

Reaction Any Moderate Severe Any Moderate SevereRedness‡ 10.9† 1.6† 0.6† 5.7 0.4 0.0 Swelling‡ 10.8† 1.9† 0.5† 3.6 0.3 0.0 Induration‡ 15.7† 2.5† 0.3 5.2 0.5 0.0 Pain§ 59.2† 12.8† 0.3 28.7 2.6 0.0 Headache|| 35.6† 9.6† 1.1 29.3 6.5 0.4 Fatigue|| 30.0† 7.5 1.1† 25.1 6.2 0.2 Malaise|| 21.9† 5.8† 1.1 16.8 3.4 0.4 Arthralgia|| 17.4† 3.6† 0.4 10.2 2.1 0.1 Diarrhea¶ 12.0 1.6 0.3 10.2 1.3 0.0 Anorexia# 10.7† 2.0 0.3 7.7 1.1 0.2 Chills|| 7.0† 1.7† 0.2 3.5 0.4 0.1 Fever** 5.1† 0.6 0.0 3.0 0.3 0.1 Vomiting†† 1.9 0.4 0.3 1.4 0.5 0.3 Rash‡‡ 1.6 1.4 Seizure‡‡ 0.0 0.0

Menactra vaccineN*=2264

Menomune–A/C/Y/W-135 vaccineN*=970

TABLE 2: PERCENTAGE OF PARTICIPANTS 11–18 YEARS OF AGE REPORTING SOLICITEDADVERSE REACTIONS WITHIN 7 DAYS FOLLOWING VACCINE ADMINISTRATION

* N = The number of subjects with available data; † Denotes p <0.05 level of significance. The p values were calculated for each category and severity using Chi Square test; ‡ Moderate: 1.0–2.0 inches, Severe: >2.0 inches; § Moderate: Interferes with or limits usual arm movement, Severe: Disabling, unable to move arm; || Moderate: Interferes with normal activities, Severe: Requiring bed rest; ¶ Moderate: 3–4 episodes, Severe: ≥5 episodes; #Moderate: Skipped 2 meals, Severe: Skipped ≥3 meals; ** Oral equivalent temperature; Moderate: 38.5–39.4°C, Severe: ≥39.5°C; †† Moderate: 2 episodes, Severe: ≥3 episodes; ‡‡ These solicited adverse events were reported as present or absent only.


Health-system pharmacists can now count

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PPC-PACPharmacy Professionals of California

Political Action Committee (PPC-PAC)

Reaction Any Moderate Severe Any Moderate SevereRedness‡ 14.4 2.9 1.1† 16.0 1.9 0.1Swelling‡ 12.6† 2.3† 0.9† 7.6 0.7 0.0Induration‡ 17.1† 3.4† 0.7† 11.0 1.0 0.0Pain§ 53.9† 11.3† 0.2 48.1 3.3 0.1Headache|| 41.4 10.1 1.2 41.8 8.9 0.9Fatigue|| 34.7 8.3 0.9 32.3 6.6 0.4Malaise|| 23.6 6.6† 1.1 22.3 4.7 0.9Arthralgia|| 19.8† 4.7† 0.3 16.0 2.6 0.1Diarrhea¶ 16.0 2.6 0.4 14.0 2.9 0.3Anorexia# 11.8 2.3 0.4 9.9 1.6 0.4Chills|| 9.7† 2.1† 0.6† 5.6 1.0 0.0Fever** 1.5† 0.3 0.0 0.5 0.1 0.0Vomiting†† 2.3 0.4 0.2 1.5 0.2 0.4Rash‡‡ 1.4 0.8Seizure‡‡ 0.0 0.0

Menactra vaccineN*=1371

Menomune–A/C/Y/W-135 vaccineN*=1159

TABLE 3: PERCENTAGE OF PARTICIPANTS 18–55 YEARS OF AGE REPORTING SOLICITEDADVERSE REACTIONS WITHIN 7 DAYS FOLLOWING VACCINE ADMINISTRATION

* N = The number of subjects with available data; † Denotes p <0.05 level of significance. The p values were calculated for each category and severity using Chi Square test; ‡ Moderate: 1.0–2.0 inches, Severe: >2.0 inches; § Moderate: Interferes with or limits usual arm movement, Severe: Disabling, unable to move arm; || Moderate: Interfereswith normal activities, Severe: Requiring bed rest; ¶ Moderate: 3–4 episodes, Severe: ≥5 episodes; # Moderate:Skipped 2 meals, Severe: Skipped ≥3 meals; ** Oral equivalent temperature; Moderate: 39.0–39.9°C, Severe: ≥40.0°C; †† Moderate: 2 episodes, Severe: ≥3 episodes; ‡‡ These solicited adverse events were reported as present or absent only.

Local and Systemic Reactions when Given with Typhim Vi VaccineThe two vaccine groups reported similar frequencies of local pain, induration, redness and swelling at the Menactra injection site, as well as at the Typhim Vi injection site. Pain was the most frequent local reaction reported at both the Menactra and Typhim Vi injection sites. More participants experienced pain after Typhim Vi vaccination than after Menactra vaccination (76% versus 47%). The majority (70%–77%) of local solicited reactions for both groups at either injection site were reported as mild and resolved within 3 days post-vaccination. In both groups, the most common systemic reaction was headache (Menactra + Typhim Vi vaccine, 41%; Typhim Vi vaccine + Placebo, 42%; Menactra vaccine alone, 33%) and fatigue (Menactra + Typhim Vi vaccine, 38%; Typhim Vi vaccine + Placebo, 35%; Menactra vaccine alone, 27%). Between the groups, differences in rates of malaise, diarrhea, anorexia, or vomiting were not statistically significant. Fever ≥40.0ºC and seizures were not reported in either group.

Post-Marketing Reports The following adverse events have been reported during post-approval use of Menactra vaccine. Because these events were reported voluntarily from a population of uncertain size, it is not always possible to reliably calculate their frequency or to establish a causal relationship to Menactra vaccine exposure. Immune system disorders - Hypersensitivity reactions such as anaphylactic/anaphylactoid reaction, wheezing, difficulty breathing, upper airway swelling, urticaria, erythema, pruritus, hypotension. Nervous system disorders - Guillain-Barré syndrome, vasovagal syncope, facial palsy, transverse myelitis, acute disseminated encephalomyelitis. Musculoskeletal and connective tissue disorders - Myalgia.

DOSAGE AND ADMINISTRATIONMenactra vaccine should be administered as a single 0.5 mL injection by the intramuscular route, preferably in the deltoid region. Do not administer this product intravenously, subcutaneously, or intradermally. The need for, or timing of, a booster dose of Menactra vaccine has not yet been determined. Parenteral drug products should be inspected visually for container integrity, particulate matter and discoloration prior to administration, whenever solution and container permit.

Concomitant Administration with Other VaccinesSafety and immunogenicity data are available on concomitant administration of Menactra vaccine with Typhim Vi, and Td vaccines (see ADVERSE REACTIONS section). Concomitant administration of Menactra vaccinewith Td did not result in reduced tetanus, diphtheria or meningococcal antibody responses compared with Menactra vaccine administered 28 days after Td.4 However, for meningococcal serogroups C, Y and W-135, bactericidal antibody titers (GMTs) and the proportion of participants with a 4-fold or greater rise in SBA-BR titer were higher when Menactra vaccine was given concomitantly with Td than when Menactra vaccine was given one month following Td. The clinical relevance of these findings has not been fully evaluated.4 Concomitant administration of Menactra vaccine with Typhim Vi vaccine did not result in reduced antibody responses to any of the vaccine antigens.4 The safety and immunogenicity of concomitant administration of Menactra vaccine with vaccines other than Typhim Vi or Td vaccines have not been determined. Menactra vaccine must not be mixed with any vaccine in the same syringe. Therefore, separate injection sites and different syringes should be used in case of concomitant administration.

STORAGE Store between 2° to 8°C (35° to 46°F). DO NOT FREEZE. Product that has been exposed to freezing should not be used. Do not use after expiration date.

REFERENCES: 1. Ball R, et al. Safety Data on Meningococcal Polysaccharide Vaccine from the Vaccine Adverse Event Reporting System. CID 2001;32:1273-1280. 2. CDC. Guillain-Barré Syndrome Among Recipients ofMenactra® Meningococcal Conjugate Vaccine - United States, June 2005-September 2006. MMWR 2006;55(41):1120-1124. 3. CDC. General recommendations on immunization. Recommendations of the Advisory Committee onImmunization Practices (ACIP) and the American Academy of Family Physicians (AAFP). MMWR 2002;51(RR02): 1-36. 4. Data on file, Sanofi Pasteur Inc. - 092503.

Manufactured by:

Sanofi Pasteur Inc.Swiftwater, PA 18370 USA

MKT16458

Product information as of April 2008 Printed in USA 5665-5666




1. Slowing of gastrointestinal motility during pregnancy can change the pharmacokinetics of an opioid by causing:

a. constipation b. delayed absorption of orally administered drugs c. slower GI transit times d. increased hepatic blood flow

2. During pregnancy, the increases in cardiac output and plasma volume can affect many drugs by:

a. causing an increase in the distribution volume of ones that are lipophilic

b. shunting more blood to the brain c. expanding both extravascular and intravascular

fluid volume d. increasing clearance through the kidneys and

possibly the liver

3. Unlike other common opioids, oxycodone is eliminated from the body by a variety of paths. Which is the best description of how this drug is eliminated?

a. 6-glucuronidation, then keto-reduction b. inactivation by COMT, then renal excretion

of the metabolite c. primarily metabolized by CYP2D6, a smaller portion

by UGT2B7 d. mostly via CYP3A4/5, some via CYP2D6, 10%

unchanged renally

4. Codeine is subject to metabolism by an enzyme that is highly polymorphic and, depending upon its form, might vary from very poor capacity to very high capacity. What is the name of this enzyme?

a. CYP3A4/5 b. UGT2B7 c. CYP2D6 d. SNP-A118G

5. The µ-opioid receptor is known to be highly polymorphic; the most commonly studied SNP variant is named what, and is associated with which clinical findings?

a. M6G, variant associated with decreased pain perception

b. A118G, wild type associated with decreased pain perception, decreased morphine usage, more vomiting

c. A118G, variant associated with increased pain perception, increased morphine usage, more vomiting

d. MCR1, wild type associated with red-haired females

6. Oxycodone and morphine are similar pharmacokinetically in some respects and differ in others. How?

a. different brain:plasma ratio, different bioavailability, similar half life

b. time to steady state in brain similar, different bioavailability, similar plasma half life

c. similar half life and bioavailability, different distribution volumes

d. similar brain:plasma ratio, different plasma half life, similar transfer half life

7. Variation in the COMT gene can change the activity of the enzyme, catechol-O-methyl transferase. In general terms, how does this affect pain perception?

a. by reducing the level of βarrestin2 activity within the cell, the number of functioning opioid receptors is increased

b. by increasing the concentration of dopamine, there is greater stimulation within the pleasure/reward center, making one lose track of pain

c. increased catechol-O-methyl transferase activity modulates P-glycoprotein expression, causing more efflux of opioids from the brain thus increasing perception of pain

d. decreased catechol-O-methyl transferase activity increases dopamine concentrations which have been associated with upregulation of opioid receptor expression, allowing for decreased pain signaling

8. Codeine is thought to be a pro-drug for which of its active metabolites?

a. hydrocodone (the 6-keto congener of codeine) b. morphine (the O-desmethyl congener of codeine) c. oxycodone (a similarly spelled congener of codeine) d. dihydrocodeine (a congener available in other

countries, used as a primary analgesic)

9. Variants of this gene have been associated with impaired P-glycoprotein activity and resulting decreases in pain scores. What is the name of this gene?

a. MDR1 b. CYPD26 c. OPRM1 d. TRPV1

10. The phone rings 2 minutes after you check into work at 7 am. It’s an ER nurse wanting you to send ibuprofen 600 mg for an outpatient because they are out of pre-packs. She mentions the patient’s name which you immediately recognize as it is the 3rd or 4th recent visit for this woman who has severe, persistent, aching chronic lower back pain which has been made worse by her pregnancy as she has come closer to term. In fact, she’s due in a week or so, maybe less. You blurt out your refusal to send the ibuprofen and the nurse puts the medical intern who ordered it on the line. After you calm him down, explaining why a cyclooxygenase inhibitor is not such a good idea for a woman close to term, he sleepily interrupts you. He says that since it took a couple of 2 mg IV morphine injections to decrease her pain, what about sending her home on oral morphine tablets? You respond:

a. okay, but be sure to use sustained-release tablets because of the decreased peristalsis in pregnancy

b. try codeine/APAP 30/325 because codeine is better absorbed than morphine

c. use oxycodone oral liquid because it is more consistently absorbed and the patient can titrate her dose more easily

d. use fentanyl lozenges because her pain probably comes and goes very frequently

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ACPE UAN: 0126-0000-10-014-H01-P A passing grade of 70% is required. Statements of Credit will be issued upon successful completion of the exercise within three weeks of receipt in the CSHP office. If you do not achieve 70% or better, you will have one opportunity to retake the test and obtain credit.

Release Date: May 1, 2010

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Target audience: Pharmacists

Mail or fax this completed answer sheet for scoring to:CJHP CE/CSHP1314 H StreetSuite 200Sacramento, CA 95814FAX (916) 447-2396

Some thoughts on Opioid Use in Ante and Post Partum Women SelfAssessmentQuestionsCPe

exam

Continued on next page

As there might be more than one correct answer, select the BESt answer.


Evaluation

Please rate how we met each of the program’s objectives on a scale of 1-5 with 5 being completely and 1 being not at all.

Identify at least two physiological alterations associated with pregnancy that can change the phar-macokinetic behavior of an opioid analgesic.

1 2 3 4 5

Distinguish among common opioid analgesics with respect to their metabolic or elimination paths.

1 2 3 4 5

Identify the primary receptor with which common opioid analgesics interact, and other receptors that might modify its behavior.

1 2 3 4 5

Compare the pharmacokinetic and pharmacodynamic behaviors of selected common opioids. 1 2 3 4 5

Select from among opioids, the one that best resolves a specified clinical problem in pain man-agement.

1 2 3 4 5

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What is your overall evaluation of the article? 1 2 3 4 5 (poor) (excellent)

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Some Thoughts on Opioid Use in Ante and Post Partum Women

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CPe exam Continued from previous page

think inside the Box: the Black Box Harminder Sikand, PharmD, FASHP, FCSHP

Clinical Director Residency Director Department of Pharmacy Scripps Mercy Hospital 4077 5th Avenue San Diego, CA 92103

•••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••ClinicalPearls

To understand the enormity of the problem, as of 2005, 14% of package insert labeling changes have been due to black box

warning (BBW) additions or revisions. From September 1997-1998, approximately 20 million people took at least 1 of the 5 medications withdrawn from the market. Of those 5 medications, 3 medica-tions were new and 2 had been on the market for less than 2 years. Furthermore, 7 medications approved since 1993, and then later withdrawn, may have contributed to 1002 deaths.1,2

In a study evaluating new chemical entities approved from 1975 to 1999, the Food and Drug Administration’s (FDA) modern era of drug surveillance, indicated that of the 548 new medications that were approved, 10.2% received a new BBW or were withdrawn. Based on Kaplan-Meier estimates, a medication has a 20% chance of acquir-ing a new BBW or being withdrawn from the market over a 25 year period. Additionally, half of the changes to medication labeling occur within the first 7 years of use, and half of the medication withdrawals occur within the first 2 years of introduction.2

To evaluate the clinical effectiveness of BBW prescribing and adherence in the ambulatory care setting, the Agency for Healthcare Research and Quality (AHRQ) funded a trial conducted by the Harvard investigators.3 During a 30-month period, the investiga-tors analyzed 930,000 health records in 10 health care plans and found 40% of the patients took a medication with a BBW. Prescriber compliance to BBW ranged from 0.3 to 49.6% and depended upon medication type. The most frequent finding in the study noted in 50% of the patients pointed to a laxity in baseline laboratory monitoring prior to initiation of therapy. The code of federal regulations, 21 CFR 201.57 (e), states that:

[Boxed warning] labeling shall describe serious adverse reac-tions and potential safety hazards, limitation in use imposed by them and steps that should be taken if they occur. The labeling shall be revised to include a warning as soon as there is reason-able evidence of an association of a serious hazard with a drug: a causal relationship need not have been proved. [Furthermore] special problems, particularly those that may lead to death or serious injury, may be required by the FDA to be placed in the prominently displayed box. The boxed warning ordinarily shall be based on clinical data, but serious animal toxicity may also be the basis of the boxed warning in absence of clinical data.4

The latter reflects warnings found based on teratogenicity in ani-mals. In lay terms, a BBW is the strongest medication-related warning that the FDA issues to highlight to the prescriber the risks of this medication. The BBW might direct the prescriber to evaluate patient specific risk versus benefit, it might enforce proper use to prevent or reduce an adverse drug reaction or it might limit the drug’s distribution by enforcing restrictions.5 As such, the FDA addresses prescribing, monitoring and distribution of medication.

Until recently, most medications received BBWs based on post-marketing reports after they had been released for widespread use. This is largely because pre-marketing studies for medication approval are generally underpowered to determine an adverse drug event; they tend to enroll a homogenous population with few concurrent thera-pies and they are of such short duration that it is difficult to determine latent side-effects. Post-marketing reports are voluntary and hence suffer from under-reporting.2

The list of medications with BBWs is extensive and for a practicing clinician very difficult to monitor. They span all therapeutic classes that are commonly prescribed to patients in an inpatient and outpa-tient setting (Table 1).

Numerous medications have been withdrawn from the market since 1980. Some medications have been re-introduced with exten-sive restrictions because the benefit to a subset of patients outweighs the risks (Table 2).

The most common single reason for medication removal from the market was, at one time, hepatotoxicity.8 Today, it is difficult to cat-egorize the etiology as the organ systems leading to withdrawal vary widely. Table 3 summarizes the most pertinent medications removed from the market from 1950 to 2009.

Today, from a regulatory perspective, each facility licensed by the Department of Health Services (DHS) has been directed to develop a facility-specific policy describing how BBWs are being addressed to safeguard patients in both hospital inpatient and ambulatory surgical care sites. In addition, the DHS has provided online best practice rec-ommendations for monitoring medications designated by the FDA to have black box warnings.9 Their intent is to assist clinicans in the safe and effective use of high risk medications. The provided recommenda-tions describe physician, nursing and pharmacist actions to consider. It is an expectation that each DHS hospital and ambulatory surgical


Pearls: think inside the Box

center review the ”DHS High Priortiy BBW List” and develop a facility policy that describes specific procedures that will be undertaken to promote patient safety. Some of their medication-specific recommen-dations are indicated in Table 4.

Implementation of BBW guidelines as suggested by DHS are chal-lenging in an era of limited labor resources. Many hospitals have used a variety of techniques to meet these regulatory needs. Some are focusing on a select group of medications for formal intervention. An example of potential intervention types are described in Table 5 that can assist in meeting the BBW monitoring requirements.

In addition to mandating that BBWs be addressed in a specific manner upon prescribing, dispensing or monitoring, the FDA has developed a risk evaluation and mitigation strategy (REMS) require-ment. REMS is a process formally mandated on March 25, 2008 and initially affected a few medications (Table 6). Its enforcement falls under the Food and Drug Administration Amendments Act (FDAAA) of 2007 and responsibility resides with the manufacturer. The REMS can be mandated or submitted voluntarily by the manu-facturer. For the present time the FDA will not review any foreign language REMS.

REMS of today mimic the RiskMaps of 2002 that applied to approximately 30 medications.11 The intent at that time for managing the risks of medications was to 1) determine the medication’s ben-efit/risk ratio; 2) develop and implement tools to minimize risk and retain its benefit; 3) evaluate the effectiveness of the tool upon use; and 4) revise the tool to improve the risk/benefit analysis. These tools varied depending on medication class but could involve education to prescribers and patients, patient consents, guidelines for labora-tory monitoring, medication administration restriction, registries or restricted dispensing.12 REMS represents an evolution in thinking and enforcement by the FDA to improve medication safety.

The FDA has the authority to request the creation of a REMS for any medication (past, present or future) when the medication or bio-logic agent has shown to have potential serious risk. What triggers a REMS is described in Table 7.

It is hoped by requesting a REMS, the FDA can avoid denial of new medications or removal from the market of an older medication. This enforcement from the FDA has civil monetary penalties that start at $250,000/violation and cap at $1 million for any single proceeding. If these penalties are not addressed, they double every 30 days to a maximum of $10 million per proceeding.7

Table 1 – Black Box Warnings by Therapeutic Class6

Analgesics Iron/Vitamins

Anticonvulsants Gastrointestinal agents

Anti-diabetics Hematological agents

Anti-infectives Hormones

Anti-neoplastics Immunologic agents and biologics

Cardiovascular agents Psychiatric agents

CNS medications Renal agents

Contrast agents Respiratory agents

Dermatological agents Vaccines

Table 2 – Medication Withdrawals in USA 1980-20097

Aprotinin Fenfluramine Rofecoxib

Astemizole Flosequinan Suporfen

Alosetron* Grepafloxacin Tegaserod*

Benoxaprofen Mibefradil Temafloxacin

Bromfenac Natalizumab* Terfenadine

Cerivastatin Nomifensine Ticranyfen

Cisapride Pemoline Troglitazone

Dexfenfluramine Phenylpropanolamine Valdecoxib

Encainide Rapacuronium Zomepirac

Fanolesomab 99mTc Rimonabant

*Brought back to market under restrictions

Table 3 – Withdrawn Medications Categorized by Adversely Affected Organ System7 1950-2009

Cardiac Hepatic Death Neurologic Teratogen Suicide Miscellaneous

GrepafloxacinAstemizoleCisaprideTerfenadinePergolideValdecoxibFentluramine/phentermineRofecoxib

TroglitazoneTolrestatPemolineTicrynafenAlpidemXimelagatran

AprotininFlosequinan

Natalizumab*Efalizumab

Thalidomide*Diethylstilbestrol

Rimonabant Rapacurium-respiratoryAlosetron-gastrointestinalTemafloxacin-hemolytic anemiaCerivastatin-rhabdomyolysis

*Brought back to market under restrictions



Table 4 – High Priority Black Box Warning Medication Guidelines9

Medication Core Formulary Restriction

Summary of the Warning Physician Action Nursing Action Pharmacist Action

Amiodarone None Pulmonary toxicity, hepatic injury, admit patient with arrhythmias for loading dose

Check LFT every 3-6 months for doses > 600 mg

Monitor pulmonary function and arrhythmias

Check LFT with new orders for doses > 600 mg

Enoxaparin DVT/PE prophylaxis, Non-Q wave MI

Spinal/epidural hematoma risk with spinal catheter

Hold 12 hours after epidural removal

Hold 12 hours after epidural removal

Advise nurse to hold enoxaparin 12 hours after epidural removal

Fentanyl patch Opioid tolerant patients (on morphine > 60 mg/day for 7 days). Do not use in acute, intermittent or mild pain.

Damaged patch may lead to rapid release and absorp-tion of fatal dose. Use with strong and moderate CYP450 3A4 inhibitors may result in potentially life threatening respiratory depression.

Do not use in opioid naive or break through pain. Develop an order form and use it for all orders.

Do not apply heat to patch; monitor respiratory func-tion; physician to use order form

Develop order form and require it prior to dispens-ing

Ketorolac In house use < 48 hours Short term pain manage-ment of moderate to severe pain; dose based on age and weight; increased risk of thrombotic events and gastrointestinal events.

Check renal function. Do not treat > 48 hours. Adjust dose for renal function, age and weight.

Do not exceed 48 hours. Discontinue in 48 hours. Check renal function

Metformin None Lactic acidosis Check serum creatinine. Contraindicated SCr > 1.5 male or 1.4 female. Hold 48 hours IV contrast.

Hold 48 hours after IV contrast.

Check SCr, contraindicated with SCr> 1.5 male and > 1.4 female. Advise physi-cian to hold 48 hours after contrast administration.

Table 5 – Examples of Interventions to Meet BBW Requirements10

Intervention Medication Examples

Technician order review and alert at order entry Select BBW drugs

Automatic discontinuation by pharmacist for criti-cal value or disease state contraindication

MetforminErythropoietin

Focused intervention prior to order entry Haloperidol IVFentanyl patchOxycontin/MS-Contin

Use of registry Clozapine

Formulary prescribing restriction PrasugrelDronaderone

Automatic addition on comment field upon order entry to alert clinicians

Select BBW drugs

Table 6 – Initial Medications with Approved REMS7

Abarelix Isotretinoin

Alosetron Lenalidomide

Ambrisertan Mifepristone

Bosetan Natalizumab

Clozapine Small pox vaccine

Dofetilide Thalidomide

Eculizumab



The classes of medications that now face a REMS requirement are shown in Table 8. While this list is not inclusive, it does reflect the seriousness with which the FDA is approaching this task.

The content required for a REMS is defined by the FDA. It is spe-cific to each medication and may require one or more components as applicable to promote safe medication use (Table 9).

In April 2008, 56 medications had a requirement for REMS and as of April 2010, 92 medications have a REMS requirement. This list is growing at a fast pace as many recently approved medications, telavancin, prasugrel, dronedarone, tocilizumab and dalfampridine all came to the market with REMS requirement. An older medication, erythropoetin and its long acting competitor darbopoetin recently (February 2010) received a REMS for cancer patients and now has a requirement for both the prescriber and

the pharmacy. The program launched by Centocor Ortho Biotech is called APPRISE (Assisting Providers and cancer Patients with Risk Information for the Safe use of ESA [erythropoiesis stimulat-ing agents]).

Currently, the most frequently mandated REMS is the provision of a medication guide followed by both a medication guide and a communication plan. Figure 1 depicts the various requirements of currently approved REMS medications.

Addressing REMS is an added complexity to an already complex world of monitoring medications with BBWs. Additionally, guidance on implementation of REMS in a hospital setting has been vague and left to the individual clinician and the individual institution. This is an area of tremendous growth for pharmacy clinicians and an area wait-ing for a best practice model. u

Table 7 – When is a REMS Considered Prior to FDA Approval of New Medication or Biological Entity?13

Size of population expected to use the medication

Seriousness of disease for which the medication will be prescribed

Expected benefit

Planned duration of treatment

Potential of serious adverse events(ADE) with use

Occurrence rates of ADE in population expected to use medication

Consideration if the medication is a new molecular entity

Table 8 – Current Key Medication Classes with a REMS Requirement 14

CNS Anti-infective Pain Mononclonals Diabetic Cardiac

Levetiracetam Ciprofloxacin diclofenac tocilizumab exanatide prasugrel

Lamotrigine levolfloxacin propoxyphene certolizumab pioglitazone dronaderone

Quetiapine moxifloxacin Hydromorphone ER infliximab rosiglitazone tolvaptan

Trazadone gemifloxacin Morphine olmalizumab sitagliptin

olanzapine ribavarin Fentanyl buccal etanercept

topiramate telavancin

doxepin mefloquine

bupropion

zolpidem

M - Medication guide, C - Communication plan, E - Elements to assure safe use, I - Implementation system. +/- These categories also include a medication guide.

Figure 1 – Number of Types of REMS for Medications14



references

1. Generali, J. The continuing dilemma of drugs with Black Box Warnings. Hospital Pharmacy 2008; 43(1) 7

2. Lasser KE, Allen PD, Woolhandler SJ, et al. Timing of new black box warnings and with-drawals for prescription medications. JAMA. 2002 May 1;287(17):2215-20.

3. Wagner AK, Chan KA, Dashevsky I, et al. FDA drug prescribing warnings: is the black box half empty or half full? Pharmacoepidemiol Drug Saf 2006: 15: 387-9.

4. 21 Code of Federal Regulations paragraph 201.57(e): 2000

5. Liang BA. FDA use of the black box warning: time for reevaluation of a safety tool. J Clin Anesth 2002; 14:561-563

6. Generali JA. Black box warnings by therapeutic class. www.blackboxrx.com. Accessed March 6, 2010.

7. Food and Drug Administration. http://www.fda.gov. Accessed March 6, 2010.

8. Temple RJ, Himmel MH. Safety of newly approved drugs: implications for prescribing. JAMA 2002; 287: 2273-5.

9. http://www.socalpatientsafety.org/Toolbox/docs/LA%20County%20DHS%20BBW%20Best%20Practices-%202009%20Update.pdf. Accessed October 3, 2009.

10. Personal Information. Scripps Health. San Diego, CA. 2010

11. Development and use of risk minimization action plans: FDA guidance for industry January 2005. www.fda.gov/ohrms/dockets/ac/05/briefing/20054136b1_03_Risk%20Minimization%20Action%20Plans.pdf

12. Murphy S, Roberts R. “Black Box” 101: How the Food and Drug Administration evaluates, communicates, and manages drug benefit/risk. J Allergy Clin Immunol 2006;117:34-6.

13. 110th Congress, Food and Drug Administration Amendments Act of 2007. http://frweb-gate.access.gpo.gov. Accessed September 2009.

14. Approved Risk Evaluation and Mitigation Strategies (REMS). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm. Accessed March 6, 2010.

Table 9 – Components of a REMS

• Product information

• Statement of goals

• Medication guide

medication with serious risks/adherence issues/prevent a serious ADE

describe mechanism of distribution

communication plan to prescribers

• Elements to assure safe use

Tools designed for safety

1. health care provider training, certification

2. pharmacies demonstrate understanding risks, show documentation of laboratory monitoring, fill prescriptions for only enrolled prescribers

3. dispensed in certain healthcare settings

4. patient monitoring and following up requirements

5. registry

• Implementation system

distribution of products, certification of wholesalers and or distributors, audit trails for shipment and frequency

• Timetable for submission of assessment

18 months, 3 and 7 years after REMS is approved and more frequently at discretion of the FDA


CASEREPORT

interaction Between disulfiram and phenytoin Ronald Floyd, PharmD, MS, BCPS, FCCP

Trung Van Nguyen, PharmD

R. Floyd was Pharmacy Manager, Villa View Community Hospital, San Diego and T. Nguyen was PharmD (4th year) candidate, Western University, School of Pharmacy, when this case presented. Direct correspondence to R. Floyd, c/o Pharmacy, Sharp Mary Birch Hospital for Women and Newborns, 3003 Health Center Drive, San Diego, CA 92123.

Phenytoin is mainly used in the management of seizure disorders. Disulfiram is used as an aid to maintaining sobriety in alcoholics.

While the use of these two drugs together occurs infrequently the combination is not without risk.1 Phenytoin is metabolized in the liver to an inactive metabolite, 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH) by a process that is susceptible to inhibition by disulfiram.2 Because phenytoin metabolism is a saturable process, inhibitors of phenytoin metabolism may produce substantial increases in serum phenytoin concentrations, resulting in clinical toxicity.

Here we report a case of phenytoin toxicity that illustrates the clinical significance of the interaction between phenytoin and disulfi-ram, and briefly discuss the mechanism of the interaction.

Case report A 42 year old, 5’7”, 137 pound male was admitted for man-

agement of symptoms of phenytoin toxicity. Other medical and psychiatric problems included paranoid schizophrenia with bipolar features, seizure disorder (possibly clozapine-related), history of alcohol use, and status post surgery on both knees. On admission to the hospital, the patient was confused, lethargic, responding only partially to verbal commands, and had slurred speech, gross ataxia, and bilateral horizontal nystagmus. The remainder of the physical examination was within normal limits. The patient’s chief complaints included “I fell down a lot,” dizziness, tremor of the extremities, and an ataxic walking gait.

Past medical history included several admissions to area hospitals and emergency rooms for psychiatric disorders. When younger, the patient abused alcohol but for the past 5 years, had only consumed 1 to 2 beers per week. He currently smokes cigarettes moderately and denies abusing any substances. Recent past medical history included admission to a nearby hospital in a post-ictal state 29 days previous to the current admission. When riding in a car earlier that day he had an observed tonic-clonic seizure which lasted about a minute. The patient was taken directly to the emergency room where an EEG revealed no encephalographic or clinical seizures. Both MRI and CT of the head were negative. Laboratory studies were non-contributory.

The patient’s blood alcohol was below detectable limits, valproic acid was 57 mcg/ml, lithium was 0.6 mEq/L; other chemistries were within normal limits and urinalysis was completely negative. The

patient’s previous medication history included clozapine 100 mg morn-ing and 200 mg bedtime (started 16 months prior to current admission), Depakote 500 mg three times daily (started 11 months prior), lithium carbonate 300 mg three times daily, disulfiram 250 mg each morning (started 4 months prior), and benztropine 2 mg at bedtime.

By the day of discharge from the other area hospital (3 weeks prior to the current admission), clozapine had been discontinued, risperi-done 2 mg twice daily and Dilantin 100 mg 3 times daily initiated, the Depakote discontinued in favor of valproic acid syrup 750 mg 3 times daily, and the lithium and benztropine continued unchanged. The disulfiram was continued but the dose was increased to 500 mg daily. During the days prior to the current admission, the patient was falling frequently because he was unsteady on his feet. 4 days prior to admission, a serum valproate concentration was determined as part of a monthly routine check; the result was 103 mcg/ml. The valproic acid was discontinued the next day. However, the patient continued to fall frequently and was taken to the other area hospital emergency room early on the day of admission to our facility.

At the emergency room the serum phenytoin concentration was noted to be 30 mcg/ml. A diagnosis of probable phenytoin intoxica-tion was made and later that day the patient was transferred to our facility where all medications were discontinued. The morning after admission (day 1), serum chemistries, hematology and urinalysis were all within normal limits except for a phenytoin serum concen-tration of 42 mcg/ml. The patient exhibited some of the typical signs and symptoms of phenytoin toxicity: he was confused and grossly ataxic. His fall risk assessments showed high risk, he fell once in the morning and was restricted to wheelchair in the evening, in which he was observed wandering around the psychiatric unit in a disoriented manner. On day 2 the phenytoin concentration was 41.6 mcg/ml, his fall risk assessments indicated no falls, and restricted to wheelchair. The patient was hyperverbal, disorganized, and had a slight hand tremor. On day 3 the phenytoin concentration was 39 mcg/ml; the patient was restricted to wheelchair. He had trouble sleeping and was restless, paranoid and confused. On day 4, phenyt-oin was 26.3 mcg/ml and his fall risk assessments were upgraded to restricted to walker. On day 5, phenytoin was 14.6 mcg/ml; he was restricted to a walker in the morning and allowed to walk unaided

Continued on page 32


Western University of Health Sciences College of Pharmacy is seeking applications for a Director of the Office of Experiential Education. The Director will be responsible for planning, development and oversight of all staff, operations and activities of the Office of Experiential Education. The Experiential curriculum at WesternU ranges from Introductory Pharmacy Practice Experience (IPPE), the Advanced Pharmacy Practice Experience (APPE), to the Advanced Elective (AE) program, and spans all four years of the PharmD curriculum.

Applicants should have a PharmD from an accredited college/school of pharmacy and a minimum of 10 years of clinical practice and education experience. Preference will be given to candidates who have an established network of professional practice contacts in pharmacy in the southern California region and those who have academic experience. Successful candidates must demonstrate excellent written and oral communication skills.

Salary and rank will be commensurate with qualifications and experience. Applicants should submit a letter of intent describing career goals, curriculum vitae

and 3 letters of references. Review of application materials will continue until the positions are filled. Electronic submission of application materials is encouraged.

The Director will serve as a full time faculty position in the College of Pharmacy and report to the Chair, Department of Pharmacy Practice and Administration in the College of Pharmacy.

The College of Pharmacy prides itself on its innovative curriculum that fosters student-centered learning, critical thinking and problem solving. Founded in 1996, the College offers Pharm.D and M.S. degrees and post-doctoral residencies and fellowships. Western University is one of the largest graduate schools for the health professions in California.

Contact information:James D. Scott, Pharm.D.Associate Professor of Pharmacy Practice Chair, Pharmacy Practice and Administration Faculty Search Committee309 E 2nd Street, Pomona, CA 91766-1854 Office (909) 469-5348, Fax (323) [email protected]

Western University of Health Sciences is an Equal Opportunity Employer

Director of the Office of Experiential Education

Case report: interaction between disulfiram and phenytoin

by the afternoon. On day 6, the phenytoin decreased to 6.5 mcg/ml and the patient continued to show improvement as he was able to walk with a steady gait all day. As the phenytoin levels continued to decrease to below 0.5 mcg/ml over the next 2 days, the patient’s motor coordination improved considerably.

Discussion Adverse effects produced by phenytoin within its therapeutic range

of 10 to 20 mcg/ml are minor and generally well tolerated; however, phenytoin serum concentrations greater than 25 mcg/ml are associ-ated with nystagmus, ataxia and other adverse central nervous system effects. Our patient was grossly ataxic, had nystagmus, and was markedly confused, an initial presentation consistent with the report by Brown et al.3 The high serum phenytoin concentrations were most likely due to the drug-drug interaction between phenytoin and disul-firam. From among the list of drugs that the patient was taking prior to admission, only valproic acid and disulfiram have the potential to increase serum phenytoin concentrations.

In general, valproic acid can interact with phenytoin and increase its serum levels by displacing bound phenytoin from protein bind-ing sites. However, in this case the contribution from a valproic acid interaction was probably minimal because: a) phenytoin was added to an existing valproate regimen and b) after the valproic acid was discontinued, the clinical signs of phenytoin toxicity persisted. Disulfiram was the most likely cause of phenytoin toxicity in our patient. Disulfiram inhibits the hepatic transformation of phenytoin into its major metabolite, HPPH. Approximately 80% of administered phenytoin can be accounted for by the appearance of HPPH in the urine. In the presence of disulfiram the net renal elimination of HPPH is substantially decreased.4 The increase in serum phenytoin concen-trations resulting from inhibition of metabolism is quite rapid, being observable within 4 hours of the administration of the first dose of disulfiram.2 The inhibition of metabolism results in a marked increase of apparent half-life and a substantially decreased clearance.5 The effect is also prolonged even after the discontinuation of disulfiram.4

In our case, serum phenytoin concentrations remained above 20 mcg/ml for about 4 days after discontinuation of both phenytoin and disul-firam. See Figure 1 for a plot of log serum phenytoin concentration versus time. Note the typical “hockey stick” curve associated with mixed zero order-first order or Michaelis-Menten elimination.

The cytochrome p450 isoenzyme 2C9 (CYP2C9) has been identified6,7 and generally accepted8 as being the major means of

phenytoin biotransformation. Levy9 proposed that any drugs that are metabolized principally by CYP2C9 should exhibit the same inhibition spectrum as phenytoin. Testing this he found that 11 of the 17 drugs, including disulfiram, which were known to interact with phenytoin, also interacted with 1 or both of 2 drugs known to be metabolized mainly by CYP2C9. Later, Nemeroff et al10 reviewed drug-drug interactions between newer antidepressants and drugs metabolized by the cytochrome p450 system. In their review, they referenced case reports for 26 patients who had their serum phenytoin concentrations increased from their normal baseline therapeutic lev-els to toxic levels after fluoxetine treatment, fluoxetine being a known CYP2C9 competitive inhibitor. Taylor et al,11 previously offered evidence for disulfiram being a noncompetitive inhibitor of CYP2C9 biotransformation of phenytoin, showing a near halving of phenytoin Vmax in the presence of disulfiram.

Conclusion Whenever phenytoin and disulfiram are concurrently administered,

the serious risk of phenytoin toxicity must be considered. This combina-tion of drugs should be avoided or, if they must be used together, the patient should be closely monitored to avoid possible toxicity. Clinical signs of phenytoin intoxication, or their absence, should be document-ed. Serum phenytoin concentrations should be monitored regularly and phenytoin dosage held or adjusted as necessary. u

references1. Kiorboe E. Phenytoin intoxication during treatment with Antabuse (disulfiram). Epilepsia 1966;7:246-249.

2. Olesen OV. Disulfiram (Antabuse) as inhibitor of phenytoin metabolism. Acta Pharmacol Toxicol 1966;24:317-322.

3. Brown CG, Kaminsky MJ, Feroli ER, et al. Delirium with phenytoin and disulfiram administration. Ann Emerg Med 1983;12:310-313.

4. Olesen OV. The influence of disulfiram and calcium carbamide on the serum diphenylhydantoin. Arch Neurol 1967;16:642.

5. Svendsen TL, Kristensen MB, Molholm Hansen J, et al. The influence of disulfiram and the half-life and metabolic clearance rate of diphenylhydantoin and tolbutamide in man. Europ J Clin Pharmacol 1976;9:439-441.

6. Relling MV, Aoyama T, Gonzales FJ, et al. Tolbutamide and mephenytoin hydroxylation by human cytochrome P450s in the CYP2C subfamily. J Pharmacol Exp Therap 1990;26:442-447.

7. Yasumori TY, Yamazoe Y, Kato R. Cytochrome P450 human 2 (p-450IIC9) in mephenytoin hydroxylation polymor-phism in human livers: differences in substrate and steroselectivities among microheterogeneous P450IIC species expressed in yeasts. J Biochem 1991;109:711-717.

8. Miners J and Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 1998;45:525-538.

9. Levy RH. Cytochrome P450 isozymes and antiepileptic drug interactions. Epilepsia 1995;36(suppl 5):S8-S13.

10. Nemeroff CB, DeVane CL and Pollock BG. Newer antidepressants and the cytochrome P450 system. Am J Psych 1996;153:311-319.

11. Taylor JW, Alexander B and Lyon LW. Mathematical analysis of a phenytoin-disulfiram interaction. Am J Hosp Pharm 1981;38:93-95.

Figure 1.

Continued from page 30


the Untraditional Path of a Pharmaceutical industry fellow Todd Okamoto, PharmD Bristol-Myers Squibb and Rutgers University, Ernest Mario School of Pharmacy [email protected]

new Practitioner Profile CaliforniaSocietyofHealth-SystemPharmacists

The ability to help patients was always at the forefront of my class-mates’ passions to pursue careers in the community, ambulatory

care, or hospital setting. I always imagined doing a pediatric residen-cy, and while I still wonder how life would be had I taken that route, I took a different path – one that is less traveled and often considered a “non-traditional” role. For the last 9 months, I have had the plea-sure of serving as the Medical Science Liaison/Medical Information Center Fellow focused on cardiovascular and metabolic products with Bristol-Myers Squibb (BMS) and the Rutgers Pharmaceutical Industry Fellowship Program.

While the transition to New Jersey was much more difficult than the transition from my home in Hawaii to USC, I knew this opportu-nity to work for a top-notch biopharmaceutical company would be priceless and, thus far, it definitely has been an amazing experience. Who better to know and understand the mechanisms of actions, drug-drug interactions, and the information pertinent to communicate to patients to ensure appropriate and safe medication use than an individual with a pharmacy background?

One of the reasons I was drawn to the industry was the fact that I would face different challenges and opportunities on a daily basis. Some activities include working on a medical letter for an inquiry from a healthcare professional regarding a BMS product, analyzing and creating competitive intelligence reports based on what our medical science liaison team hears in the field, and attending scientific sessions at major meetings and providing debriefs back to the medical team. I was even fortunate enough to participate in the launch of a new diabetes product and support our commercial colleagues as a medical information specialist during training meetings.

While companies are closed on weekends, as a fellow you may find yourself using the weekend to catch up on the multiple activities that need to be completed. Fellows are exposed to wonderful experi-ences that allow continual learning and better understanding of the industry and the multiple teams that are involved in launching and supporting a product through its lifecycle. Further, the importance of networking and developing relationships with other industry col-

leagues is emphasized to learn about professional opportunities in other areas and help answer the question, “What do I want to be when I grow up?”

This is an exciting time to be involved with the pharmaceutical industry. With PhRMA guidelines and healthcare reform bills now passed, the industry is changing to adapt to customer needs and ensure that patients are able to obtain affordable care. Industry continues to stress the importance of innovation in creating new drug therapies to address unmet medical needs in the community and provides patient assistance programs to allow for access to these medications.

As part of the fellowship program, I also teach a weekly class in “Pharmacy Communications” as Adjunct Faculty at the Rutgers Ernest Mario School of Pharmacy. Presenting weekly lectures and grading student pharmacists on their patient counseling skills and presenta-tions has helped me enhance communication skills of these future pharmacists, while enhancing my understanding of academia – an area where I can see myself in the future.

With another year remaining in my fellowship program, Rutgers has allowed me to take a more active role as a Co-chief Fellow of the program for 2010-2011 and build upon the leadership experiences I developed during my time as a student pharmacist and with my involvement in CSHP. I quickly learned that a key quality to being successful in the industry is flexibility. With an industry that demands more with fewer resources, it is important to be able to prioritize projects, show effective time management skills, and produce qual-ity work in a timely manner. Effective communication is equally important, and a skill I believe all pharmacists should display in their professional interactions with patients and other healthcare providers.

The more opportunities I am exposed to, the more I realize the many places I can be in 5 years. While I do miss the direct interaction with patients and seeing how pharmaceutical interventions impact patient health, I realize that I have thoroughly enjoyed my experiences and still have time to determine where my career will take me. In an environment that is rapidly adapting to meet customer needs, it is with excitement that I welcome the challenges and opportunities that lie ahead as I continue my professional development. u


tech talkCaliforniaSocietyofHealth-SystemPharmacists

When policies and procedures for dispensing medications are being developed, medication error reduction and safety should

be the driving force. Below are some examples of how this focus helped shape how we operate with patient safety in mind at UC Davis Medical Center, where I’ve worked as a technician since 1987.

To ensure that all technicians follow the same procedures, we have developed check lists, which are posted in all pharmacy areas, and outline step-by-step instructions for filling orders for unit dose tablets/capsules and oral liquids, topical and ophthalmics, patient specific ready-to-administer oral liquids, IVs, and chemotherapy orders. Once check lists were created, staff training and development was com-pleted and continues on a periodic basis, including observational audits for quality assurance purposes. Individual feedback is provided as necessary.

Chemotherapy preparation is an area where technicians need to be extremely competent and detail oriented. Check lists are taken a step further. Both the technician and pharmacist must document all required steps on a paper checklist for the greatest degree of accu-racy. Compounding cannot begin until both checklists have been completed and verified by both parties. Additionally, only one che-motherapy agent is compounded at a time. Once the medication has been compounded and labeled, a second independent pharmacist completes the final check. Finally, the chemotherapy technician deliv-ers the medication to specially marked bins in the patient care area. As an added layer of safety, only the technician that compounded the chemotherapy is allowed to make the delivery.

For our pediatric patients, double-checks are in place for all IV preparations. Technicians remove the required amount of base solu-tion to ensure total volume and draw up the prescribed amount of medication from the stock solution. Syringes and medication stock solution are placed next to the label for a “pre-check.” Once the pharmacist has completed the pre-check, the technician completes the IV compound. The finished product and medication stock solution are then set on the counter for a second independent pharmacist to complete the final check.

When our Pediatric Pharmacy is closed, pediatric medication labels are generated along side adult medication labels. We add “PEDSPEDSPEDSPEDSPEDS” at the top and bottom of each label to significantly help identify pediatric labels and make them stand out as unique. This concept has proven most helpful and successful in reducing errors.

Medication Error reduction and Safety By Darren R. Besoyan, CA TCH [email protected]

Sound-alike look-alike drugs (SALAD) are especially challenging and require special attention and diligence when filling. To aid in pull-ing the correct medication, several helpful identifiers have been put in place: identifying stickers are on all SALAD bins, which are red, and tall-man lettering appears on every SALAD label. These measures are in place to make these drugs stand out and alert staff to employ due diligence when filling.

At UCDMC, anticoagulants are closely monitored by pharmacists. Special training has been given to technicians to educate them since it would be very harmful if a patient were to receive an extra dose. In the event that a dose goes missing, technicians have been instructed never to dispense another dose without conducting a thorough investiga-tion. If the missing dose cannot be found (which thankfully it usually is), a replacement dose cannot be generated without the express per-mission of the anticoagulation pharmacist.

Insulin has been identified as a high-alert medication. We’ve taken several steps to help separate these medications from each other in all pharmacy and patient care areas. We stock all insulin products alphabetically, not side by side, but vertically on different shelves on both sides of the refrigerator. Red bins, with high-alert stickers are used to make them stand out even more. At UCDMC, the 3 most common insulin products are Regular, Novolog, and Lantus. Each of these products is dispensed and stored in totally different forms and locations in an effort to aid nursing to take pause prior to administering to patients.

Regular insulin, because it is most commonly used, is the only floor-stock insulin product stocked in vial form in patient care area refrigerators. Novolog stands out as different because it is the only product we purchase in a pen and we deliver them to the patient medication cassettes, not the refrigerator, with a 28 day expiration date. Lantus it is the only insulin product that pharmacy prepares daily by drawing up and labeling each patient specific dose into an insulin syringe, which are then delivered to the medication refrigerators in the patient care areas. All other insulin products, which are rarely used (N, 70/30, L & U), are given a 28 day expiration date, and delivered to the patient’s medication cassette (not the refrigerator).

These are just a few examples of how medication error reduction and safety drives not what we do, but how we do things. I encourage you to let medication error reduction and safety drive your decisions. Our patients will be safer as a result. u


Programs for Directors and Managers:• Pharmacy Directors’ Roundtable• Exhibit Hall• Town Hall• Open Forum• Administrative/Management Education

Track with courses such as MERP Surveys with Loriann DeMartini from CDPH; PIC Survival; The Joint Commission Update; USP 797 & Compounding; Dealing with FDA Alerts; Medicare Part D; Legislative & Regulatory Update.

Programs for Residents & New Practitioners:• Poster Session• Financial Awareness & Planning• Career Roundtable• How to Prevent Career Limiting Moves• The Dos and Don’ts of Social Networking• Professional Development Education

Track with courses such as PowerPoint Presentations & Presentation Skills; Project Management; Stress Management; Pharmacist Roles Pearl.

Programs for Student Pharmacists:• Quiz Bowl• Residency Showcase• Financial Awareness & Planning• Poster Session• Clinical Skills Competition• NAPLEX Review• Career Roundtable• How to Prevent Career Limiting Moves• The Dos and Don’ts of Social Networking

Programs for Accomplished Clinical Pharmacists:• Exhibit Hall• Town Hall• Open Forum• Clinical Education Track with courses

such as New Drugs in Endocrinology & Diabetes; Advances in Cardiology; Advances in Oncology; New Guidelines on Hyperlipidemia; New HIV Guidelines; New Drugs in General Medicine; Clinical Guideline Updates During the Last Year.

Programs for Pharmacy Technicians:• Exhibit Hall• Technician Town Hall• Open Forum• Technician Education Track; with courses

such as; Implementing Tech-Check-Tech; Maximizing Technician Roles in the Inpatient Setting; Setting up an Externship in Your Facility; Best Practices in Medication Reconciliation; Technician Roles Pearl; USP 797 & Compounding.

October 21-24

The Hilton San Francisco Union Square

333 O’Farrell Street

San Francisco, CA

Please check the Seminar website for updates: http://seminar.cshp.org

Seminar 2010 Features: • Keynote Speaker Ed O’Neil, PhD,

MPA, FAAN, Director and Professor of the UCSF Center for the Health Professions

• Exhibit Hall and Poster Session

• House of Delegates and Open Forum

• Town Hall and Technician Town Hall

• Industry Sponsored Exhibitor Theaters

• Volunteer Reception honoring the Distinguished Service Award recipient

• President’s Reception honoring the Pharmacist of the Year

• Golf Tournament and Silent Auction to benefit the CSHP Foundation

• Phun Run

• Schools of Pharmacy Alumni Receptions

Continuing Pharmacy Education (CPE):Seminar 2010 will feature four CPE Tracks: Administrative/Management; Clinical; Professional Development; and Technicians. Attendees will be able to earn as many as 16 hours of ACPE accredited CPE during Seminar 2010.

Documents

California Journal of HealtH-SyStem PHarmaCy