THE PHARMACY ADVISOR
A Publication of the Beth Israel Deaconess Medical Center
Department of Pharmacy and Pharmacy & Therapeutics Committee
Volume II, Issue 2
Medication Safety
“ It’s Time For Standards To Improve Safety With
Electronic Communication Of Medication Orders”
The above title is taken from a feature article in a recent medication
safety alert from the Institute For Safe Medication Practices
(ISMP). This timely communication coincides with the medication
safety initiatives that have been underway for some time at BIDMC
as we have constructed our Provider Order Entry and Pharmacy
computer systems. The article states that, “Among its many
benefits, electronic communication of medication orders allows for
more accurate conveyance of information than handwritten
formats. However, if the conventions used to communicate
electronic information are not considered carefully, computerized
order processing actually may contribute to medication errors.” It
is further communicated that, “To avoid problems, healthcare
technology vendors need a set of accepted standards for the
electronic communication of medication information.”
Outlined in the safety alert are preliminary guidelines intended to
serve as a starting point for standards in the way prescribed
medications are presented and communicated in electronic formats.
Excerpts from the guidelines are included later in this article. The
complete medication safety alert and guidelines can be found on the
ISMP web site at http: www.ismp.org. The authors recognize that
these initial guidelines are incomplete and certain portions are
expected to attract discussion about their benefits and limitations.
Individual practitioners and institutions are encouraged to share
comments and suggestions on this very important issue. Please send
comments to ismpinfo@ismp.org.
Continued on page 2
INSIDE THIS ISSUE
1
2
3
Medication Safety With Electronic Communication Of
Medication Orders
Drug Shortage Management:
IV Pantoprazole (Protonix®)
Formulary Update: Ziprasidone (Geodon®)
4
Kinetics Corner: Antimicrobials: When
Pharmacokinetics meets Pharmacodynamics
5
BIDMC Guidelines for Anticoagulation in Patients
with Heparin Induced Thrombocytopenia
The Pharmacy Advisor is a publication of the Department Of
Pharmacy and the Pharmacy & Therapeutics Committee at
the Beth Israel Deaconess Medical Center, Boston, MA 02215
Writing/Editorial Board:
Katherine Giampietro, PharmD
Christopher McCoy, PharmD
Diane Soulliard, PharmD
Bruce Bistrian, MD, Co-Chair P&T
James Heffernan, MD, Co-Chair P&T
Francis P. Mitrano, M.S., RPh
February 2003
Drug Shortage Management:
IV Pantoprazole (Protonix®)
A nation-wide drug shortage of parenteral pantoprazole has
affected product availability at BIDMC and elsewhere for several
months. The shortage is attributed to increased demand and
supply constraints and is expected to continue through mid-2003.
Until the shortage is resolved, the manufacturer, Wyeth-Ayerst,
communicates that product availability will be on an allocation
basis and institutions will be limited to a 50% monthly allocation
of previous purchases. To ensure that patient-care needs can be
met with the limited allocation of parenteral pantoprazole, the
BIDMC will enforce the following Proton Pump Inhibitor (PPI)
utilization guidelines:
 Oral administration of pantoprazole is the preferred
route of therapy for patients requiring acid blockade
with a PPI and are able to tolerate oral medications.
 Pantoprazole delayed–release tablets should not be crushed
and therefore, the preferred PPI for patients requiring
therapy via the nasogastric or enteral route is
lansoprazole suspension. Such patients requiring PPI
administration will receive a bicarbonate-based simplified
lansoprazole suspension (SLS) prepared by pharmacy.
 Patients who require acid blockade and are unable to
receive therapy (PPI or H2 receptor antagonist) via the
oral or enteral route should receive a parenteral H2
receptor antagonist (IV famotidine) as the preferred
parenteral agent of choice unless it has been shown to
be ineffective or contraindicated.
 Parenteral pantoprazole (Protonix) will be reserved for
those patients unable to receive therapy via the oral or
enteral route and for whom parenteral famotidine is
ineffective or contraindicated.
More specifically, use of parenteral pantoprazole will be
limited to those patients who meet the above conditions and
have one or more of the indications listed below:
 Patients with severe erosive GERD:
Dose: Pantoprazole 40mg IV QD
 Patients with hypersecretory disease (i.e. Zollinger
Ellison Syndrome): Dose: Pantoprazole 80mg IV
Q12H (some patients may require higher doses)
 Patients with an active GI bleed with an erosive
source (i.e. ulcers or severe erosive esophagitis)
Pantoprazole 80mg IV load, followed by 8mg/hour
 Recommendation by GI Consult
There is no literature to suggest that use of an intravenous PPI is
superior to conventional agents used for stress ulcer prophylaxis,
such as the H2-receptor antagonists. Accordingly, patients
requiring a parenteral agent for this indication should receive IV
famotidine as the first-line agent of choice.
The pharmacy will continue to provide updates regarding the IV
pantoprazole shortage.
P&T Formulary Update
Medication Safety: continued from page 1
Ziprasidone added to the inpatient BIDMC formulary
Below are excerpts from the ISMP Draft Guidelines For Safe
Electronic Communication of Medication Orders.
Medication safety has been at the forefront of the POE and
Pharmacy system development at BIDMC and many of the
recommended guidelines have already been incorporated into
our electronic systems.
Safe presentation of drug nomenclature and dose
expressions in electronic systems:

Ziprasidone (Geodon ) is an atypical antipsychotic agent.
FDA Approved Indications: Ziprasidone is indicated for the
treatment of schizophrenia. Ziprasidone intramuscular (IM) is
indicated for the treatment of acute agitation in schizophrenic
patients for whom ziprasidone treatment is appropriate and IM
antipsychotic medication is required for rapid agitation control.
Pharmacokinetics: Ziprasidone is well absorbed orally,
reaching peak plasma concentrations in 6-8 hours. Bioavailability
is approximately 60% and is increased up to two-fold in the
presence of food. Advanced age, sex, and race do not appear to
influence kinetics to a significant extent and dosage modification
for age or gender are therefore, not recommended.
The bioavailability of intramuscular ziprasidone is 100%. After
administration of single IM doses, peak serum concentrations
typically occur at approximately 60 minutes post-dose or earlier
and the mean half-life ranges from two to five hours. Exposure
increases in a dose-related manner and following three
consecutive days of IM dosing, little accumulation is observed.
Contraindications, Warnings, And Precautions:
Ziprasidone has been associated with dose-related prolongation
of the QT interval. Because of this and the consequent danger of
life-threatening arrhythmias (e.g. torsade de pointe and sudden
death), its use is contraindicated in patients with a known history
of QT prolongation, cardiac arrhythmias, recent acute
myocardial infarction, or decompensated heart failure.
Concomitant administration of drugs that interfere with
ziprasidone metabolism, drugs known to prolong the QT
interval, or drugs likely to cause electrolyte imbalance should be
avoided. Baseline serum potassium and magnesium screening
should be performed and continually monitored during therapy.
Adverse Reactions: Side effects in clinical trials have included
dyspepsia, constipation, nausea, abdominal pain, dry mouth,
sedation, headache, postural hypotension, dizziness, insomnia,
akathisia, and rash. See package insert for the full listing.
Dosing: The initial daily dosing of ziprasidone is 20 mg BID
with food. When required, dose adjustment should be made at
intervals of not less than 2 days to a recommended maximum
dose of 80mg bid. The recommended dose of IM ziprasidone is
10 to 20 mg up to a maximum of 40 mg per day. Therapy with
IM ziprasidone for more than 3 consecutive days has not been
studied and oral ziprasidone should replace IM administration as
soon as possible if continued therapy is required.
Conclusion: Ziprasidone is an effective antipsychotic with
efficacy comparable to haloperidol. It has not been associated
with weight gain, making it unique in this class of pharmacologic
agents. Ziprasidone has been associated with increases in QTc
interval, which will restrict its use in some populations and may
make it a second-line agent. The IM product offers an alternate
choice to current therapies and based on preliminary evaluation,
appears as effective as haloperidol in the management of acute
psychosis and better tolerated with regard to sedation and
movement disorders.
BIDMC Restrictions: Parenteral ziprasidone will be reserved
for use in the emergency department, psychiatric emergencies
(Code Purple) and in-patient psychiatry, when intramuscular
antipsychotic medication is required for rapid agitation control.






List all products by generic name as the primary drug
nomenclature.
Do not include the salt of the chemical when expressing a
generic name unless there are multiple salts available.
As appropriate, list brand names in a requisite field.
Express suffixes that are part of the brand name (e.g., SR,
SA) within both the generic name and the brand name field.
Avoid use of all potentially dangerous abbreviations and
dose expressions including the following:
a. Do not use trailing zeros (5 mg, never 5.0 mg).
b. Use leading zeros for doses less than one
measurement unit (0.3 mg, never .3 mg).
c. Spell out the word UNITS.
d. Express weights and measures in a standard fashion
and use USP standard abbreviations for dosage units
To avoid confusion, do not abbreviate drug names.
Design features for electronic order entry systems
(pharmacy and prescriber) that support safe
communication of orders:








Provide adequate space for items in data fields used to
communicate drug names, dosing units, routes of
administration, and frequencies.
Provide a field that requires entry of the purpose for the
following types of medication orders: all prn medications.
Provide the ability to clearly communicate medications
prescribed for specific, non-routine administration times or
under certain conditions (e.g., with dialysis, while NPO,
until tolerating liquids, prior to surgery).
Provide the capability to link medications only to the
appropriate routes of administration available for each drug.
Provide a mechanism to facilitate safe order entry of
complex medication regimens (e.g., chemotherapy, sliding
scale insulin) and medications that require a tapering dosing
schedule (e.g., steroids) so that the orders appear clearly and
in a logical order for those who dispense and administer the
medications.
Provide the capability for clinicians to select the time or
date to begin drug administration, regardless of when the
order was entered.
Provide a mechanism to place medication orders on hold
under specified conditions, and to alert users at specified
times while a medication is on hold.
To prevent the risk of misinterpretation, limit the potential
for free-text entries in CPOE systems.
The complete guidelines and additional topics for electronic
medication safety standards are included in the full text ISMP
article. Should you have any comments or suggestions regarding
medication safety in the BIDMC POE system, please forward
them to the Department of Pharmacy.
Kinetics Corner
Antimicrobials: when pharmacokinetics meet pharmacodynamics
Optimization of antimicrobial therapy includes consideration of
both the pharmacokinetic and pharmacodynamic properties of the
antimicrobial agent selected for use. An overview is presented here
to provide a general understanding of these principles as they relate
to antimicrobial selection and utilization.
Pharmacokinetics is the study of the time-dependent evolution of
drug concentrations and distribution within various body
compartments, often through use of differential equation models.
More specifically, the pharmacokinetics of a medication rests in the
absorption, distribution, metabolism and elimination of the drug
and its relationship to efficacy and safety.
Pharmacodynamics refers to the effectiveness of a medication as a
function of time-dependent concentrations. More specifically, the
pharmacodynamics of an antimicrobial agent rests in the activity of
the drug at the site of action, ordinarily on the outer surface (e.g.,
penicillin binding proteins) or inner structures (e.g., ribosomes) of
the microbial pathogen. Antibiotics are classified as demonstrating
optimal pharmacodynamic activity depending upon the amount of
time they are exposed to the site of action (time dependence) or
the ability to “supersaturate” the site of action at a high
concentration (concentration dependence) for a short period of
time. For every organism, there is a minimum concentration of
antimicrobial above which, there is consistent inhibition of growth
and/or replication and a trend toward decreased bacterial resistance.
This is termed the minimum inhibitory concentration (MIC).
Concentration dependent antimicrobials have been demonstrated to
achieve optimal antimicrobial activity when the ratio of the
antibiotic peak (Cmax) to the MIC, also known as the peak to MIC
ratio, is highest without reaching a toxic range. Generally,
acceptable ratios are 8 to 10 times the MIC for that agent. Hence,
there has been a trend toward the application of supratherapeutic
doses at an extended interval for antibiotics that fall within this
category (e.g., extended interval aminoglycosides). Other models
have demonstrated the benefit of measuring a 24-hour area under
the curve (AUC), which is the total concentration of antibiotic over
a 24h period and its relationship to the MIC (termed the AUC to
MIC ratio.) The goal AUC/MIC ratio varies dependent on the
organism and is generally higher for gram-negative organisms, about
100, versus gram-positive organisms, including Streptococcus
pneumoniae, about 35. Examples of concentration dependent
antimicrobials include the aminoglycosides (e.g., tobramycin,
gentamicin and amikacin) and the fluoroquinolones (e.g.,
ciprofloxacin and levofloxacin).
The translation for drug monitoring of concentration dependent
antibiotics in practice is that a peak level drawn on an extended
interval high dose regimen of gentamicin will result in a level that far
exceeds the “standard” peak levels reported by the laboratory, e.g.,
6-10 mcg/ml. This may alarm some, but the intent of the high dose
is to “overwhelm” the microbial site of action. This practice has not
been associated with increased toxicity as the time of the peak
concentration is short, and the nephrotoxic effects of
aminoglycosides, are related to the saturation of the renal tubules
over prolonged periods. This provides the rationale for not
repeating a 5mg/kg dose at the standard q8hourly interval. Active
transport mechanisms are allowed to facilitate drug elimination from
the tubules when true trough levels (within 30 minutes of the next
dose at steady state) remain below 1 or 2.
Additional data supports the relationship of optimizing the 24-hour
AUC/MIC ratio in acutely ill patients. Thomas, et.al. (Antimic
Agents Chemother 1998;42:521-7) demonstrated that a 24-hour
AUC/MIC ratio greater than or equal to 100 was associated with a
reduced risk of emergence of resistance, 9% vs. 82%. In some cases,
this AUC/MIC ratio was measured when therapy had included both
a beta lactam and fluoroquinolone antibiotic to target a single
pathogen, a method of measurement that has not been well
translated in vitro to in vivo. Additionally, this AUC/MIC ratio and
its relationship to resistance was not reproducible among patients
treated with beta lactam antibiotics alone. Only the patients treated
with ciprofloxacin demonstrated a statistically significant difference
lending more evidence that a higher total concentration for
fluoroquinolones may be associated with less resistance. This does
not imply that resistance will not occur with fluoroquinolone
antibiotics, but rather that certain dosing strategies with
fluoroquinolones can optimize outcomes.
Time dependent antimicrobials achieve optimal antimicrobial
activity when the steady state trough concentrations remains above
the MIC for at least 50% of the treatment course and the AUC
remains at an appropriate level. Models of continuous infusions or
longer infusion times of larger doses have been investigated.
Examples of time dependent antimicrobials include the beta-lactam
antibiotics (e.g., penicillin, ampicillin, ceftazidime, cefepime,
meropenem), which demonstrate optimal killing with a prolonged
time above MIC and no killing effect below the MIC. Other drugs
that are deemed time-dependent are the macrolide antibiotics (e.g.,
azithromycin, erythromycin and clarithromycin), vancomycin,
clindamycin and linezolid, which demonstrate optimal killing with a
prolonged time above MIC and a killing effect below the MIC.
The translation for drug monitoring of time-dependent antibiotics
in practice is that the trough level should remain above the MIC for
at least half of the 24-hour period. For example, the goal trough
levels for vancomycin are 5 to 15mcg/ml, above a general MIC of
2mcg/ml. Peak levels are not necessary for vancomycin as the ratio
of peak/MIC is not as important for time dependent antimicrobials.
The clinical significance and application of these theories is variable.
Drug levels are not routinely drawn nor recommended for betalactam or fluoroquinolone antibiotics. However, drug levels are
often ordered for aminoglycosides and vancomycin. The usefulness
of these levels lies in the appropriateness of timing of serum
samples relative to dose administration and their interpretation.
Common errors include drawing levels too often or at less than
optimal times and adjusting dose or schedule without consideration
of these factors. The intent of antimicrobial therapeutic drug
monitoring is focused on optimizing activity while preventing drug
related toxicities. This includes the monitoring and consideration of
objective measures of efficacy, (e.g., WBC count, temperature,
sputum production) and measures of toxicity, (e.g., BUN/Cr, urine
output, ataxia). Laboratory based pharmacokinetic models help to
elucidate more predictable and improved general practice models
without the need for drug levels for every patient on a daily basis.
Important pharmacokinetic concepts to consider include the
premise that in patients with varying degrees of renal deficiency,
extension of the drug interval at a higher dose may be more
appropriate for concentration dependent antimicrobials,
aminoglycosides and fluoroquinolones, e.g., gentamicin 6mg/kg
q48h or levofloxacin 500 mg q48h. Contrarily, reduction in the
dose of a drug may be more appropriate for time dependent
antimicrobials, e.g., cefazolin 1gram IV q8h versus 2 g IV q8h.
For assistance in the interpretation of antimicrobial levels, dosing
and/or scheduling of antimicrobials, please call your unit based
pharmacist, or Christopher McCoy, PharmD, pager 39392.
BIDMC Guidelines for Anticoagulation in Heparin-Induced Thrombocytopenia
Heparin-induced thrombocytopenia (HIT) is a serious
complication associated with heparin therapy and occurs
independent of the route of administration, indication and dose
of heparin.
Two distinct types of HIT, Type I and Type II, are recognized
and involve different causal mechanisms. The more serious,
immunologic form (HIT Type II), is characterized by the
formation of antibodies against the heparin-platelet-factor 4 (PF4) complex with an acute drop in platelets (often dropping to
60,000/µL or below) and generally occurs 5 to 14 days following
initiation of heparin (earlier, if the patient has been previously
exposed to heparin.) The second, non-immunologic form (HIT
Type I) occurs in 10-20% of patients and is characterized by a
decrease in platelet count (usually not less than 100,000/µL)
occurring 1-2 days following initiation of heparin. Type I HIT
often resolves on its own, despite continued heparin therapy,
without significant clinical sequelae
If HIT type II is suspected, all heparin products must be
discontinued and the patient evaluated for the need of further
anticoagulation. If anticoagulation is required, a PF-4 test may
be requested and alternate anticoagulant agents selected. Low
molecular weight heparins are not appropriate alternatives due to
the high risk of cross-reactivity to HIT antibodies. Direct
thrombin inhibitors (DTI) are newer anticoagulants that
inactivate both soluble and clot-bound thrombin and do not
cross-react with the HIT antibody. Available DTI’s include
argatroban, bivalirudin and lepirudin. All three are administered
by continuous infusion and require monitoring of aPTT or ACT.
Argatroban and lepirudin have been shown to reduce the risk of
death, amputation and new thromboembolic complications and
are both FDA approved for use in patients with HIT.
Argatroban is preferred to lepirudin in HIT patients [not
undergoing percutaneous coronary intervention (PCI) or
catheterization] since 40% of patients receiving lepirudin
develop antibodies on first exposure and are at risk of
anaphylaxis upon re-exposure. Bivalirudin is FDA approved for
use in patients undergoing PCI or cardiac catheterization and
can also be used as an alternative to argatroban or lepirudin for
patients with HIT not undergoing PCI.
Use of argatroban in patients with moderate to severe hepatic
impairment (Child-Pugh score >6) should be avoided as the
drug is hepatically metabolized. Lepirudin and bivalirudin are
renally eliminated and require adjustment for renal impairment
(estimated CrCl < 60 ml/minute). Extreme caution is required in
dosing lepirudin in patients with a CrCl  15 ml/minute and it
should be avoided in patients undergoing hemodialysis.
Guideline for Management of Heparin-Induced Thrombocytopenia (HIT)
HIT suspected in patient receiving heparin in setting of platelet count drop  50% below a pre-heparin platelet count value,
and/or with clinical signs & symptoms of heparin-induced thrombocytopenia with thrombosis (HITTS)
STOP ALL HEPARIN AND HEPARIN FLUSHES
Request PF4-heparin antibody test if patient requires anticoagulation 
PF4 Positive - Stop all heparin including flushes; Choose alternative Antithrombotic if patient requires anticoagulation
PF4 Negative - Clinical Decision Making; Consider alternative Antithrombotic if HIT likely and patient requires anticoagulation
HIT patients requiring anticoagulation and NOT undergoing
PCI/Cath and NOT with Acute Coronary Syndrome
Moderate to Severe Hepatic Impairment
NO
ARGATROBAN
(Preferred Direct Thrombin
Inhibitor in Non-PCI/Cath patients)
HIT/HITTS:
2 mcg/kg/min by continuous
infusion with no bolus dose
Monitor aPTT to goal and follow
INR closely if on warfarin
therapy
Dosing adjustment required in
hepatic impairment.
(0.5 mcg/kg/min)

YES
LEPIRUDIN¶
HIT/HITTS:
0.4 mg/kg bolus followed by
0.15 mg/kg/hr infusion*
Monitor aPTT to goal
¶ Anaphylaxis can occur on reexposure to lepirudin due to
antibody formation
*If estimated creatinine clearance
< 60 ml/min must adjust Lepirudin
dose or consider Argatroban.
Consult a pharmacist for assistance
in dosing
HIT patients undergoing PCI/CATH or
with Acute Coronary Syndrome (ACS)
BIVALIRUDIN*
PCI dose:
ADMINISTER IN CATH LAB ONLY
0.75 mg/kg bolus then
1.75 mg/kg/hr during the procedure;
Obtain ACT 5 minutes into infusion;
If < 225 give one 0.3 mg/kg bolus
Monitor ACT to 225
ACS dose:
0.2 mg/kg/hr
Monitor ACT to goal
* If estimated creatinine clearance < 60 ml/min must
adjust bivalirudin dose when continuing therapy beyond
the cath lab procedure or when using for ACS or DVT.
Consult a Pharmacist for assistance in dosing
 Child-Pugh classification of severity of liver disease considers degree of ascites, serum bilirubin and albumin, prothrombin time and degree of encephalopathy.
 The PF4 test assays for the presence of antibodies directed against platelet factor 4 (PF4)-heparin complexes, which can result in thrombocytopenia, platelet
activation/aggregation, and prothrombotic complications.
The Pharmacy Advisor 4