THE PHARMACY ADVISOR
A Publication of the Beth Israel Deaconess Medical Center
Department of Pharmacy and Pharmacy & Therapeutics Committee
Volume II, Issue 4
Medication Use Evaluation (MUE):
Drotrecogin alfa (Xigris)
Recombinant human activated protein C, drotrecogin alfa (Xigris),
was FDA approved in November 2001 and is indicated for the
reduction of mortality in adult patients with severe sepsis (sepsis
associated with acute organ dysfunction), who have a high risk of
death. FDA approval was largely dependent upon the results of
PROWESS, a randomized, placebo controlled trial wherein it was
demonstrated for the first time that use of an immunomodulator
had a statistically significant effect (absolute risk reduction 6.2%,
p=0.005) on 28 day mortality.
Drotrecogin alfa mimics the activity of endogenous protein C
depleted during acute sepsis. Its activity as an anticoagulant
(inactivation of factors Va and VIIIa), anti-inflammatory (inhibition
of production of inflammatory cytokines-TNF, IL-1, IL-6,
monocyte and neutrophil migration, and activation of lipid A at
monocytes and tissue factor) and profibrinolytic (inhibition of
thrombin production and inactivation of plasminogen activatable
inhibitor-1) may help to explain its activity in the septic process.
A MUE was performed at BIDMC to examine and evaluate the use
of the drotrecogin alfa within the medical center and to determine
congruence to established practice guidelines. Four key areas were
addressed within the MUE: 1.) patient selection criteria as matched
to current established hospital guidelines; 2.) safety [bleeding
complications]; 3.) outcomes of therapy [mortality]; and 4.)
prevalence of obesity with potential for application of a dosing
body weight protocol.
continued on page 3
INSIDE THIS ISSUE
1
Medication Use Evaluation: Drotrecogin alfa (Xigris)
2
Formulary Update:
3
BIDMC Guideline for Use of Sedatives and
Analgesics in the Critical Care Patient
4
Topical Steroid Review
Ramipril (Altace); Valsartan (Diovan)
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
May/June 2003
P&T Formulary Update
The following medications have recently been approved for
addition to the BIDMC formulary
Ramipril (Altace): Angiotensin Converting Enzyme Inhibitor
FDA Approved Indications:
 Hypertension:Ramipril is indicated for the treatment of hypertension
as monotherapy or in combination with thiazide diuretics.
 Heart Failure Post Myocardial Infarction: Ramipril is indicated in
stable patients who have demonstrated clinical signs of congestive
heart failure within the first few days after sustaining acute myocardial
infarction. Administration of ramipril to such patients has been shown
to decrease the risk of death (principally cardiovascular death) and to
decrease the risks of failure-related hospitalization and progression to
severe/resistant heart failure.
 Reduction in Risk of Myocardial Infarction, Stroke, and Death
from Cardiovascular Causes: Ramipril is indicated in patients 55
years or older at high risk of developing a major cardiovascular event
because of a history of coronary artery disease, stroke, peripheral
vascular disease, or diabetes that is accompanied by at least one other
cardiovascular risk factor (hypertension, elevated total cholesterol
levels, low HDL levels, cigarette smoking, or documented
microalbuminuria), to reduce the risk of myocardial infarction, stroke,
or death from cardiovascular causes.
Contraindications/precautions: Hypersensitivity to the drug or
other ACEIs (including angioedema), bilateral renal artery
stenosis; primary hyperaldosteronism; pregnancy (2nd and 3rd
trimesters.) Careful blood pressure monitoring with first dose
(hypotension can occur especially in volume depleted patients).
Use with caution in hypovolemia; collagen vascular diseases;
valvular stenosis (particularly aortic stenosis); hyperkalemia; or
before, during, or immediately after anesthesia. Avoid rapid
dosage escalation, which may lead to renal insufficiency.
Adverse effects: Similar to other ACEI’s.
Dosing:
 Hypertension: The recommended initial dose for patients not
receiving a diuretic is 2.5 mg once a day and should be adjusted
according to the blood pressure response. The usual maintenance
dosage range is 2.5 to 20 mg per day administered as a single dose or
in two equally divided doses.
 Reduction in Risk of Myocardial Infarction, Stroke, and Death
from Cardiovascular Causes: Ramipril should be given at an initial
dose of 2.5 mg, once a day for 1 week, then 5 mg once a day for the
next 3 weeks. Increase as tolerated, to a maintenance dose of 10 mg,
once a day. If the patient is hypertensive or recently post myocardial
infarction, it can also be given as a divided dose.
 Failure Post Myocardial Infarction: For the treatment of postinfarction patients who have shown signs of congestive failure, the
recommended starting dose of ramipril is 2.5 mg twice daily (5 mg per
day). A patient who becomes hypotensive at this dose may be
switched to 1.25 mg twice daily, and after one week at the starting
dose, patients should then be titrated toward a target dose of 5 mg
twice daily, with dosage increases being about 3 weeks apart.
Dosage Adjustment in Renal Impairment is required. Please refer to
the manufacturer’s package insert for complete recommendations.
BIDMC Restrictions: Inpatient formulary
Formulary Update Continued on Page 4
The Pharmacy Advisor 1
BIDMC Guideline for Use of Sedatives and Analgesics in the Critical Care Patient
Clinical Practice Guidelines for the Sustained Use of Sedatives
and Analgesics in the Critically Ill Adult were recently updated
by the Society of Critical Care Medicine (SCCM), the American
College of Critical Care Medicine (ACCM), and the American
Society of Health-System Pharmacists and published in the
January 2002 issue of Critical Care Medicine. The guidelines are
in accordance with current literature describing the benefits of
intermittent dosing of sedatives and analgesics and daily wake
ups in the intensive care units (ICU’s) and have provided the
foundation for newly revised guidelines at BIDMC. The
algorithm format, with accompanying legend, is designed to
guide the user through assessment, treatment and monitoring of
pain, anxiety, agitation and delirium in the ICU patient with the
goal of incorporating daily awakening from analgesia and
sedation, facilitating more effective medication titration at lower
total doses and ultimately improving outcomes with shorter
ventilation and ICU days. Key components of the guideline are
summarized here:
Assessment of the ICU patient experiencing pain, anxiety
and/or delirium: Prior to the use of medication for the
management of pain, anxiety and delirium, it is recommended
that reversible causes be ruled out, that non-pharmacological
treatment be considered and that the hospital environment be
optimized to avoid premature or unnecessary use of
medications. Once reversible causes have been ruled out and/or
addressed, standardized methods of assessment of pain, anxiety
and delirium are recommended.
Assessment of pain and the response to analgesia can be
measured using a numeric rating scale or, for those patients who
cannot communicate, assessment of pain can be made through
the subjective observation of pain-related behaviors (movement,
facial expression, posturing) and physiological indicators (heart
rate, blood pressure, respiratory rate). Changes following
analgesic therapy can be assessed using the same scale. The
Riker Sedation-Agitation Scale is a validated scale that can be
used in the critical care setting for evaluating anxiety and the
level of sedation. Delirium is assessed using the Confusion
Assessment Method for the ICU (CAM-ICU scale).
Analgesia: Adequate analgesia and pain management is
paramount in the critically ill patient and a therapeutic plan and
goal for analgesia should be established and reviewed on a
regular basis to assure optimal patient care. The selection of
parenteral opiods (fentanyl, morphine) for pain control should
be made based on the medication’s properties as well as the
patient’s clinical condition. Fentanyl’s rapid onset makes this
agent preferable in the acutely distressed patient as well as for
hemodynamically unstable patients and/or patients with renal
insufficiency. The longer duration of effect of morphine makes
this agent preferable for intermittent dosing regimens in
hemodynamically stable patients.
Following the selection of analgesic medication, initial
intermittent bolus dosing is recommended over a continuous
infusion regimen to minimize the risks of overmedication (e.g.
fentanyl 25-50 mcg or morphine 2-10 mg every 5-15 minutes for
the first 2 hours, with subsequent dosing at q 2 to 4 hour
intervals.) If adequate pain management is not attained after 4
hours of bolus doing, then a continuous infusion may be
considered. When a continuous infusion is considered, the
infusion should be of low rate and supplemented with as needed
boluses. Consideration should be given to accumulation of
analgesics and sedatives in patients receiving continuous
infusions, particularly in the critically ill patient, in whom drug
metabolism and excretion may be impaired. Once goal analgesic
therapy has been reached, continuous infusions should be tapered
to the lowest effective dose. Analgesic goals and response to
therapy should be assessed regularly. For patients receiving
continuous opiod infusions for prolonged periods (greater than 7
days), it is recommended that the patient be monitored for signs
of opiate withdrawal as outlined in the guideline legend. Doses
should be tapered systematically to avoid withdrawal symptoms.
Sedation: Sedation in the agitated critically ill patient should be
initiated once an adequate pain management plan has been
implemented and reversible causes of anxiety have been ruled
out. Commonly used anti-anxiety medication used in the critical
care setting include: lorazepam, midazolam and propofol.
Optimal drug selection is based on the underlying cause of
anxiety and/or agitation, the patient’s disease state (including comorbid conditions), clinical status and the anticipated duration
of therapy. Midazolam is generally reserved for short-term
management of anxiety (<48 hrs) because it produces
unpredictable awakening and time to extubation when infused
for prolonged periods (>48-72 hrs.) Lorazepam has a slower
onset and its longer duration of action lends to the management
of ongoing sedation in the ICU. Similar to analgesic therapy in
the critically ill patient, sedation with either lorazepam or
midazolam should be initiated using an intermittent bolus dose
regimen (e.g. lorazepam 1 to 4 mg IV P every 10 to 20 minutes
until goal followed by scheduled doses every 2 to 6 hours plus as
needed doses.) If goal sedation is not met after 2 to 4 hours of
bolus dosing, then a continuous infusion may be considered.
Patients with a history of drug or alcohol dependency will likely
require a continuous infusion of either lorazepam or midazolam.
High dose lorazepam infusions (>10 mg/hr over prolonged
periods) have been associated with nephrotoxicity secondary to
the polyethylene and propylene glycol solvents contained in the
IV product. Sedation with continuous infusions of midazolam or
propofol should be considered as an alternate in such patients.
Propofol is the preferred sedative agent when rapid awakening is
desired, such as in the setting of neurosurgery or neurotrauma,
as it facilitates frequent neurological assessments due to its rapid
onset and systemic clearance when stopped. Propofol infusions
(beginning with a 5mcg/kg/min infusion titrated every 5
minutes to goal) should be converted to lorazepam by the 3rd day
(with the exception of neurosurgical patients with elevated
intracranial pressures) if continued sedation is required.
Regardless of the selection of sedation medication, a patientspecific sedation goal should be established and the sedative
dose titrated and tapered to maintain that goal with patient
assessment and response to therapy monitored regularly.
Delirium: Assessment of delirium should be made using the
CAM-ICU scale in patients with suspected delirium. Delirium
management with haloperidol is addressed in the guideline with
appropriate QTc monitoring. Delirium control goals should be
established and therapy adjusted based on response to maintain
that goal. Therapy extending beyond several days should be
systematically tapered prior to stopping.
Approved by the Critical Care Executive and P& T Committees,
the guidelines are posted on the Critical CareWeb site of the
BIDMC intranet under ICU Protocols & Practice Guidelines
and also on the Pharmacy intranet page under guidelines.
The Pharmacy Advisor 2
Medication Use Evaluation (MUE): Drotrecogin alfa (Xigris ) continued
MUE data was concurrently collected and evaluated on fifteen
patients who had received drotrecogin alfa between November
2001 and December 2002. Data included admission diagnosis,
systemic inflammatory response syndrome (SIRS) criteria, time
SIRS criteria noted, number of organ system failures, suspected
or documented infection, concomitant antibiotic therapy,
APACHE II score, if done, presence of relative and/or absolute
contraindications, dose, body weight, duration of therapy,
adverse reactions, costs and outcomes. Data was compiled and
summarized to evaluate the following key measures:
Treatment Inclusion Criteria: Given that FDA approval was
granted based on two large clinical trials, enrollment criteria for
these trials was important in the consideration of this drug for
the BIDMC formulary status. At the time of formulary approval,
Drotrecogin Medication Use Guidelines were established to
assist practitioners in determining if targeted patients met
treatment criteria and ultimately to: improve outcomes, avoid
untoward adverse events and to improve cost effectiveness of
this costly therapy. To ascertain if drotrecogin therapy was
warranted, intensivists evaluated patients for objective evidence
of severe sepsis (as defined by the Society of Critical Care
Medicine and American College of Chest Physicians) and
evidence of more than one organ failure. For patients meeting
treatment criteria and, in the absence of exclusion criteria,
treatment with drotrecogin was recommended to commence
within 24 to 36 hours of the onset of septic physiology.
Medication safety: A notable side effect of drotrecogin
administration is an increased risk of bleeding which was noted
during phase II and III clinical trials. In the PROWESS trial,
despite heavy exclusion of bleeding risks, there was a noted
increase in bleeding events over the 28-day period (3.5 vs. 2.0%
for serious bleeds, p=0.06) in the treatment versus placebo
groups. Consistent with the manufacturer’s recommendations,
important exclusion criteria in the BIDMC guidelines were:
bleeding risks, with objective measures (APTT, INR), active
internal bleeding, presence of an epidural catheter, head trauma,
cerebrovascular accident within 3 months, platelet count less
than 30,000, and concomitant use or use of anticoagulants within
a defined treatment period. Subsequent warnings from the FDA
and drug manufacturer would further include exclusion criteria
of INR>3.0, or GI bleed within 6 weeks.
Outcomes: Subsequent to the PROWESS trial and FDA
approval of drotrecogin, additional information from a posthoc
subgroup analysis of the PROWESS trial revealed that outcome
differences existed in select patient subsets. Those who did
better with drug treatment were patients who were scored above
the first and second APACHE II quartiles (score > 25), patients
with evidence of more than one organ system dysfunction,
patients with septic shock and patients with DIC. The converse
of these patients fared statistically worse in terms of outcomes.
Dosing: The pharmacokinetic profile of drotrecogin suggests
that use of an alternate, adjusted body weight-dosing regimen,
may improve outcomes, safety and cost effectiveness. Its
0.24L/kg volume of distribution is small, with poor distribution
into fat tissues. The manufacturer’s 24 mcg/kg/hr dosing
recommendation was determined in a dose finding study,
evaluating infusions of 12, 18, 24 and 30 mcg/kg/hr, using
actual body weight. Maximum D-dimer decreases appeared in
the 24 mcg/kg/hr group and statistically significant changes in
IL-6 were noted at 96 hours post infusion.
MUE findings: MUE data collection yielded the following
observations:
1.
2.
3.
4.
5.
6.
Three of the 15 patients (20%) treated had evidence of only a
single organ failure, two of the three with bleeding complications.
Seven patients (47%) were obese, BMI>30 and were candidates
for a dosing body weight model.
Six patients (40%) had at least one contraindication for therapy
according to BIDMC guidelines; all experienced bleeding
complications.
Only two patients (13%) completed 90 to 96 hours of therapy.
Nine patients (60%) survived past 28 days post therapy.
Ten patients (67%) experienced a bleeding complication during
therapy.
All evaluated patients received drotrecogin within a 36-hour
window after septic physiology was identified, and all were
appropriately treated with antibiotics, however an APACHE II
severity score was not consistently documented. Total drug
costs for this cohort of patients were approximately $43,000. It
was determined that if an adjusted dosing weight model had
been used, the total drug cost could potentially have been cut by
approximately $12,000.
Based on the MUE findings, a number of proposals and
recommendations from the P&T and Critical Care Executive
committees and the Clinical Resource Management team were
made to improve outcomes, reduce adverse bleeding events and
promote drotrecogin cost effectiveness. The proposals included:
1.)
2.)
Use of a computer based APACHE II scoring system
Guideline revision to include all relative and absolute
contraindications and visual enhancement of select factors (i.e.,
active bleeding, concurrent anticoagulation, INR >3.0 without
DIC, infective endocarditis, etc.
3.) Application of a dosing body weight model based on
pharmacokinetic considerations in obese patients
Note that these enhancements may not all be operational at the
time of this publication.
Table 1: Summary of changes/enhancements to
drotrecogin alfa prescribing guidelines
1) Selection of patients/
optimization of outcomes
2) Increased awareness of
patients with relative risks
for adverse outcomes
3) Application of a dosing
body weight model based
on pharmacokinetic
considerations in obese
patients.
Use of a computer based APACHE II
scoring system (see clinical page of
home.caregroup.org, see Med calc 3000clinical criteria) and reconsideration of
treatment with drotrecogin alfa for
patients with APACHE II score <25.
Guideline revision and update of web
based version with emphasis on:

Active bleeding

Concurrent anticoagulation

INR >3.0 w/o DIC
 Infective endocarditis
Inclusion of a dosing body weight
nomogram with specific directions for
rate and concentration of final product
for pharmacists and infusion sheet for
nursing MAR
Since the initial MUE, the number of patients treated per month
has nearly doubled and more patients have completed therapy
with an increased survival rate from the original cohort to (73%).
Total drug costs have increased due to more patients treated for
longer durations, however utilization of the dosing body weight
model in four patients has yielded an $8,000 savings without a
negative impact on outcomes. Data collection continues with the
goal of improved outcomes, enhanced safety and cost
effectiveness of this multidisciplinary process.
The Pharmacy Advisor 3
Formulary Update continued:
Valsartan (Diovan): Angiotensin II receptor blocker
Adverse effects: In the treatment of hypertension, adverse
effects were similar in incidence to placebo; independent of race,
age, and gender. >1%: Central nervous system: Dizziness (2%
to 8%), fatigue (2%) Endocrine & metabolic: Serum potassium
increased (4.4%) Gastrointestinal: Abdominal pain (2%)
Hematologic: Neutropenia (1.9%) Respiratory: Cough (2.6%
versus 1.5% in placebo) Miscellaneous: Viral infection (3%)
FDA Approved Indications: Valsartan is indicated for the
treatment of hypertension (either as monotherapy or in
combination with other antihypertensive agents.) It is also
indicated in the treatment of heart failure (NYHA class II-IV) in
patients intolerant of angiotensin converting enzyme inhibitors.
Contraindications: Hypersensitivity to valsartan or any
component of the formulation; hypersensitivity to other A-II
receptor antagonists; primary hyperaldosteronism; bilateral renal
artery stenosis; pregnancy (2nd and 3rd trimesters)
Dose:
Hypertension: The recommended starting dose of valsartan is
80 mg or 160 mg once daily when used as monotherapy in
patients who are not volume-depleted. Patients requiring greater
reductions may be started at the higher dose. The usual valsartan
dose range is 80 mg to 320 mg administered once daily.
Warnings / Precautions: Avoid use or use a smaller dose in
volume depleted patients; correct depletion first. Deterioration
in renal function can occur with initiation. Use with caution in
unilateral renal artery stenosis, pre-existing renal insufficiency;
significant aortic/mitral stenosis. Use caution in patients with
severe renal impairment or significant hepatic dysfunction.
Heart Failure : The starting dose of valsartan is 40 mg twice
daily. Upward titration to 80 mg and 160 mg twice daily should
be done to the highest dose, as tolerated. The maximum daily
dose administered in clinical trials is 320 mg in divided doses.
Consideration should be given to reducing the dose of
concomitant diuretics. Concomitant use with an ACE inhibitor
and a beta blocker is not recommended.
Heart failure: Concomitant use of valsartan, an ACE inhibitor,
and a beta-blocker is not recommended; this combination has
been associated with unfavorable outcomes in clinical trials.
Monitor renal function closely in patients with severe heart
failure; changes in renal function should be anticipated and
BIDMC Restrictions: Inpatient formulary
dosage adjustments of valsartan or concomitant medications
may be needed.
_________________________________________________________________________________________________________
Topical Steroid Review
Topical steroids were recently reviewed by the P&T Committee and upon recommendation from the Department of Dermatology; several
changes were made to the inpatient formulary. The following table lists available topical steroids by potency and the medications on
inpatient formulary are highlighted.
Potency
Ultra high
High
Mid
Low
Generic name and strength
Betamethasone dipropionate, augmented 0.05%
Trade Name
Formulations
Formulary Status

Ointment
Formulary

Formulary
Diprolene and generics
Clobetasol propionate 0.05%
Temovate and generics
Cream, Gel, Ointment
Halobetasol propionate 0.05%
Ultravate
Cream, Ointment
Non-formulary
Diflorasone diacetate 0.05%
Psorcon
Cream, Ointment
Non-formulary
Betamethasone dipropionate 0.05%
Diprosone and generics
Cream, Lotion, Ointment
Formulary
Desoximetasone 0.25%
Topicort
Cream, Ointment
Non-formulary
Diflorasone diacetate 0.05%
Psorcon E
Emollient Cream and Ointment
Non-formulary
Fluocinonide 0.05%
Lidex and generics
Cream, Ointment, Solution
Formulary
Fluticasone propionate 0.05%, 0.005%
Cutivate
Cream, Ointment
Non-formulary
Halcinonide 0.1%
Halog
Cream, Ointment, Solution
Non-formulary
Triamcinolone acetonide 0.1%
Kenalog and generics
Cream, Ointment
Formulary
Betamethasone valerate 0.1%
Betamethasone valerate
generics
Cream, Ointment
Formulary
Desonide 0.05%
DesOwen, Tridesilon and
generics
Cream, Ointment
Formulary
Fluocinolone acetonide 0.01%
0.025%
Synalar and generics
Cream, Solution,
Cream, Ointment
Formulary
Hydrocortisone 0.05% - 2.5%
Hytone and generics
Cream, Ointment
Formulary
Triamcinolone acetonide 0.025%
Triamcinolone acetonide
generics
Cream
Formulary
The Pharmacy Advisor 4