THE PHARMACY ADVISOR
A Publication of the Beth Israel Deaconess Medical Center
Department of Pharmacy and Pharmacy & Therapeutics Committee
Volume II, Issue 3
March 2003
Nutrition Services Report to P&T
Discontinuation of Blue Dye to Detect Aspiration
From Enteral Tube Feeding
P&T Formulary Update
The following medications have been approved by the
P&T Committee as additions to the BIDMC formulary
Recent reports of adverse events associated with the use of adding
blue dye to enteral formulas to test for possible aspiration have
prompted both clinicians and manufacturers to review this practice.
Based on these reports and recommendations taken from the
Consensus Statement of the North American Summit on Aspiration in
the Critically Ill Patient, two of the leading manufacturers of the
FD&C Blue Dye No. 1, Novartis Nutrition and Nestle, have
announced that they are discontinuing production of this product.
Effective April 15th, blue dye will no longer be available for use at
BIDMC.
Early experiments with FD&C Blue Dye No. 1 demonstrated that
the dye was nontoxic and was not absorbed in healthy subjects,
leading to its approval for use by the FDA. Over time, the addition
of the blue dye to tube feeding formulas as a gauge to determine if
patients aspirate has become commonplace, despite the lack of
strong scientific evidence demonstrating that this is an effective way
to detect aspiration. With increased use, especially in hospitals and
in critically ill patients, there is increasing evidence that there can be
systemic absorption of the blue dye and with that, potential toxic
adverse effects, including death.
In November 2002, the findings from the North American Summit
on Aspiration in the Critically Ill Patient, held earlier that year, were
published in a Consensus Statement. The Summit panel of enteral
nutrition experts concluded with respect to the use of blue dye to
test for aspiration: "Benefits of this test are poor and risks are
substantial. This practice should be abandoned."
Continued on page 4
Famotidine:
Cimetidine
PO
Nizatidine
PO
Ranitidine
PO
Famotidine
PO
INSIDE THIS ISSUE
300mg QID or
400mg BID
150mg BID
150mg BID
20mg bid
800mg HS
300mg HS
300mg HS
40 mg HS
1
2
3
Nutrition Services Report: Discontinuation of Blue Dye
to Detect Aspiration From Enteral Tube Feeding and
Recommendations for Preventing Aspiration During
Enteral Tube Feeding
Formulary Update: Famotidine; Caspofungin
(Cancidas®); Oxaliplatin (Eloxatin®)
Changes in POE ID Approval for Vancomycin IV and
Levofloxacin IV
Spotlight on Pharmacy: Recognition of Awards and
Accomplishments in Pharmacy
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
4
Both oral and parenteral formulations of
famotidine will now be available on the inpatient formulary as the
H2- Receptor Antagonist of choice. In alignment with the
outpatient PSN formulary, on which ranitidine is a preferred
agent, oral ranitidine will remain on the inpatient formulary as a
second line agent.
Famotidine is indicated in the therapy and treatment of duodenal
ulcer, gastric ulcer, control of gastric pH in critically ill patients,
symptomatic relief in gastritis, gastroesophageal reflux, active
benign ulcer, and pathological hypersecretory conditions. Usual
adults doses are as follows:
GERD: Oral: 20 mg twice daily for 6 weeks.
Esophagitis and accompanying symptoms due to GERD:
Oral: 20 mg or 40 mg twice daily for up to 12 weeks.
Duodenal ulcer: Oral: Acute therapy: 40 mg/day at bedtime for
4-8 weeks; maintenance therapy: 20 mg/day at bedtime.
Gastric ulcer: Oral: Acute therapy: 40 mg/day at bedtime.
Hypersecretory conditions: Oral: Initial: 20 mg every 6 hours,
may increase in increments up to 160 mg every 6 hours.
The following chart provides selected histamine H2 receptor
antagonists and comparative adult dosage ranges used for primary
therapeutic indications:
For those patients requiring parenteral therapy, IV famotidine
continues as the formulary H2 antagonist of choice. The usual
dose of IV famotidine is 20mg q12 hours. Parenteral famotidine
is available in premixed minibags containing 20mg famotidine in
50ml iso-osmotic sodium chloride. Each dose is administered
over 15-30minutes. Higher doses may be required in some
hospitalized patients with pathological hypersecretory conditions
or intractable ulcers.
Conversion of parenteral famotidine to oral or enteral therapy is
recommended for clinically stable patients with a functional GI
tract.
Dose adjustment is required for patients with renal impairment:
CrCl: >50 ml/minute: 20mg IV/ PO q12H
CrCl: < 50 ml/minute: 20mg IV/ PO q24H
Some newer references suggest that further dose reduction to
20mg q48H is warranted for CrCl < 30ml/minute.
Continued on page 2
P&T Formulary Update

continued

Caspofungin (Cancidas ); Oxaliplatin (ELOXATIN ) Added to the BIDMC Formulary
Caspofungin (Cancidas) is an echinocandin antifungal agent,
the first approved by the FDA in its class with a wide spectrum
of activity against fungal pathogens including fluconazole
resistant species. Caspofungin has comparable activity to
amphotericin B, voriconazole and itraconazole against Aspergillus
species, and activity that exceeds fluconazole for resistant
Candida species, e.g. glabrata and krusei. Caspofungin is less active
against Histoplasmosis and Cryptococcus than other antifungal
agents. The site of activity is at the fungal cell wall, unlike other
antifungal agents that are bioactive at the cell membrane.
Caspofungin inhibits production and incorporation of beta D
glucan into the cell wall leading to fungal cell death.
FDA Approved Indications: Caspofungin is indicated for use
in the treatment of invasive aspergillosis refractory to or
intolerant to other therapies, i.e., amphotericin B and
voriconazole. Caspofungin is also indicated for the treatment of
invasive candidiasis, including blood borne, peritoneal,
intraabdominal, esophageal or intrapleural.
Pharmacokinetics:
There is no oral dosage form of
caspofungin. Caspofungin exhibits dose proportional linear
kinetics. It is highly bound to albumin and distributed
extensively into tissues. Unlike the azole antifungal agents,
caspofungin is not extensively metabolized through the CYP 450
enzyme system nor is the drug a potent inhibitor or inducer of
the system. It is hydrolyzed and acetylated by other hepatic
enzyme systems and is not appreciably eliminated by the kidney.
Drug Interactions: While caspofungin is not a potent inhibitor
or inducer of the CYP 450 enzyme system, it has been shown to
decrease tacrolimus levels when given concomitantly. When
administered with cyclosporine, caspofungin levels are increased
by an unknown mechanism, posing an increased risk for LFT
elevation. Rifampin administration with caspofungin has been
associated with a reduction in caspofungin levels. This reduction
may also be observed with the use of other enzyme inducers.
Potential Adverse Drug Reactions: Common side effects of
caspofungin therapy include infusion site reactions, e.g.,
erythema, pain. Allergic type reactions have been noted
including flushing, wheals and rash, facial edema and respiratory
symptoms in up to 0.9% of patients. A higher incidence of rash
has been observed in patients receiving caspofungin with
itraconazole. Additionally, ALT and AST increases greater than
the upper limit of normal have been observed, particularly in
patients receiving concomitant cyclosporine.
Dosing: The IV loading dose for empiric or documented
invasive candidiasis or aspergillosis treatment is 70mg, followed
by 50mg q24h. A loading dose is not required for patients with
esophageal candidiasis. Patients with moderate hepatic
impairment (Child-Pugh score 7-9) should receive the standard
IV loading dose, followed by a reduced maintenance dose of 35
mg q24h. Increased maintenance doses to 70 mg qd may be
required in patients with invasive aspergillosis who are not
responding well to therapy within 48 hours or are concomitantly
receiving rifampin, carbamazepine, phenobarbital or other
enzyme inducers.
BIDMC Restrictions: Caspofungin has been approved for
inpatient use following Infectious Disease approval. This agent
should be reserved for suspected or confirmed resistant fungal
infections, particularly in the case of multiple drug intolerance.
Guidelines to prevent inappropriate use are forthcoming.
Oxaliplatin (ELOXATIN) Oxaliplatin is a newly approved
antineoplastic agent.
FDA Approved Indications: Oxaliplatin is indicated for use in
combination with infusional 5-fluorouracil/leucovorin for the
treatment of patients with metastatic carcinoma of the colon or
rectum whose disease has recurred or progressed during or
within 6 months of completion of first-line therapy
(combination of bolus 5-flurouracil/leucovorin and irinotecan).
Pharmacokinetics: Oxaliplatin undergoes rapid and extensive
nonenzymatic biotransformation resulting in up to 17 platinumcontaining derivatives. At the end of a 2-hour intravenous
infusion, approximately 15% of the administered platinum is
present in the systemic circulation. The remaining 85% is
rapidly distributed into tissues or eliminated in the urine. Plasma
protein binding of platinum (primarily to albumin and gammaglobulins) is irreversible and greater than 90%. The primary
route of platinum elimination is renal excretion and the area
under the curve (AUC) of the plasma ultrafilterable platinum
increases as renal function declines.
Warnings,
And
Precautions:
Hypersensitivity
and
anaphylactic/anaphylactoid reactions to oxaliplatin have
occurred within minutes of oxaliplatin administration.
Manifestations include rash, urticaria, erythema, pruritus,
bronchospasm, and hypotension. All patients should be closely
monitored, as reactions can occur after any cycle.
Adverse Reactions: The most frequently occurring adverse
effects in patients treated with oxaliplatin mono or combination
therapy in clinical trials were peripheral sensory neuropathies,
anemia, leukopenia, neutropenia, thrombocytopenia, nausea,
emesis, and diarrhea. Both oxaliplatin and 5-fluorouracil are
associated with gastrointestinal and hematologic toxicities, and
the incidence of each is increased with the combination.
Premedication with antiemetics is recommended. Ice for
mucositis prophylaxis should be avoided, as cold temperatures
can exacerbate the acute neuropathy. Oxaliplatin extravasation
may result in severe local pain and inflammation. Complications
including necrosis have been reported. Injection site reactions,
swelling, and pain have also been reported.
Dosing: The recommended dose of oxaliplatin plus 5fluorouracil/leucovorin is administered every 2 weeks.
Premedication with antiemetics, including 5-HT3 blockers with
or without dexamethasone, is recommended. Prehydration is
not necessary.
Day-1: Oxaliplatin 85 mg/m2 as an IV infusion in 250 to 500
mL D5W and leucovorin 200 mg/m2 as an IV infusion in D5W,
both given over 120 minutes at the same time in separate bags
using a Y-line. This is followed by 5-fluorouracil 400 mg/m2 as
an IV bolus given over 2 to 4 minutes, followed by 5fluorouracil 600 mg/m2 as an IV infusion in 500 mL D5W as a
22-hour continuous infusion.
Day-2: Leucovorin 200 mg/m2 as an intravenous infusion,
followed by 5-fluorouracil 400 mg/m2 as an intravenous bolus
given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2
as an intravenous infusion in 500 mL D5W as a 22-hour
continuous infusion. The cycle is repeated every 2 weeks.
BIDMC Restrictions: Oncology
Integrated Physician Order Entry (POE) Upgrades for Vancomycin IV and Levofloxacin IV
The BIDMC provider order entry system has enabled improvements in the medication ordering process, including improvements in safety,
e.g., reductions in errors associated with handwriting illegibility; dosing suggestions for special populations; and comments to help
maximize efficacy, e.g., dosing defaults and recommendations. The in-house customization of our POE computer system has facilitated
incorporation of the medical centers’ anti-infective program of requiring Infectious Disease approval for use of select antibiotics, a process
implemented manually in many hospitals as a means to optimize anti-infective prescribing. The desired outcome of such a program is the
selection of an anti-infective that is “bug” specific, resulting in good killing activity with less likelihood to select for resistance to broadspectrum agents. Additionally, the program is intended to promote cost effective choices, including promotion of oral dosage forms when
the agent is bioequivalent and more narrow therapeutic agents once culture results return. These are programs supported by the Society
for Healthcare Epidemiology of America and the Infectious Diseases Society of America Joint Committees for the prevention of
antimicrobial resistance, the Centers for Disease Control and the Hospital Infection Control Practices Advisory Committee.
The current system for prescribing a “restricted” anti-infective medication includes the requirement to page the Infectious Disease fellow
on call (39244) during the hours of 7 am to 11 P.M. to briefly discuss patient specific information relating to the case. Based on the
discussion, the ID fellow will agree to approve the prescriber’s antibiotic selection or recommend an alternate. Once the prescriber enters
the order into the computerized POE, the fellow is able to electronically approve the drug, dose, schedule and duration in a virtual queue.
This information is simultaneously transmitted to the unit-based pharmacist to be verified and dispensed. If the order is not discussed with
the fellow and remains in the computer, the status of the order remains in limbo “pending ID approval.” The system therefore works best
when the Fellow is paged in a timely manner and the order has been entered into the computer.
One of the limitations of the POE system has been its inability to electronically communicate the medical center’s policy of restricting
vancomycin use beyond 72 hours of empiric therapy. Initially, the POE system was built without a 72-hour stop time so that there would
not be any interruption of care in patients who required continuous therapy. Given the increased incidence of beta-lactam resistant grampositive infections nationally and here (53% for Staphylococcus aureus), empiric vancomycin use is appropriate in select patients (e.g., patients
with sepsis, endocarditis, nosocomial pneumonia, skin/soft tissue infections with underlying co-morbidities) with close follow up of culture
and sensitivity results. The goal of the 72-hour stop time has been to encourage this culture and sensitivity review, however, since the POE
go-live, compliance with 72-hour review and streamlining of therapy has been suboptimal. A potential solution, developed by the
multidisciplinary Anti-infective subcommittee and the POE programmers , will be to have a virtual clock associated with each vancomycin
order (see example below.) This enhancement allows the prescriber to enter the vancomycin order and with each subsequent time he or
she reviews the active medication profile, they will see how many hours remain until the order must be approved by an Infectious Disease
fellow by the standard process. If the prescriber has not contacted the ID fellow for approval prior to the 72 hour cut-off time, the order
will automatically be “converted” to an order that requires ID approval as with other restricted anti-infectives and cannot be released by
the Pharmacy until approval is received. Timely communication with the ID fellow will prompt approval and antibiotic dispensing
Example: “Vancomycin intravenous orders will be flagged by a countdown clock pending culture/sensitivity results and will
require Infectious Disease approval at the 72 hour mark.”
Vancomycin HCl 1000 mg IV Q12H
ID Approval will be required for this order in 56 hours.
Another limitation of the ID Approval process has been in the time efficiency for ordering parenteral levofloxacin for patients who cannot
take oral medications or have a documented “problem” with absorption or gastrointestinal obstruction. Currently, oral levofloxacin dosage
forms are available without restriction. At present, intravenous levofloxacin requires that the prescriber contact the ID fellow for approval,
which is generally granted if the patient is unable to receive oral therapy. To facilitate this process and avoid delay in the timely
administration of antibiotic therapy, a change has been implemented to computerize this aspect of the prescriber/ ID fellow conversation
to determine appropriateness for the selection of the intravenous levofloxacin dosage form. For new levofloxacin orders, a new screen will
now prompt the prescriber to select a requirement for intravenous therapy. These criteria include patients who are NPO (including
medications), active emesis or diarrhea, active malabsorption syndrome, gastrointestinal obstruction or those who are clinically unstable.
Due to space constraints, a definition of clinically unstable is not included on the POE screen, but may be defined to include patients who
meet sepsis criteria or are admitted or transferred to an intensive care area. If the patient's condition matches one of the listed criteria and
this is so noted on the POE screen, the order will be passed through without ID approval. If the patient does not meet one of these
criteria, ID approval will be required for parenteral levofloxacin.
Example: “Levofloxacin intravenous orders will prompt for a reason for intravenous therapy. Infectious disease approval will be
waived with an appropriate entry.”
Requirements for
IV Therapy:
o
o
o
o
N.P.O., including medications
Vomiting or significant diarrhea
Gastrointestinal malabsorption, ileus or bowel obstruction
Clinically Unstable
Follow up of intravenous levofloxacin orders should be done by the prescribers to determine when the patient becomes clinically stable, no
longer has diarrhea or emesis or where a gastrointestinal obstruction is cleared. At this point, the order should be changed to oral therapy.
In parallel, the unit-based pharmacists will also monitor the progress of patients on intravenous therapy to assess for transition to oral
therapy. These changes will become effective April 1st 2003 to make way for more computerized POE enhancements. Monitoring of
the program will be assessed by changes in vancomycin and levofloxacin intravenous utilization over a three to six month period.
Additionally, individual provider entries will be monitored weekly for erroneous entries in order to bypass the system.
The Pharmacy Advisor 3
Spotlight on Pharmacy:
"Spotlight on Pharmacy" is a new column that will appear in the
Pharmacy Advisor giving recognition to those members within the
BIDMC Department of Pharmacy, who have received awards or
other recognition in pharmacy, have published articles, presented
posters or performed other professional public services pertaining
to the profession of pharmacy.
Publications:
Christopher McCoy, PharmD co-authored two articles, which
were, published in the February 2003 issue of Clinical
Therapeutics. “Drotrecogin Alfa (Recombinant Human
Activated Protein C) for the Treatment of Severe Sepsis” and
“Thalidomide: A Review of Approved and Investigational Uses”
Poster Presentations:
Several BIDMC posters were presented at the December 2002
Midyear Meeting of the American Society of Health Systems
Pharmacists in Atlanta, Georgia.
Diane Soulliard, PharmD, Mia Hong, RPh and Lisa
Saubermann, PharmD:
Development of a pharmacy managed medication dictionary in a
newly implemented computerized provider order entry system
Lisa Saubermann,PharmD:
Impact of a computerized provider order entry (POE) system
greatly improves allergy documentation in a pharmacy computer
system.
Katrina Berlage, PharmD and Diane Soulliard, PharmD:
Nesiritide use in decompensated congestive heart failure:
A medication utilization evaluation
Alina Youssef, PharmD and Margarita V. DiVall, PharmD,
BCPS:
Development and Implementation of Guidelines for the Use of
Enoxaparin in an Urban Medical Center
Service Award:
Gregory Dumas, RPh was one of the first recipients of the
Department of Neonatology Douglas K. Richardson "How Can I
Help You" Awards. Greg was selected for this award for his
knowledgeable support of the NICU's pharmacy patient safety
initiatives, development of the neonatal formulary and
improvements in pharmacy-related NICU operations.
Pharmacotherapy Board Certification:
Margarita V. DiVall, PharmD, BCPS; Northeastern School of
Pharmacy Faculty Preceptor at BIDMC has recently passed the
specialty certification examination in Pharmacotherapy certifying
her as a Board Certified Pharmacotherapy Specialist
Pharmacy Technician Certification:
The following pharmacy technicians have recently received
certification having attained a passing score on the national
pharmacy technician certification examination:
James Chin; Jeanna Duvall; Jackie Emery; Kim Grant; Elizabeth
Libman; Stephen Maynard; Beverly Perry; Joseph Senesi; Mulu
Teferra; Alem Weldekidan
Other Certified Pharmacy Technicians on staff include: Holly
Creveling; Abdullahi Elmi; Patricia Gerrin; Stephanie Keller; Terry
Ann Thompson.
Discontinuation of Blue Dye to Detect Aspiration
From Enteral Tube Feeding: continued from page 1
Within the consensus report, other methods for detecting
aspiration from tube feeding are discussed. The panel concluded
that due to the low specificity and accuracy of existing methods,
the primary focus should be on the prevention of aspiration in
patients receiving tube feedings. Prevention recommendations
provided in the Consensus report align with those provided by
Novartis Nutrition in their Blue Dye Discontinuation Notice. The
Novartis recommendations are listed here to serve as a guideline
for initiatives at BIDMC to prevent aspiration during enteral tube
feedings.
“Preventing Aspiration During Enteral Tube Feeding”
Pulmonary aspiration is a serious complication of tube feeding and
can be life-threatening in malnourished patients. Symptoms include
dyspnea, tachypnea, wheezing, rales, tachycardia, anxiety, agitation
and cyanosis. Aspiration of small amounts of formula may not
cause immediate symptoms (silent aspiration), but a fever may
suggest development of aspiration pneumonia. Prevention of
aspiration is crucial to the success of enteral tube feeding. The
following are standard care procedures that help reduce the risk of
formula aspiration.
 Confirm tube placement with X-ray.
 Choose intermittent or continuous feedings rather than bolus
feedings.
 Elevate head of bed 30-45during and 30-40 minutes after
feeding.
 Monitor gastric residual volumes. If > 200 mL, hold tube feeding
and recheck in 2 hours.
 If gastric residuals continue to be high, use a feeding tube that
reaches the distal duodenum or proximal jejunum. Patients can
continue to aspirate gastric contents when being fed into the small
bowel, so this does not eliminate the need for other precautions.
 Use gastric motility agents in select patients to increase gastric
emptying.
 Assure proper inflation of low-pressure cuffs for patients on
mechanical ventilators or with tracheostomies.
 In addition to taking precautions to prevent aspiration, it is
important to monitor for nosocomial pneumonia. Suspect a
problem when three or more of the following are present:
temperature greater than 100.4 F (38 C), decreased or altered
breath sounds, positive sputum culture, elevated white blood cell
count, or more than 25 neutrophils seen on Gram's stain of
sputum. Obtain a chest X-ray and check for pulmonary infiltrate.
References:
Metheny NA et al. Efficacy of dye-stained enteral formula in
detecting pulmonary aspiration. Chest 2002; 122:276-281.
Czop M and Herr DL. Green skin discoloration associated with
multiple organ failure. Crit Care Med 2002; 30:598-601.
Maloney JP et al. Food dye use in enteral feedings: a review and a
call for a moratorium. NCP 2002; 17:169-181.
McClave SA et al. North American summit on aspiration in the
critically ill patient: consensus statement. JPEN 2002; 26:S80-S85.
Russell M, Cromer M, Grant J. Complications of enteral nutrition
therapy. In: The Science and Practice of Nutrition Support: A Case-Based
Core Curriculum. ASPEN/Kendall Hunt Publishing 2001; 194-195.
Howland WA. Defending your patient against nosocomial
pneumonia. Nursing95; Aug:62-63
The Pharmacy Advisor 4