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THE PHARMACY ADVISOR
A Publication of the Beth Israel Deaconess Medical Center
Department of Pharmacy and Pharmacy & Therapeutics Committee
Volume 1, Issue 2
August/September 2002
Renal Dosage Guidelines:
The 2002 update of the BIDMC Renal Dosage Guidelines is currently
available from the Department of Pharmacy. This concise pocket card
features general dosage and administration recommendations for
common medications that require adjustment in patients with renal
dysfunction or renal insufficiency. The guidelines are based on
published data from several sources referenced on the pocket card.
The renal dose guidelines listed in the pocket card correspond to dose
recommendations for renal adjustment in POE. In both cases, it is
important to note that while the guidelines serve as a useful reference
tool for the majority of patients, patient-specific conditions and
clinical circumstances may require dose modification to meet
individual patient care needs. Please consult with a unit-based
pharmacist to discuss patient-specific medication dosing.
Other information found within the Pocket Card includes:
Extended-Interval Aminoglycoside Guidelines, useful formulas for
calculating Creatinine Clearance; Ideal, Adjusted and Dosing weights
for patients; and recommendations for converting select medications
from IV to PO. The estimated cost savings for each IV to PO
interchange is provided. For copies of the 2002 Renal Dosage
Guidelines, contact a unit-based pharmacist or page the clinical
pharmacy pager at ext 31195
INSIDE THIS ISSUE
1
2
Renal Dosage Guidelines: Updated 2002 Pocket Card
is available from the Department of Pharmacy
Formulary Update: Meropenem (Merrem™);
Aspirin/Extended-Release Dipyridamole (Aggrenox);
Tramadol; Dorzolamide Hydrochloride 2% (Trusopt™);
Dorzolamide 2% and timolol 0.5% (Cosopt™);
Latanoprost 0.005% ( Xalatan™)
3
Medication Safety: Updated IV Administration
Guidelines for Potassium Chloride
5
Kinetics Corner: Phenytoin
Medication Use Evaluation:
Liposomal Amphotericin (Ambisome™)
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
Lisa Saubermann, PharmD
Diane Soulliard, PharmD
Bruce Bistrian, MD, Co-Chair P&T
James Heffernan, MD, Co-Chair P&T
Francis P. Mitrano, M.S., RPh
6
P&T Formulary Update
Meropenem (Merrem) is selected as the preferred
carbapenem on the BIDMC Formulary
Overview: Meropenem is one of three commercially available
carbapenem antibiotics (imipenem-cilastatin, meropenem and
ertapenem) available in the United States. Meropenem, like the
other agents in this class, is a bactericidal compound that acts
primarily by binding to penicillin binding proteins. Meropenem
has a very broad spectrum of activity that encompasses Gram
negative, Gram positive and anaerobic bacteria. Furthermore,
meropenem is impervious to many β-lactamase enzymes.
Compared with imipenem-cilastatin, it is somewhat more active
against Gram-negative organisms and slightly less active against
Gram-positive bacteria.
Indications: In addition to it’s FDA-approved indications for
intrabdominal infections and bacterial meningitis in patients
aged 3 months and older, meropenem’s favorable clinical and
microbiologic activity make this agent valuable in the treatment
of other infections including: respiratory tract infections, skin
and skin-structure infections, urinary tract infections, obstetric
and gynecologic infections, septicemia and febrile neutropenia.
Meropenem’s primary place in therapy at BIDMC will be in the
treatment of suspected or documented serious polymicrobial
infections and those caused by multi-drug resistant (particularly
Gram-negative) bacteria that are susceptible to meropenem.
Dosing: The usual dosage of meropenem in adults is 1 g every
8 hours, administered as an intravenous infusion over 15 to 30
minutes. Dose adjustments are required in patients with renal
insufficiency. Please refer to the BIDMC Renal Dosage
Guidelines for specific recommendations.
Side Effects/Precautions: Carbapenems share a lactam ring
with beta-lactam antibiotics and should be avoided or used
with caution in patients with hypersensitivity reactions to other
beta-lactams. Seizures and other CNS adverse events have
been reported during carbapenem therapy. Meropenem is
generally considered to be somewhat less epileptogenic than
imipenem/cilastatin, though some of these data are based on
doses of imipenem/cilastatin that are higher than those
currently used. Either carbapenem should be used with
caution in patients with a history of or at increased risk of
seizures. Dose adjustment is recommended in patients with
advanced age and/or reduced renal function especially in
patients with known factors that predispose to convulsive
activity.
Conclusion: Meropenem will be utilized at BIDMC as the
preferred carbapenem on formulary. Favorable contract pricing
in addition to proven clinical efficacy support this formulary
decision. Imipenem/cilastatin will be remain on formulary as
an alternate agent. Both carbapenems will continue to require
ID approval.
The Pharmacy Advisor 1
Medication Safety
IV Administration Guidelines for Potassium Chloride Updated
The medical literature is replete with citations related to dangers associated with the parenteral administration of potassium. The
Institute of Medication Safety (ISMP) places injectable potassium in a category of medications termed as “high-alert medications.” Highalert medications are those that have the highest risk of causing injury and/or adverse patient outcomes when administered improperly.
The top five high-alert medications identified by the ISMP are insulin; opiates and narcotics; injectable potassium chloride (or phosphate)
concentrate; intravenous anticoagulants (heparin); and sodium chloride solutions above 0.9 percent. The Joint Commission on
Accreditation of Healthcare Organizations (JCAHO), recently announced that their National Patient Safety Goals for 2003 would include
initiatives to improve the safety of using high-alert medications. Pertinent to the use of parenteral potassium, JCAHO recommends the
removal of concentrated electrolytes from patient care units and the standardization and limitation of the number of drug concentrations
available in health care facilities. JCAHO further recommends that health care facilities develop special procedures for high-alert drugs
using a multi-disciplinary approach. Such procedures would include written guidelines, checklists, pre-printed orders, double-checks,
special packaging, special labeling, and education.
The BIDMC has established ongoing initiatives to address medication safety, including the use of “high-alert medications.” Past
initiatives have included removing concentrated injectable potassium from patient-care areas and more recently a multi-disciplinary
committee was convened to review the aforementioned medication safety concerns with the administration of parenteral potassium.
Specific goals of the committee were to review the standard concentrations of potassium infusions available within the medical center
and to update the BIDMC IV administration guideline for potassium. Key medication safety points from the updated IV guideline are
highlighted here. Please refer to the full text IV guideline located on the BIDMC intranet site in the IV Administration Guideline section
on the Pharmacy intranet page or in the Medications and IV Administration section of The Manual of Nursing practice.
The IV Administration Guidelines for Potassium contains information to assist in the utilization and dosing of parenteral potassium
administration. Included in the guidelines are suggested rates for intravenous potassium infusions for patients in both ICU and
non-ICU settings. The guidelines are not intended to replace clinical judgment where individual patient characteristics may require
modification of the recommendations.
Dose:
The dose and rate of administration of parenteral potassium is based upon the patient’s clinical condition and serum
potassium levels (normal range: 3.5 - 5.0 mEq/L)
The maximum daily dose generally recommended is 120 mEq/ 24 hours. Certain patients, due to their clinical condition
or concomitant medications, will require potassium supplementation beyond general replacement needs. A total (oral and
parenteral) daily dose of potassium ranging up to 240 mEq/ 24 hours may be required in select patients. For example: patients
with serious hypokalemia (serum potassium less than 3.0 mEq/L); patients on amphotericin or high dose steroid therapy;
patients receiving acute leukemia induction therapy, and others.
IV Administration
 Potassium Chloride concentrate for injection must be diluted with a compatible IV solution prior to administration.
 Infusion Pump Required: Potassium containing solutions must be administered via an infusion pump.
 Intravenous Cardiac Monitor Required for potassium infusion rates > 10 mEq/hour in ICU and non-ICU areas.
Infusions of potassium in excessive amounts or at an excessive rate can produce adverse effects on the cardiac conduction
system. IV administration at controlled rates, via an infusion pump is aimed at minimizing such adverse effects.
 IV access: Concentration dependent (see specifics below for peripheral and central administration) Potassium chloride
injection is a vesicant and pain, venous irritation and/or phlebitis can occur during IV administration of potassium. Limiting
the peripheral concentration of potassium will assist in minimizing this adverse effect.
 Peripheral Administration:
Maximum rate:
10 mEq/hr
Maximum concentration:
60 mEq/1000 mL
Acceptable products:
10 mEq/100 ml bag*
20 mEq - 60 mEq per 1000 mL bag
40 mEq/500 mL **
*10 mEq/100 ml may be hung peripherally and will be stocked in pyxis in inpatient areas. The concentration of this product
exceeds general recommendations for peripheral administration of potassium; therefore the number of doses of this particular
product should not exceed two in 12 hours.
**40 mEq/500 ml is available per MD request for fluid restricted patients with a peripheral line, in which the concentrated 20
mEq/50 ml product is prohibited.
Central Administration:
Maximum rate:
20 mEq/hr
Maximum concentration:
60 mEq/1000 mL
Acceptable products:
20 mEq/50 ml bag ¶
20 mEq - 60 mEq per 1000 mL bag
40 mEq/500 mL **
¶ 20 mEq/50 ml bags are reserved for patients with a central line who require rapid replacement of potassium for severe
hypokalemia. This product is stocked in ICU areas only. The pharmacy will send this product to non-ICU areas for specific patients
only. Use in non-ICU areas must be in patients with a central line and cardiac monitoring.
The Pharmacy Advisor 2
Kinetics Corner: Phenytoin
Formulary Update continued:
Phenytoin is a commonly prescribed anticonvulsant agent. Individualization of
dosage is aimed at achieving target therapeutic drug concentrations to optimize
seizure control while minimizing any potential for adverse effects. Optimal dosing
is challenging in some patients and may be related to phenytoin’s unique
pharmacokinetic profile. Phenytoin metabolism is dose dependent and elimination
kinetics are non-linear. Phenytoin follows first-order kinetics at low concentrations
where the amount metabolized is proportional to concentration. At higher
concentrations, elimination follows zero-order kinetics, where a fixed amount is
metabolized in a given time. This kinetic change reflects a saturation of metabolic
pathways. Thus, very small changes in dosage may result in disproportionate
increases in serum levels (possibly 3 to 4 fold). The combined pharmacodynamic
effect results in considerable inter- and intra- patient variability. Additionally,
phenytoin is highly protein bound and changes in albumin or in the binding affinity
of phenytoin to albumin (i.e. resulting from concomitant drug therapy or addition
of tube feeding) can affect phenytoin serum concentrations. As a consequence of
these variables, it is difficult to make predictions regarding optimal therapeutic
dosing regimens in some hospitalized patients, especially those who are critically ill
or have significant end-organ dysfunction. Several key points relating to phenytoin
kinetics are provided here to assist in phenytoin dosing and monitoring.
The following medications have recently been
approved for addition to the BIDMC formulary
Dosing: Phenytoin is available in both parenteral and oral dosage forms and
different bioavailability exists for each formulation. Phenytoin chewable tablets and
suspension (both 100% phenytoin acid) are immediate-release medications. Both
products should be administered in divided daily doses. Phenytoin sodium
capsules (92% phenytoin acid) are extended release and can be administered in
divided daily doses or as a once-daily regimen. Oral administration of phenytoin is
preferred in non-emergent situations. A typical oral loading dose is in the range of
15-20 mg/kg administered in 3 divided doses. The doses are given every 2-4 hours
to decrease GI adverse effects and to ensure complete oral absorption. The
loading dose is typically followed by a maintenance regimen of 300 mg per day.
Adjustments to the daily maintenance regimen should be made in small increments
(30-100mg maximum). Monitor serum levels 7-10 days following each dosage
FDA Approved
change to assess the trend. Steady state is usually achieved after 10-14 days;
however, it may be much longer than this in some patients (range 5-30 days.)
When rapid parenteral administration of phenytoin is required, IV phenytoin is
available. Caution is required with IV phenytoin due to potential cardiac toxicities
associated with rapid IV administration including: hypotension, bradycardia, atrial
and ventricular conduction abnormalities, and ventricular fibrillation. Additionally,
phenytoin injection is highly alkaline and significant venous irritation can occur
when administered peripherally via a small vein. The IV loading dose is 15-20
mg/kg administered at a maximal rate of 50 mg per minute. IV maintenance is
generally initiated at 100mg IV q8H and further adjusted based on drug levels and
seizure activity.
Therapeutic Drug Monitoring (TDM): Since phenytoin has a low therapeutic
index and exhibits saturation kinetics (i.e. small increases in dose result in large
increases in serum drug concentrations), TDM serves as a useful guide to dosage
adjustment. It is important to note that blood levels of phenytoin reflect total
serum concentrations (bound and unbound drug), however only free, unbound
phenytoin, has biological activity. The goal therapeutic concentration during
maintenance therapy is 10-20 mcg/ml (total phenytoin) or 1–2 mcg/ml (free
phenytoin). Examples of situations when TDM would be appropriate include:
during initial therapy to achieve therapeutic serum concentrations; when seizures
recur after a period of control; when there is concurrent illness or a change in
physiological state exists (pregnancy, hypoalbuminemia, renal failure...) or if drug
toxicity is suspected.
Protein Binding: Phenytoin is greater than 90% bound to serum albumin,
therefore patients with renal or hepatic dysfunction and other disease states
associated with hypoalbuminemia may have a higher free fraction of phenytoin
circulating in the serum. Free phenytoin levels may be a more reliable means of
monitoring phenytoin therapy in such patients. If a free phenytoin level is not
available, a corrected phenytoin level can be calculated using the below equation to
adjust total phenytoin concentrations for hypoalbuminemia.
Corrected Phenytoin
=
Phenytoin Level (Observed)_______
Level
(α x Patient’s Albumin) + 0.1
Where α is:
0.2 for Creatinine Clearance > 30 ml/minute
0.15 for Creatinine Clearance 10- 30 ml/minute
0.1 for Creatinine Clearance < 10 ml/minute
Aspirin 25mg / extended release-dipyridamole 200mg
capsules (Aggrenox™): is a combination antiplatelet agent
intended for oral administration.
FDA Approved Indications: Aggrenox™ is indicated to
reduce the risk of stroke in patients who have had transient
ischemia of the brain or completed ischemic stroke due to
thrombosis.
Dosing: The recommended dose of Aggrenox ™ is one
capsule given orally twice daily, one in the morning and one
in the evening. The capsules should be swallowed whole
without chewing and may be given with or without food.
Aggrenox ™ is not interchangeable with the individual
components of aspirin and dipyridamole tablets.
___________________________________________________________
Tramadol: Tramadol is a centrally acting analgesic with dual
opioid and nonopioid mechanisms.
FDA Approved Indications: Tramadol is indicated for the
treatment of moderate to moderately severe pain.
Dosing: Adults: Moderate to severe chronic pain: 50-100
mg every 4-6 hours, not to exceed 400 mg/day.
For patients not requiring rapid onset of effect, tolerability
may be improved with a starting dose of 25 mg/day and
increasing the dose by 25 mg every 3 days, until reaching 25
mg 4 times/day. The dose may then be increased by 50 mg
every 3 days as tolerated, to reach a dose of 50 mg 4
times/day.
Elderly: >75 years: 50-100 mg Q4-6H (not to exceed 300
mg/ day
Dosing adjustment in renal impairment: Clcr<30 mL/
min: Administer 50-100 mg dose Q12H (max: 200 mg/day)
Dosing adjustment in hepatic impairment: Cirrhosis:
Recommended dose: 50 mg every 12 hours
BIDMC Restrictions: Tramadol has been approved for
addition to the BIDMC formulary without restriction.
The combination product (tramadol 37.5mg/acetaminophen
325mg) [Ultracet™] was not approved for formulary
status. Prescribers must write separate tramadol and
acetaminophen orders when both products are required for
patient care. Please note that the tramadol component of
Ultracet™ is not commercially available in this dosage
strength (37.5mg) and should not be requested as such.
Please write tramadol orders in increments of the 50mg
tablet as appropriate.
___________________________________________________________
Ophthalmic Class Review: As part of ongoing
formulary review process the following products were
moved to formulary status:
Dorzolamide Hydrochloride 2% (5ml) Trusopt™
Dorzolamide 2% and timolol 0.5% (5 mL) Cosopt™
Latanoprost 0.005% (2.5 mL) Xalatan™
___________________________________________________________
___________
The Pharmacy Advisor 3
Medication Utilization Evaluation: Liposomal Amphotericin B
Amphotericin B, an intravenous antifungal agent with activity
against multiple fungal isolates including fluconazole resistant
aspergillus and select candidal species, is uniquely manufactured
in four different delivery systems. The newer lipid formulations
were developed in the 1990’s in an attempt to reduce the
predictable side effects of amphotericin B deoxycholate. In
September 2000, the Pharmacy & Therapeutics (P&T)
committee approved liposomal amphotericin B (Ambisome)
for treatment of fungal infections in patients who are refractory
to or intolerant of conventional amphotericin B deoxycholate
with associated guidelines for use based on the Infectious
Disease Society of America (IDSA) guidelines from the year
2000. Direct cost differences between liposomal amphotericin B
and amphotericin B deoxycholate are remarkable. Therapy with
liposomal amphotericin B (Ambisome) is approximately $500
per day at a dose of 5mg/kg in a 70 kg patient. A comparative
dose of amphotericin B deoxycholate (1mg/kg/day) in this same
patient costs $9 per day. A follow up medication utilization
evaluation (MUE) was conducted and presented to the P& T
committee in July 2002.
This evaluation, a retrospective and concurrent chart review, was
performed to compare prescribing trends at BIDMC for
liposomal amphotericin B (Ambisome) to the evidence based
criteria developed by the P& T Anti-infective Subcommittee (see
insert). All adult inpatients treated with Ambisome were
evaluated for the study period of November 2001 through
March 2002 with no exclusion criteria. Sixteen patients were
identified and medical records were reviewed for the following
indicators:
 Indication for use
 Fungal isolates identified
 Previous therapy with amphotericin b deoxycholate
 Documented intolerance or history of intolerance to
amphotericin B deoxycholate
 Documented treatment failure with amphotericin B
deoxycholate
 Serum creatinine prior to liposomal amphotericin B therapy
 Creatinine clearance prior to liposomal amphotericin B
therapy
 Recent rise in serum creatinine of >0.5 mg/dl
 Initial dose of liposomal amphotericin B therapy
The indicators were compared with the approved criteria for use
and dosing recommendations to determine congruence. Results
of the study demonstrated that the majority of cases were
empiric therapy of fever of unknown origin in neutropenic
patients (38%) followed by documented Candidemia (19%),
Cryptococcemia (12%) and empiric therapy for fever or
unknown origin in patients post Bone Marrow Transplant, nonneutropenic. Fungal isolates were identified in 50% of the
patients treated. The remaining patients either had no cultures
performed or no growth identified. A large majority (87%) were
patients who had not been prechallenged with amphotericin B
deoxycholate. Of the patients treated previously with amphotericin B deoxycholate (13%), one had a documented previous
history of intolerance and none had been classified as a
treatment failure. Renal dysfunction, defined as serum creatinine
>2.5mg/dL and creatinine clearance <40mL/min was identified
respectively in 13% and 50% of those initiated on the liposomal
therapy. Recent rises in serum creatinine (>0.5mg/dL) were
noted in 25% of patients prior to therapy. Dosing regimens
ranged from 2 to 6 mg/kg per day.
An analysis of these results revealed the following important
summary points. Ten of the sixteen patients (63%) met at least
one of the criteria for appropriate use of the liposomal product
but six (37%) did not meet any. Guideline based dosing was
observed in 75% of those treated and 25% of patients were
found to be dosed above these recommended doses. It should
be noted, that limitations to this descriptive study may lie in the
method of data collection, i.e. by simultaneous retrospective and
concurrent chart review, the lack of formal statistical analysis and
the small number of patients.
It is the recommendation of the P&T committee that prescribers
carefully review the BIDMC guidelines prior to initiating therapy
with liposomal amphotericin B. Initial trials of amphotericin B
deoxycholate
with
appropriate
infusion
parameters,
premedication and fluid loading are strongly encouraged.
Liposomal amphotericin B remains a restricted drug product,
subject to approval by an Infectious Disease specialist. Cost
consideration for the liposomal product dictate that all doses
should be rounded to the nearest 50 mg to maximize unit of use
(e.g, 285 mg: round to 300 mg, or 312 mg: round to 300 mg).
BETH ISRAEL DEACONESS MEDICAL CENTER
PHARMACY & THERAPEUTICS ANTIBIOTIC SUBCOMMITTEE
(May 2002)
LIPOSOMAL AMPHOTERICIN-B (AMBISOME) GUIDELINES
(Note: liposomal amphotericin will be released ONLY with ID approval)
CRITERIA FOR USE:

Liposomal amphotericin B is indicated for patients with systemic mycoses, who are
intolerant of, or refractory to conventional amphotericin B*

Amphotericin B intolerance should be defined by:

A minimum trial of conventional amphotericin B deoxycholate (example:
0.6mg/kg/day x 5 doses) with

An increase of >1.5mg/dl in serum creatinine compared to the baseline prior to
amphotericin B therapy, OR

Severe or persistent infusion-related adverse events despite premedication or
comedication regimens (example: pre and post-dose hydration with saline,
acetaminophen, diphenhydramine, meperidine, etc.)

Refractory treatment to conventional amphotericin B should be defined by:
Disease progression after > 500mg or 7mg/kg total dose amphotericin B (example: 1mg/kg
daily dose x 7 doses =7mg/kg total dose)

Liposomal amphotericin B without challenge of conventional amphotericin B is
reserved for the following patients:

Patients with a baseline serum creatinine of >2.5mg/dl; OR

Patients with a baseline CrCl of  40ml/min, OR

Patients with a rise in serum creatinine > 0.5mg/dL in the absence of rapidly
reversible causes (i.e. recent contrast, dehydration, etc.) despite adequate hydration
and discontinuation of other nephrotoxins, OR

Patients with a history of severe and/or persistent adverse infusion related reactions
with conventional amphotericin B, OR

Bone Marrow Transplant Patients with febrile neutropenia and/or documented
fungal infections
DOSING:
Liposomal amphotericin B should be dosed by indication as follows:
INDICATIONS
DOSE(mg/kg/day)
Empiric Therapy
3
Systemic fungal infections:
3-5
Aspergillus; Candida; Cryptococcus
Visceral Leishmaniasis
(immunocompromised patient)
4 (days 1-5) and 4 on
days 10,17,24,31,38
 empiric therapy for presumed fungal infection in febrile(38C) neutropenic patients
Dosage in Renal Failure (SrCr >2.5 mg/dl): (similar to conventional Amphotericin-B)
CrCl >10ml/hr
dose q24h
CrCl < 10ml/hr
dose q 24-36h
PREMEDICATIONS:

Liposomal amphotericin-B does NOT require use of pre-medications, nor pre and posthydration

Liposomal amphotericin B does NOT require the use of a test dose
MONITORING GUIDELINES:

Daily monitoring of plasma K+ , Mg, BUN, creatinine levels, and signs of nephrotoxicity
*Practice guidelines for the treatment of fungal infections, Clinical Infectious Diseases, 2000:30; 652-718
http://www.journals.uchicago.edu/CID/journal/issues/v30n4/990664/990664.html
This guideline has been designed to assist the clinician in the utilization and dosing of liposomal amphotericin. It is not
Intended to replace clinical judgment where individual patient characteristics may require modification of the recommendations.
The Pharmacy Advisor 4
The Pharmacy Advisor 5