Clinical Pks Anticoagulation Manual PDF
Clinical Pks Anticoagulation Manual PDF
Clinical Pks Anticoagulation Manual PDF
PHARMACOKINETICS
SERVICE
&
ANTICOAGULATION
GUIDELINES
Pharmacy Services
UK HealthCare
University of Kentucky
Editor:
Editions 20-27 and 29-now
George A. Davis, PharmD, BCPS
2
Anticoagulation Program Coordinator
Pharmacy Services, UK HealthCare
Associate Adjunct Professor, Pharmacy Practice & Science
University of Kentucky College of Pharmacy
Past Editors:
Editions 28-34, 2006-2012
Daniel Lewis Pharm.D, BCPS
Clinical Specialist, Pharmacy
South Pointe Hospital, Warrensville Hts, OH
Disclaimer:
The Clinical Pharmacokinetics Service and Anticoagulation Guidelines are provided to assist with
clinical pharmacokinetic monitoring and anticoagulation management of selected drugs for the Pharmacy
Services at UK HealthCare. Although the information contained in the guidelines has been obtained
from reputable sources in accordance with currently available information, the editors do not assume any
liability in connection with the use of any specific information contained herein. While great care has been
taken to ensure the accuracy of the information presented, the reader is advised that it is possible that
these pages contain some errors and omissions. If you find an error, please report it to George Davis at
georgedavis@uky.edu or (859) 323-1789.
The information provided in the guidelines is not intended to replace sound clinical judgment in the
delivery of healthcare. Dosing of monitorable drugs and anticoagulation management require
independent and informed decisions by appropriate healthcare professionals. Also, the information in this
manual may not be applicable to other healthcare institutions. Complete information concerning drug
administration, dosage, sampling times, clinical laboratory procedures, pharmacokinetic data, and
pharmacological and toxic effects of monitorable drugs should be assessed and contrasted with other
sources prior to its clinical use.
Table of Contents Page
UK Pharmacy Services on Clinical Pharmacokinetics Service 1
Therapeutic Drug Monitoring (TDM) Laboratory Critical Value Call Policy 4
List of Monitorable Drugs and Therapeutic Ranges 5
Basic Pharmacokinetic Concepts 7
Guidelines for Pharmacokinetic Monitoring 14
General Equations for BSA, IBW, and Clcr 16
Monitorable Drugs
Aminoglycosides – Conventional Dosing 19
Aminoglycosides – High Dose Extended Interval 31
Carbamazepine 41
Digoxin 44
Lidocaine 51
Lithium 53
Methotrexate 57
Pentobarbital 60
Phenobarbital 63
Phenytoin 66
Phenytoin, Free 75
Theophylline 76
Valproic Acid 83
Valproic Acid Continuous Intravenous Infusion Protocol 87
Vancomycin 89
Anticoagulation Guidelines
UK Pharmacy Services Policy on Anticoagulation 99
Warfarin 101
Heparin, Unfractionated 107
Enoxaparin 108
Direct Thrombin Inhibitors 110
Heparin Induced Thrombocytopenia (HIT) Guidelines 113
Direct Oral Anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban) 118
VTE Prophylaxis Assessment and Management 120
1
FUNCTIONS
AFFECTED: Clinical Pharmacist Specialists, Clinical Staff Pharmacists, Pharmacy Residents,
and Pharmacy Students
Monitoring Responsibility
Within the pharmaceutical care process, the primary pharmacist/resident who attends rounds or precepts
pharmacy students on the primary medical team is responsible for providing appropriate and cost-
conscious therapeutic drug monitoring and provision of clinical pharmacokinetic evaluations. The CPS is
responsible for overseeing the kinetic monitoring process for all patients and providing pharmacokinetic
assessments for any patient that does not have an assigned primary pharmacist/resident. This
responsibility is met through a team approach including a faculty member who serves as the Manager of
Clinical Pharmacokinetics Service along with Pharmacy Practice Residents and PY4 pharmacy students
as part of a resident/student rotation in Clinical Pharmacokinetics.
Patients with serum drug concentrations on non-covered services are identified on a daily basis utilizing
Sunrise Clinical Manager (SCM). Also, the Therapeutic Drug Monitoring (TDM) Laboratory provides an
electronic report of all completed serum drug concentrations of patients admitted to the hospital twice
daily. This allows for identification of any non-covered patients who are prescribed monitorable drugs
which have not obtained serum concentrations. Physicians may also initiate a request for pharmacy to
provide a clinical pharmacokinetic evaluation by verbal communication or through a pharmacy to dose
requisition in (SCM).
Information:
All new orders for monitorable drugs will be assessed by a clinically trained pharmacist within 48 hours of
initiation. If further monitoring is determined to be necessary by the pharmacist, the primary service will
be contacted with the initial recommendation. At that time, the consulting pharmacist may request a
verbal order for a pharmacy to dose order for that patient’s medication regimen in order to continue to
follow the medication regimen. Alternatively, at any time, a physician may choose to order a pharmacy to
dose consult.
Pharmacy to Dose:
1. Any physician may request a pharmacist to provide therapeutic dosing and/or monitoring services for
any specified pharmacologic agent. Such a request may be made by submitting a pharmacy to dose
order in Sunrise Clinical Manager (SCM) or by giving a verbal order entered on his/her behalf.
a. Such requests by the physician will result in the pharmacist being authorized to write orders
for the initial drug dose, laboratory tests relevant to monitoring the drug, and/or subsequent
orders for dosing adjustments as deemed appropriate by the pharmacist. Examples of these
include ordering drug concentrations and/or assessments of renal/hepatic function relative to
the dosing of an agent.
b. At any time, the physician may alter the dosing and/or monitoring orders that have been
initiated by the pharmacist.
c. At any time, the physician may request the pharmacist discontinue the dosing/monitoring
consult services being provided to a particular patient.
2. Upon receiving an order for pharmacy to dose a specific medication, a pharmacist will assess the
patient and collect relevant information necessary to appropriately dose/monitor the specified drug so
as to achieve therapeutic drug levels and minimize any potential risks of toxicity. Such items of
information may include, but are not limited to:
a. Indication for therapy (i.e. type and site of infection for antibiotic dosing/monitoring consults)
b. Age
c. Sex
3
d. Height/Weight
e. Renal/Hepatic function
f. Estimated pharmacokinetic parameters
g. Medication history and/or time of last dose (if applicable)
h. Current/last known serum drug concentration (if applicable)
3. Upon selecting a dosing and/or monitoring plan, the pharmacist will enter applicable orders into SCM.
Any orders written by the pharmacist in response to a pharmacy to dose order will be entered under
the requesting physician with the specified source of “Per Protocol”.
4. The pharmacist will provide a progress note in the chart to provide information regarding the course
of the dosing and/or monitoring services in accordance with department of pharmacy policies PH-02-
04 and PH-02-05.
5. The pharmacist will be responsible for follow-up monitoring and/or dose adjustments if the
pharmacist deems such actions necessary as documented in the progress notes.
Pharmacokinetic Guidelines
Refer to Clinical Pharmacokinetics Service and Anticoagulation Guidelines (updated annually)
4
Purpose: To define guidelines for communicating supratherapeutic critical values at the University of
Kentucky Medical Center.
Information:
• Supratherapeutic critical values for common TDM medications are listed in Appendix I.
• Supratherapeutic critical values (except cyclosporine, tacrolimus, and sirolimus) for patients admitted to a
hospital service will be called to a pharmacist 24 hours a day based on the following schedule:
o Monday through Friday from 8:00AM – 4:00PM: Critical values will be called to the pharmacist
covering the medical service (list of service coverage will updated monthly by the Department of
Pharmacy Services and provided to the TDM Lab Manager)
If no response in 30 minutes from initial page, then TDM lab will page the Pharmacy Resident
on Call (Pager #330-7400)
If no response in 30 minutes from initial page, then TDM lab will contact the pharmacist in the
Central Pharmacy at 3-5641.
o Monday through Friday from 4:00PM – 8:00AM: Critical values will be called to the Pharmacy Resident
on Call (Pager #330-7400)
If no response in 30 minutes from initial page, then TDM lab will contact the pharmacist in the
Central Pharmacy at 3-5641.
o On weekends (beginning Friday at 4:00PM and ending Monday at 8:00AM) and holidays, critical values
will be called to the Pharmacy Resident on Call (Pager #330-7400)
If no response in 30 minutes from initial page, then TDM lab will contact the pharmacist in the
Central Pharmacy at 3-5641.
• Supratherapeutic critical values for patients located in the Emergency Department will be called to a pharmacist
24 hours a day based on the following schedule:
o Daily from 1:00PM - 11:00PM: Critical values will be called to the ED Clinical Pharmacist Specialist
(Pager# 330-4327)
If no response in 30 minutes from initial page, then TDM lab will page the Pharmacy Resident
on Call (Pager #330-7400)
If no response in 30 minutes from initial page, then TDM lab will contact the pharmacist in the
Central Pharmacy at 3-5641.
o Daily from 11:00PM – 1:00PM: the Pharmacy Resident on Call (Pager #330-7400)
If no response in 30 minutes from initial page, then TDM lab will contact the pharmacist in the
Central Pharmacy at 3-5641.
• Immunosuppressants (cyclosporine, tacrolimus, and sirolimus) will be called to the transplant coordinator on
the transplant service.
o Heart/Lung: 330-2484
o Renal: 323-5953, 323-6099, 323-5737
o Liver: 323-4661
• Supratherapeutic critical values for patients in the University of Kentucky Clinics will be called directly to the
ordering physician.
5
Appendix I. THERAPEUTIC DRUG MONITORING (TDM) CRITICAL VALUE CALL CRITERIA
List of monitorable drugs and therapeutic ranges.
10 – 20
vancomycin (trough) VANCT µg/mL >25.0 5.0 150.00
15 – 20
(life threatening
infections)
*Sent to outside laboratory and may require 2-3 days to report results. End point = sample can be diluted up to 3X.
Basic PK Concepts 7
Basic Pharmacokinetic Concepts:
Linear pharmacokinetics:
• Serum concentrations change proportionally with increase in dose (e.g., increase dose
from 500mg/day to 1000mg/day, concentrations and AUC double).
• Most drugs follow linear pharmacokinetics
Concentration (mg/L)
40
30
20
10
0
0 500 1000
Dose (m g/day)
40
Concentration (mg/L)
dX Vmax*Css
Drug elimination rate = =
30 dt Km+Css
Dose
20 τ (S)(F)(K m )
Css =
10 Dose
(Vmax ) - (S)(F)
τ
0
0 500 1000
Dose (mg/day)
Basic PK Concepts 8
Clearance (Cls):
• Represents the volume of plasma (or blood) from which drug is removed, in a
given time period
• Expressed in volume/time (e.g., ml/min, L/hr)
• Most IMPORTANT pharmacokinetic parameter Cls = ClHep + ClRen + ClOther
• Model-independent parameter used to estimate average steady-state
concentrations and adjust maintenance doses (“c-bar equation”):
Ko S ⋅ F ⋅ Xo S ⋅ F ⋅ Xo Cls ⋅ C ⋅ τ
C= ; C= or Cls = or Xo =
Cls Cls ⋅ τ C ⋅τ S ⋅F
fub *ClInt
Extraction (E) =
QH + (fub *ClInt )
where QH = hepatic blood flow; fub = fraction unbound; Clint - intrinsic clearance
ClHep = QH X E
QH *fub *ClInt
ClHep =
QH + (fub *ClInt )
For HIGH EXTRACTION (>70%) drug, fub *ClInt >>>>> QH , the equation reduces to:
ClHep = QH
For LOW EXTRACTION (<30%) drug, QH >>>>> fub *ClInt , the equation reduces to:
ClHep = fub *ClInt
Plasma drug concentration versus time after an Same with a log scale y-axis.
intravenous (bolus) drug dose, assuming a one-
compartment model with first-order elimination
(linear y-scale).
5mg/L 0.693
t1/2 = = 4 hrs
0.173
2.5mg/L
4hrs
1
0 2 4 6 8 10 12
Time (hours)
Basic PK Concepts 10
Volume of distribution (Vd):
• Vd is a hypothetical volume that is the proportionality constant that relates amount of drug
in body to the serum concentration.
• Expressed in liters (L) or liter/kg (L/kg).
• Drugs distribute based on composition of body fluids and tissues.
Xo
• Vd =where X o = dose administered; Co = initial concentration
Co
• Useful for calculating loading dose: LD = Vd ⋅ C
• Can calculate Vd using steady-state peak concentration after multiple dosing:
K o (1 − e −Kt ) e-KT
Vd =
ss
Cpk ⋅ K(1 − e −Kτ )
One-compartment model
IV bolus K
1
Concentration (mg/L)
80
60
10
40
20
0 1
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Time (hours) Time (hours)
Basic PK Concepts 11
Two-compartment model:
• Many drugs follow 2-compartment model (see model and concentration-time plot
below)
• However, 1-cpt model is sufficient to individualize doses of selected drugs (e.g.,
aminoglycosides, vancomycin) in the clinical setting if concentrations are drawn
appropriately.
K12
IV bolus 1 2
K21
K10
100
Concentration (mg/L)
10
1
0 4 8 12 16 20 24
Time (hrs)
Basic PK Concepts 12
Multiple dosing and steady-state equations:
K o (1 − e −Kt ) e-KT
C ss
=
Vd ⋅ K(1 − e −Kτ )
pk
ss
Cpk = concentration (referred to as peak) drawn at T, time post infusion
Ko = dosing rate in mg/hr
-1
K = elimination rate in hr
t = infusion time in hours (e.g., usually 0.5hrs for aminoglycosides)
ss
T = post infusion time in hours that corresponds with Cpk (e.g., usually 0.5hrs for aminoglycosides)
Vd = Volume of distribution in liters
τ = Tau, dosing interval in hours
This equation is used for aminoglycosides and vancomycin which when dosed as intermittent IV
infusion.
You can build the steady-state multiple dosing equation using the following equations (also see
next page):
1. The infusion (e.g., 30 min for aminoglycosides, 60 min for vancomycin) is a continuous
infusion:
Ko (1-e-kt ) Ko (1-e-kt )
C= or where t = infusion time
Cl Vd ⋅ K
This above equation will calculate the concentration at the end of an intermittent IV
infusion following the first dose (assuming 1-cpt model and 1st order elimination).
Ko (1-e-kt )
pk
C1st dose = ⋅ e-kT
Vd ⋅ K
16
Concentration (mg/L)
12
0
0 8 16 24 32
Time (hours)
Ko
(1- e -kt ) e -kT
Vk
Concentration
Accumulation
Factor
1
t T
(1 − e −kτ )
τ
Guidelines for PK Monitoring 14
A. Assess the necessity for serum drug concentrations and address this issue
with the medical team.
A. Using the collect/received time reported in the lab computer and the EMAR,
verify that the concentration is a peak or a trough.
B. Document that the doses preceding the concentration were on time to verify
that the concentration represent steady-state conditions.
E. Document any information, not retrievable from the medical records, that was
used in making your calculations or recommendations (weight, height, or
information obtained directly from the patient or healthcare provider).
III. How does Clinical Pharmacokinetic Monitoring fit into the Pharmaceutical Care
Process?
Ht(cm) x Wt(kg)
BSA (m2 ) = (Mosteller; NEJM 1987;317:1098)
60
1.73m2
Clcr (standardized to BSA, ml/min/1.73m2 ) = Clcr X
BSA
Ucr X
1dL X Uvol X 1
=
100ml 1440min
1dL
Scr X
100ml
Ucr = urine creatinine concentration (mg/dL);
Uvol = total urine volume (ml/24 hrs);
Scr = serum creatinine (mg/dL)
Modification of Diet in Renal Disease (MDRD) Equation (Ann Intern Med. 1999 Mar
16;130(6):461-70.)
• Among adults, the MDRD Study equation provides a clinically useful estimate of GFR
(up to ~ 90 mL/min/1.73 m2)
• The MDRD Study equation derived based on:
– GFR measured directly by urinary clearance of 125I-Iothalamate;
– A large sample of >500 individuals with a wide range of kidney diseases;
– Inclusion of both European-American and African-American participants;
– Validated in a large (n > 500) separate group of individuals
• This equation provides estimates of GFR standardized for BSA.
Equations for BSA, IBW and Clcr 18
• The abbreviated version (J Am Soc Nephrol. 2000;11: A0828) requires only serum
creatinine, age, sex, and race.
• Basic metabolic panel at UKCMC uses the abbreviated equation to report GFR.
• Per National Kidney Foundation recommendations: “Nonetheless, questions remain
about the equation’s generalizability because it has not been validated in diabetic
kidney disease, in patients with serious comorbid conditions, in normal persons, or in
persons older than 70 years of age. Clinical conditions in which it may be necessary
to measure GFR by using clearance methods include extremes of age and body size,
severe malnutrition or obesity, diseases of skeletal muscle, paraplegia or
quadriplegia, vegetarian diet, rapidly changing kidney function, and calculation of the
dose of potentially toxic drugs that are excreted by the kidneys.” Many of these
limitations also apply to the use of Cockcroft-Gault.
• Please note there are not sufficient studies to date that use the MDRD equation for
adjusting drug dosages for patients with renal insufficiency. This may change in the
near future as more studies with the MDRD equation are published.
=
Clcr (children 1 to 16 years of age, mL/min/1.73m2) ( 0.413 × Height in cm ) / Creatinine in mg / dL
Schwartz GJ, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009; 20 : 629 − 637.
Aminoglycosides – Conventional Dosing 19
a. Relative to Dose
Cpk at 30 min after end of 30 min infusion (IV); 1 hr after injection (IM)
Ctr within 30 min prior to dose
at ss (4 to 5 estimated half-lives; normal renal function: t½ = 2-3 hrs)
usually around 3rd maintenance dose (or later) preferably during day
repeat Cpk and Ctr, at new steady state, if initial values differ > 25%
from predicted (i.e. suggestive of unusual kinetic parameters or
deviation from sampling guidelines)
Scr and BUN at least 2x/week; monitor other signs of renal function
repeat Cpk and Ctr q 1-2 wks, when duration of therapy > 2 wks
repeat Cpk and Ctr weekly (or more frequently as dictated by clinical
condition).
Aminoglycosides – Conventional Dosing 20
Patients with normal renal function: Conventional dosing for gentamicin and
tobramycin ~1-2 mg/kg-DBW/dose q8hrs and amikacin ~5mg/kg-DBW/dose
q8hrs. NOTE: Elderly patients often require a q12hr or longer dosing interval.
See table below for general recommendations for desired Cpk based on type of
infection. *Final decision for desired concentrations should be based on clinical
outcomes in addition to a pharmacokinetic assessment.
Suggested Target
Peak Concentrations (mg/L)
Types of infections* (gentamicin or tobramycin)
Abdominal infections 6-8
Bacteremia 6-8
Empiric therapy in cystic fibrosis 8-12
Endocarditis, Bacterial (prevention & treatment)
gram positive (synergy: 1mg/kg/q8hrs) 3-5
gram negative 8-10
Eye infections 6-8
Meningitis 8-10
Neutropenic patients 6-10
Peritonitis 6-8
Pneumonia 8-10
Skin and soft tissue infections 6-8
Urinary tract infections 4-6
Aminoglycosides – Conventional Dosing 21
4. General Guidelines for Monitoring
a. Initial Dosing
1. Select desired Cpk and Ctr based on site and severity of infection, causative
organism and MIC, immunocompetence of patient, intent of therapy.
1.73m2
= Clcr ×
Clcr (std)
actual BSA
For obese patients use DBW = [IBW + 0.4 (TBW-IBW)] in the Cockcroft-Gault
equation to estimate Clcr and standardize to 1.73m2 to estimate
aminoglycoside K. (Leader WG, Tsubaki T, Chandler MHH. Am J Hosp
Pharm 1994; 51:2125-30)
3. Estimate K:
K= 0.00293 ∗ Clcr(std) + 0.014
4. Estimate t½:
0.693
t½ =
K
5. Estimate Vd*:
Vd = 0.25 L/Kg, average
Vd = 0.20 L/Kg, if dehydrated
Vd = 0.30 L/Kg, with CHF, volume overload, ICU patients
*Use ABW unless patient is obese (>125% IBW or TBW/IBW > 1.25)
If obese use dosing body weight: DBW = IBW + 0.4 (TBW-IBW)
−KT '
tr = C pk ⋅ e
9. Estimate trough: C ss ss
(1-e-Kτ ) (1 − e-Kt )
2. Calculate K:
ss
Cpk T’ is determined by subtracting the time difference between Cpk and Ctr
ln ( ss
) from the Tau. For example, if the time difference between Cpk and Ctr
C
K= tr was 1.5hrs and the Tau = q8hrs, then T’ = (8 - 1.5) = 6.5hrs.
T'
3. Calculate t½:
0.693
t½ =
K
6. Calculate Vd:
If doses have NOT reached steady state AND there are at least 3
concentrations after a multiple dose (e.g., trough, peak, & random) or 2
concentrations after the 1st dose (e.g., peak and random or 2 random
concentrations) use:
K o (1-e-Kt ) Cmax
pk
= peak extrapolated to END of infusion
Vd = t = time of infusion
K (Cmax
pk - Ctr e-Kt' ) t' = time between Ctr and Cmax
pk
ln 1
Ctr Ctr1 = high Ctr; Ctr2 = desired Ctr
Ctr2
t' = t' = time required from Ctr1 to Ctr2
K
10. Round dose to nearest 10mg or available stock bag dose (80,100,120mg) then
recalculate the actual Cpk:
9/2/2001 Patient is 50yo WM being treated with tobramycin 120mg IV q8hrs (1.45 mg/kg/dose)
12:00 and Zosyn 3.375gm IV q6hrs for nosocomial pneumonia based on positive sputum
cultures for Pseudomonas aeruginosa. Current Tmax 102.5, WBC = 15K.
ABW = 90kg
Ht = 6’0” Tobramycin concs drawn around 3rd dose on 9/2:
IBW = 77.6kg Trough = 2.2 mg/L C: 07:30
DBW = 82.6kg Dose = 120 mg IV infused from 08:00 – 08:30
BSA = 2.13m2 Peak = 7 mg/L C: 09:00
Scr = 1.2 (today) Assessment of concs: Previous doses administered on time & represent steady-
Clcr = 86ml/min state;
Clcr (std) = Ctr & Cpk drawn appropriately; Cpk is below recommended range for pneumonia (8-
70ml/min/1.73m2 10mg/L) & Ctr above therapeutic range (<2mg/L). Renal function stable.
Recommendations:
HIE
4 mg/kg IV Q36H
(Hypoxic Ischemic Encephalopathy)
Comments:
Don’t confuse “once daily” dosing with every 24-hour dosing interval in neonates.
Neonates require a longer dosing interval (decreased clearance) and larger mg/kg dose (increased volume).
Concentrations may not be warranted in all neonatal patients.
If extended therapy is indicated (e.g., positive blood culture), concentrations (peak and trough) should be
obtained with the 3rd dose.
If urine output decreases < 1ml/kg/hr for at least 8 hours, concentrations are warranted.
Goal concentrations usually: peak = 5-8mg/L; trough < 2mg/L.
Dose may be infused over 30 minutes (always check administration technique as possible source of error).
Aminoglycosides – Conventional Dosing 27
Pediatric Guidelines (gentamicin, tobramycin)
Age Dosage
Q12hr dosing should be considered for patients started on aminoglycosides for first
time and if documented half-life is <2 hours based on patient-specific PK parameters
Q24hr dosing should be considered in patients on other nephrotoxins (e.g.,
5-7 mg/kg/dose IV vancomycin)
Larger Vd (0.4-0.45 L/kg) due to decreased body fat and increased Cl due to
q12hrs increased GFR.
Pediatric CF patients are excluded from the once-daily aminoglycoside dosing but
or some patients may be receiving a “high dose regimen” twice a day.
For CF patients, levels are usually obtained on the 3rd day rather than the 3rd dose
to allow for rehydration.
10-14 mg/kg/dose Concentrations should be obtained at 4 and 10 hours post dose (12 hours may not
IV q24hrs be measurable). Peak and trough levels appropriate for q8h dosing.
(concurrent Usually require higher doses to achieve desired concentrations (Cpk > 12 mg/L; Ctr
Vancomycin < 1mg/L).
therapy or past Must be very cautious of nephrotoxicity and ototoxicity because of long term and
recurrent use.
history dictates) Repeat concentrations are usually not obtained unless significant changes in dose
are warranted (e.g., >30%), available concentrations are not reliable, or therapy is
continued beyond 14 days.
If duration of concentration < 0.5 mg/L is greater than 6-8 hours with q24hr dosing,
may need to consider lower dosing at more frequent dosing intervals
Aminoglycosides – Conventional Dosing 28
Effect of hemodialysis
1. Removes approximately 30-50% with typical HD session (e.g., 3-4 hour)
2. Levels taken 1 hour post dialysis are true troughs; levels taken prior to dialysis
can be used during the 30-50% removal assumption.
Concentrations
1. Single drug level approach (synergy dosing)
a. Most commonly utilized approach at UK
b. Pre-dialysis (random) concentration
c. Extrapolate post-dialysis concentration (trough) by assuming 50% drug
removal during a 4 hour dialysis session
d. Target of trough < 2 mg/L to conserve remaining kidney function and
minimize risk for ototoxicity.
2. Multiple drug level approach (aggressive management)
a. Peak concentration drawn 2 hours after dose
b. Pre-dialysis (random) concentration
Levels
1. Two random serum concentrations will be obtained 4 and 12 hours after
completion of the 1st dose.
2. Determine appropriate maintenance dose based upon calculated PK
parameters (ensure CRRT uninterrupted between concentrations)
Useful References
1. Dager WE, King JH. Aminoglycosides in intermittent hemodialysis: pharmacokinetics with individual
dosing. Ann Pharmacother 2006;40:9-14.
2. Trotman RL, Williamson JC, Shoemaker M, Salzer WL. Antibiotic dosing in critically ill adult patients
receiving continuous renal replacement therapy. CID 2005;41:1159-66.
Aminoglycosides – Conventional Dosing 30
Inclusion Criteria: All adult patients ordered aminoglycosides for prophylaxis, empiric therapy,
or documented infection. (Aminoglycosides are usually indicated as synergistic or adjunctive
therapy with other antibiotics as double coverage for gram-negative infections).
Exclusion criteria:
1. Patients with ascites
2. Patients with burns on >20% of total body surface area
3. Pregnant patients
4. Patients on dialysis
5. Patients with gram positive bacterial endocarditis
6. Pediatric patients (<18yo) – please refer to pediatric dosing guidelines
7. Patients with cystic fibrosis (with/without lung transplant) – please refer to specific
guidelines for CF patients
Initial Dose: Doses should be based on DOSING BODY WEIGHT, ideal body weight plus 40%
of estimated adipose tissue mass above IBW (see Dosing Guidelines).
• Patients with estimated creatinine clearances < 40 mL/min/1.73m will receive an initial
gentamicin dose of 3 mg/kg, infused over 30 minutes.
Aminoglycosides – High-dose, Extended Interval Dosing 32
Males Clcr =
(140-Age ) ×ABW Females Clcr =Clcr *0.85
72×Scr
2. Estimate Body Surface Area (BSA) using the Mosteller equation:
Ht(cm) x Wt(kg)
BSA (m2 ) =
60
3. Calculate Standardized Creatinine Clearance:
1.73m2
Clcr(Std) = Clcr *
BSA
4. Determine Ideal Body Weight (IBW).
IBW (kg) = 50 (kg) + (2.3 (kg) x ea. inch over 5 ft) male
= 45 (kg) + (2.3 (kg) x ea. inch over 5 ft) female
5. Calculate Dosing Body Weight (DBW):
6. Calculate the patient’s dose (gentamicin & tobramycin) based on Dosing Body Weight.
Amikacin: Doses used for single daily administration of amikacin range from 15 to
20 mg/kg/day (Marik et al, 1991; Maller et al, 1993 - 20mg/kg/dose: Cpk ~40mg/L
and Ctr24hr <4mg/L).
7. Dilute dose in 100 ml of either 5% Dextrose or Normal Saline and infuse over 30 minutes.
8. Order two concentrations at 4 and 12 hours after the end of 1st dose.
Aminoglycosides – High-dose, Extended Interval Dosing 33
Monitoring: Two concentrations (ordered as “random” concentrations) will be obtained:
1) 1st concentration will be drawn ~4 hours* after completion of the 1st dose.
NOTE: The random concentration at 4 hours post-infusion may range from 4-13 mg/L depending
on renal function and volume status. Patients with normal renal function (>100 ml/min) usually
average a 4-hour random ~5-8 mg/L (see mean concentration-time curve on page 41).
The rationale for obtaining a “4-hour” sample versus a “peak” is to determine the serum
concentration after the distribution phase. A prolonged distribution phase has been described in
trauma patients (Jennings HR, et al. Pharmacotherapy. 2000;20(10):1265) and healthy volunteers
(McNamara DR, et al. J Clin Pharmacol 2001 Apr;41(4):374-7) who received 7 mg/kg. Post-
distribution concentrations provide a more accurate calculation of elimination rate and the
estimation of the 24-hour concentration.
2) 2nd concentration will be drawn ~12 hours after completion of the 1st dose.
NOTE: The concentration at 12 hours post-infusion will vary depending on renal function. The
12-hour concentration may be <1 mg/L in patients with normal renal function.
Patients with normal renal function should have a prolonged “drug-free” period. ODA
therapy should usually NOT be used as the single antibiotic agent and patients should not
receive a dose of 7mg/kg more frequently than once every 24 hours until more studies are
available. Some patients may warrant conventional dosing to maintain concentrations.
Please consult the Clinical Pharmacokinetic Service (257-8403) or ID service regarding any
concerns about ODA therapy or patient eligibility.
Subsequent Doses: The goal of the initial concentrations after the 1st dose is to verify that the
drug is eliminated appropriately before the 2nd dose and to establish the dosing interval.
Subsequent doses will be the same as the initial dose, but the dosing intervals will be adjusted
to achieve troughs < 1 mg/L. Appropriate dosing intervals include every 24, 36, or 48 hours.
Scr/BUN should be measured at baseline and 2X/week thereafter.
• Patients with normal renal function will usually have a “drug-free” period with an undetectable
trough concentration < 0.3 mg/L.
• For patients with trough concentration > 0.3 mg/L, renal function should be monitored closely
and risks of nephrotoxicity and ototoxicity evaluated carefully.
• If the serum concentration following a 7mg/kg dose requires > 48 hours to decline to <1mg/L,
then 3mg/kg or conventional dosing may be warranted.
• Patients should not receive a single dose of 7mg/kg more frequently than every 24 hours until
more studies are available.
Follow-up monitoring: If ODA therapy is continued for > 7days, a trough concentration should
be obtained weekly to check for drug accumulation and assess risk of nephrotoxicity. Scr/BUN
should also be monitored at least 2X/week to assess any changes in renal function and risk of
nephrotoxicity. Concomitant nephrotoxic drugs should be avoided if possible.
Ototoxicity should be monitored closely. Ototoxicity results from damage to the vestibular and
cochlear portions of the eighth cranial nerve. Auditory symptoms include tinnitus, roaring,
ringing, or “buzzing” in the ears, and varying degrees of hearing impairment. Loss of
high-frequency perception is only detectable by audiometric testing and usually occurs before
clinical hearing loss. Vestibular symptoms include nausea, vomiting, dizziness, vertigo,
nystagmus, oscillopsia, and ataxia. A feeling of fullness in the ears and tinnitus are early
signs of ototoxicity. Symptoms are exacerbated in the dark. Hearing loss may be
irreversible, but patients usually retain normal conversational hearing. Other ototoxic drugs
(e.g., lasix) should be avoided if possible.
Aminoglycosides – High-dose, Extended Interval Dosing 34
CALCULATE PARAMETERS:
1) Calculate K:
C1random = 1st random ~4hrs after dose
ln random
C1 C2random = 2nd random ~12 hrs after dose
C2random T’ = time between C1random and C2random
K=
T'
C=
24hr
tr
0.5hr
Cpk ∗ e-K∗23 If 24hr Ctr ≤ 1 mg/L continue q24hr dosing
If 24hr Ctr > 1 mg/L extend dosing interval
e-Kt
K o (1 − e−Kt )
V= t = infusion time
K(Cmaxpk )
If assistance is required in selecting patients or determining the proper dose or dosage interval, contact
the pharmacist rounding with the service, the Clinical Pharmacokinetics Service (257-3378, UK beeper
#1740), the Pharm.D. Resident on call (UK beeper #1875), or the Infectious Disease Service.
Aminoglycosides – High-dose, Extended Interval Dosing 35
35
Gentamicin 7mg/kg-DBW
Mean±StdDev Serum Concentrations
30 Trauma Patients (n=13)
University of Kentucky Chandler Medical Center
25
Concentration (mg/L)
20
15
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Time Post 30-minute Infusion (hrs)
Jennings HR, Coyle EA, Kearney PA, Davis GA. . Characterization of once-daily aminoglycoside (ODA)
pharmacokinetics (PKS) in the critically ill: Suggestions for clinical monitoring. Pharmacotherapy.
2000;20(10): 1265.
SUGGESTED REFERENCES:
J Infect Dis 1987; 155:93-9
J Infect Dis 1990; 162:414-20
Antimicrob Agents Chemother 1995; 3:650-5
Ann Pharmacother 1994; 28:757-66
Pharmacotherapy 1995; 15:297-316
Pharmacotherapy 1995; 15:201-9
Ther Drug Monit 1996; 18:263-6
Ann Intern Med 1996; 124:717-25
J Antimicrob Chemother 1997; 39:677-686
J Burn Care Rehab 1997; 18:116-24.
Ann Pharmacother 1998; 32:417-21.
J Clin Pharmacol 2001;41(4):374-377.
HDEI in Pediatrics:
J Pediatr 1997;131:76-80.
J Antimicrob Chemo 1997; 39:431-33. (cystic fibrosis patients)
J Antimicrob Chemother. 1998 Jul;42(1):103-6. (cystic fibrosis patients)
J Pediatr Surg. 1998 Jul;33(7):1104-7.
Pediatrics. 1999 Jun;103(6 Pt 1):1228-34.
Ther Drug Monit. 2001 Oct;23(5):506-13.
Pediatr Infect Dis J. 2001 Dec;20(12):1169-73.
Aminoglycosides – High-dose, Extended Interval Dosing 36
HDEI Dosing for Adult Cystic Fibrosis Patients:
Inclusion criteria:
Adult patients 18-35 years of age
Estimated Clcr > 60ml/min
Must obtain baseline Scr in patients at increased risk of renal insufficiency
o History of renal dysfunction
o Diabetes mellitus
Must consider if CF patient is post-lung transplant and the time since transplant due
to altered pharmacokinetics:
o Tobramycin pharmacokinetics have been shown to be altered in patients with CF
after bilateral lung transplantation (Walsh KA et al. Transplant Infect Dis 2011).
Concentrations were evaluated at 0-3 weeks and ≥6 weeks post-transplant.
Elimination rate constant decreased 38% from 0.26±0.1 to 0.16±0.1/h (P<0.001), with
a related increase of 200% in half-life from 2.8±0.8 to 8.4±8.7 h (P<0.001).
Clearance decreased 25% post-transplant from 67.3±32.3 to 50.2±15.9 mL/min
(P=0.04).
Dosage requirements after transplantation were significantly lower, 10.7±2.5 and
7.6±1.6 mg/kg/day, pre- and post-transplant, respectively (P<0.001).
Cl and Vd ≥6 weeks post-transplant did not significantly differ from pre-transplant
values (P=0.28 and 0.54, respectively), suggesting that changes may be temporary.
PK parameters should be reassessed during each treatment course post-transplant
to determine appropriate dosage.
o CF patients post-lung transplant may require a lower initial dose and extended
dosing interval. Subsequent doses should be determined based on indication,
risk of nephrotoxicity, concentrations, and individual PK parameters.
Indications:
• Postpartum endometritis
• Postpartum treatment of chorioamnionitis
o Prior to delivery, use conventional gentamicin dosing (e.g., 1-2 mg/kg/dose ABW IV
q8hrs); start once daily dosing 8 hours after conventional dose. Some practitioners may
also utilize high dose extended interval dosing using 5mg/kg of antepartum actual body
weight q24hrs for treatment of chorioamnionitis prior to delivery. Literature suggests that
many patients will have resolution of symptoms with short course therapy (stop after 1
dose post -delivery) compared with standard treatment of 24-48hrs after symptom
resolution.
Inclusion criteria:
• Current postpartum weight
• Age ≥ 18 years old, or if deemed medically appropriate in younger patients
• Normal renal function (serum creatinine < 1.4mg/dL)
o Obtain baseline serum creatinine in patients with increased risk for renal insufficiency
prior to receiving once daily gentamicin including:
Exclusion criteria:
• History of renal dysfunction
• Diabetes mellitus
• Preeclampsia
• Toxemia
Dosing Recommendation:
3. Additional monitoring:
a. If duration of aminoglycoside therapy continues > 3 days, suggest checking a serum
creatinine
b. If duration of aminoglycoside therapy continues > 7 days, suggest checking follow-up
gentamicin TROUGH CONCENTRATION to assess for potential accumulation
References
• Locksmith, et al. High Compared with Standard Gentamicin Dosing for Chorioamnionitis: A
comparison of Maternal and Fetal Serum Drug Levels. J Obstet Gynecol 2005 Mar; 105(3):473-9.
• Mitra A et al. A Randomized, Prospective Study Comparing Once-Daily Gentamicin versus
Thrice-Daily Gentamicin in the Treatment of Puerperal Infection. Am J Obstet Gynecol 1997;
177:786-92.
• Black LP, Hinson L, Duff P. Limited course of antibiotic treatment for chorioamnionitis. Obstet
Gynecol. 2012 Jun;119(6):1102-5.
• Lyell, D et al. Daily Compared with 8-hour Gentamicin for the Treatment of Intrapartum
Chorioamnionitis. Obstet Gyncelo. 2010 Feb; 115(2 ):344-9.
• Ward K and Theiler R. Once-daily Dosing of Gentamicin in Obstetrics and Gynecology. Clin
Obstet and Gynecol 2008; 51(3):498-506
• Del Priore G, Jackson-Stone M, Shim E, et al. A comparison of once-daily and 8-hour gentamicin
dosing in the treatment of postpartum endometritis. Obstet Gynecol 1996;87:994–1000.
• Livingston J, Llata E, Rinehart E, et al. Gentamicin and clindamycin therapy in postpartum
endometritis: the efficacy of daily dosing versus dosing every 8 hours. Am J Obstet Gynecol
2003;188:149–152.
• Sunyecz J, Wiesenfeld H, Heine R. The pharmacokinetics of once-daily dosing with gentamicin in
women with postpartum endometritis. Infect Dis Obstet Gynecol 1998;6:160–162.
Aminoglycosides – High-dose, Extended Interval Dosing 39
Other methods used for ODA dosing (NOTE: This information is provided for
comparison only, please refer to UKCMC approved protocol):
AUCtarget
• nd
Calculate 2 dose: Dose 2 = X Dose 1
AUCobserved
a. Relative to Dose
3. Therapeutic Range
a. Initial Dosing
b. Maintenance Dose
5. Pediatric Guidelines
Baseline CBC
CBC every month (x 2), then every 6 months after stabilized
7. Drug Interactions
General:
Drug Interactions:
a. Relative to Dose
Initial level at ss
Initial level at ss
3. Therapeutic Range**
UK: 0.8-2.0 ng/ml (conversion note: 1ng/ml = 1µg/L)
C×V S =1
X* = F = 0.7 (tablet)
o S×F = 0.8 - 0.85 (elixir; capsule)
1.73m2
=
e.g. std Clcr Clcr ∗
actual BSA
b. Maintenance Dose:
c ⋅ Cls ⋅ τ
Xo (mcg) =
F⋅S
(Helpful hint: use mcg/L for c, 24hrs for τ , and L/hr for Cl )
Dosing Adjustments
Calculate actual Cls, based on c(level, usually obtained at τ), F, and Xo (dose
administered).
S ⋅ F ⋅ Xo
Cls =
c ⋅τ
Calculate new maintenance dose.
c ⋅ Cls ⋅ τ
Xo =
F⋅S
One should check if the therapeutic response to digoxin correlates well with the level(s)
obtained, prior to making dosage adjustment(s). The failure of digoxin levels to correlate
with therapeutic/toxic response is often due to aberrations in serum and tissue
concentrations of sodium, potassium, magnesium, and calcium. Patients with low
potassium, magnesium, or sodium levels or high calcium levels may be more sensitive to
digoxin) or due to presence of DLIS in certain subpopulations (e.g. renal failure patients,
combined renal and hepatic failure patients, pregnant women, neonates, infants).
Chart note
Monitoring parameters should include heart rate, ECG, serum electrolytes (K,
Mg, Na, Ca), Scr, Clcr, interacting medications and monitoring for signs and
symptoms of toxicity. PK parameters should include digoxin Cls in ml/min.
Drug interactions:
Drugs associated with ↓ digoxin absorption include: antacids,
cholestyramine, colestipol, kaolin-pectin, metoclopramide, neomycin,
sulfasalazine; ↑absorption include: propantheline.
Quinidine - ↓ digoxin Cls; multiply digoxin Cls by 0.5
Verapamil - ↓ digoxin Cls; multiply digoxin Cls by 0.7
Spironolactone - ↓ digoxin Cls; multiply digoxin Cls by 0.5
Amiodarone - ↓ digoxin Cls; multiply digoxin Cls by 0.7
Digoxin 47
6. Pediatric Guidelines
2. Park MK. Use of digoxin in infants and children with specific emphasis on dosage. J
Pediatr 1986; (6): 871-7.
* Administer ½ of the total digitalizing dose in the initial dose, then ¼ of the total dose
in each of two subsequent doses at 6-8 hour intervals. The doses are divided to
allow sufficient time for distribution and maximum effect to assess for therapeutic
response and potential toxicity after each dose.
7. Other Considerations
Vd: 6-20 L/kg (caution: wide patient variability may be secondary to design
problems in initial studies)
Drug interactions:
1. Indications
a. Acute ingestion of known amount: Each vial of Digoxin Immune Fab will bind
approximately 0.5mg of digoxin. Can calculate the total number of vials required
by dividing the total digitalis body load by 0.5mg/vial:
Total body load (mg) = 0.8 x [amount (mg) digoxin tablets or elixir ingested]
Total digitalis body load in mg
Dose (in # of vials)=
0.5 mg of digitalis bound/vial
Purpose:
Total serum digoxin levels obtained immediately after administration are unreliable.
The Fab fragments bind to free digoxin, causing tissue-bound digoxin to be
released from receptors and subsequently bind to the Digoxin Immune Fab.
Digoxin levels drawn within 72 hours (for patients with normal renal function) or 7
days (in patients with renal failure) of administration will be falsely elevated.
a. The pharmacist will alert TDM lab when Digoxin Immune Fab is ordered for any
patient in the hospital.
b. TDM lab will not measure total serum digoxin levels for a period of at least 72
hours following administration for patients with normal renal function.
c. TDM lab will not measure total serum digoxin levels for a period of at least 7
days following administration for patients with severely impaired renal function.
References
2. Antman EM., Wenger TL Butler VP., Haber E, Smith TW. Treatment of 150
cases of life threatening digitalis intoxication with digoxin specific Fab
antibody fragments. Circulation; 81: 6: 1744-1752, 1990.
3. Schaumann W., Neubert P., Smolarz A., Kinetics of the Fab fragments of
digoxin antibodies and of bound digoxin in patients with severe digoxin
intoxication. European Journal of Clinical Pharmacology; 30: 527-533,
1986.
4. Ujhelyi MR., Colucci RD., Cummings DM., Green PJ., Robert S, Vlasses
PH, Zarowitz BJ., Monitoring serum digoxin immune Fab therapy. DICP,
The Annals of Pharmacotherapy; 25: 1047-1049, 1991.
Lidocaine 51
LIDOCAINE
1. Time of Sampling
a. Relative to Dose
2h after load or 6-12h after initiation of therapy without load (ie @ ss)
Send out lab, may take 2-3 days for results to be reported
3. Therapeutic Range
a. Initial Dosing*
Load
MULTIPLE-BOLUS REGIMEN:
or
RAPID-INFUSION METHOD:
* For obese patients, it has been suggested that loading doses be based on TBW and
maintenance infusions be based on IBW. [Abernathy (1984) Am J Cardiol 53: 1183)].
** α-1 acid glycoprotein (AAG) concs are elevated in AMI patients. Plasma protein
binding of lidocaine is also conc-dependent. Consequently, free concentrations may
be more useful for monitoring therapy.
Ko
Dosing Adjustments: c=
Cl
Cimetidine co-administration:
Empirically ↓ usual infusion rate by 25%. Feely (1982) Ann Intern Med 96:592.
Elderly patients:
Empirically ↓ usual infusion rate by 20-30%. Abernethy (1984) J Cardiovas
Pharmacol 5:1093.
Lithium 53
LITHIUM
1. Time of Sampling
a. Relative to Dose
3. Therapeutic Range
a. Initial Dosing
b. Empiric Dosing
Perry Nomogram
1200mg test dose of lithium carbonate
One lithium serum concentration 24 hours later
Converts observed lithium concentration to maintenance dosage for
desired steady-state concentration
If using in acutely manic patient, anticipate a decrease in lithium
maintenance dose once patient starts sleeping due to decrease in
lithium clearance
Lithium 55
Multiple-Point Method
Perry Method
• 600 – 1500mg test dose
• Two lithium serum concentrations 12 and 36 hours after the test dose
• Calculate elimination rate, half-life, accumulation factor, and so on
• Lithium serum concentration must be zero prior to test dose administration
6. Products on UK Formulary
Lithium carbonate SR TAB 450MG
Lithium carbonate CAP 300MG
Lithium carbonate SR TAB 300MG
Lithium carbonate 300MG TAB
Lithium citrate LIQ 8MEQ/5ML 500ML
7. References
Absorption
• Incomplete & erratic absorption from GI tract
– Highly variable absorption
• n = 12 pediatric ALL F = 13-76%, DR=13-120mg/m2)
– Dose-dependent absorption (Michaelis-Menten pharmacokinetics)
• ↑DOSE = ↓F
– Generally at lower doses (≤ 25mg/m2) F ~100% but still variable
• Tmax = 1-5hrs, Cmax = 0.25-1.25µM
– Rate/extent of absorption affected by:
• Food, oral nonabsorbable antibiotics, shortened intestinal time
• IM injection
– Less variable, possible alternative if oral route problem
Distribution
• Very polar, requires active transport mechanisms to enter mammalian cells.
• Drug displays a bi or tri-exponential elimination curve resulting in a 2 or 3 compartment
model
• Initial Vd ~ 0.2 L/kg
• Apparent Vd ~ 0.7 L/kg (variable, incr. w/higher concs. due to saturation of active transport
system)
• Third spacing (e.g. by ascites or pleural effusion) creates a site of storage and “sustained
release” of drug
– Results in prolonged elevation of plasma concentrations and more severe toxicity and
additional doses of antidote
• 50% bound to plasma proteins (albumin)
– Potential drug interactions:
• Sulfonamides
• Salicylate
• Chloramphenicol
• Phenytoin
• CSF relatively impermeable, CSF concentrations 3% of plasma concentration; intrathecal
administration is usually required
Metabolism
• Metabolism is minimal; 3 metabolic pathways
– Intracellular polyglutamylation
• Important pathway for selective retention of folates
• Addition of up to 5 additional glutamate residues by the enzyme folyl polyglutamate
synthetase (FPGS)
• ACTIVE metabolite, contributes to cytotoxicity
• Polyglutamylated MTX is potent DHFR inhibitor as MTX
Methotrexate 58
– Hydroxylation
• 7-hydroxy metabolite (low H2O solubility) can accumulate leading to nephrotoxicity
• 1/100th the affinity for DHFR (inactive)
– Removal of glutamate residue (DAMPA)
• Conversion performed by intestinal bacteria
• Low levels in plasma may interact with MTX assay but NOT clinical significant
Excretion
• Excreted unchanged in the urine with minor biliary secretion
• Bi or tri-exponentional elimination (see figure below)
– α t½ ~ 3 hrs
– β t½ ~ 10 hrs - not apparent until concentrations < 5X10-7 molar
• Primarily renal eliminated
– Combination of GFR & TS
• At low concentrations correlates with GFR
– MTX Cl(ml/min) ~ 1.6 X Clcr(ml/min)
– Normal MTX Cl = 40-400ml/min
• High concentrations saturation of TS which ↓ net renal Cl
– RENAL FUNCTION MOST IMPORTANT DETERMINANT OF MTX
PHARMACOKINETICS
• Hydration status and urine pH
– More acidic pH = decreased Cl
• Drug interactions:
– Reduce renal blood flow (e.g. NSAIDs)
– Inhibit renal transport of MTX (e.g. sulfisoxazole, weak acids)
– Nephrotoxic (e.g. cisplatin)
MTX concentrations
requiring increased
rescue factor doses
1 X 10-6
β t1/2 = 10 hours
“Rescue Concentration”
1X 10-7
0 12 24 36 48 60 72 84 96 108
Time (Hours)
Toxicities
• Cytotoxic effects due to inhibition of DHFR
– Function of both concentration & duration of exposure
• Pancytopenia (sometimes irreversible)
• Severe mucositis
• GI and skin desquamation
• Renal and hepatic dysfunction
Leucovorin rescue
• To ensure that MTX toxicities do not occur, rescue factor (citrovorin factor or leucovorin) is
administered every 4-6 hours in doses that range from 10 to 500 mg/m2.
• Usual course is 12 to 72 hours until the plasma concentration of MTX falls below the critical value of 1
X 10-7 molar.
• If MTX conc. > 1X10-6 molar at 48 hours, leucovorin rescue dose is usually increased to 50 to
100mg/m2 every 3-6 hours until concentration < 1 X 10-7 molar; also see alternative dosing below:
MTX serum concentration ≥42 hr from Approximate leucovorin dose required
beginning of infusion
20-50 µmol 500 mg/m2 IV q6hr
10-20 µmol 200 mg/m2 IV q6hr
5-10 µmol 100 mg/m2 IV q6hr
1-5 µmol 30 mg/m2 IV or PO q6hr
0.6-1 µmol 15 mg/m2 PO q6hr
0.1-0.5 µmol 15 mg/m2 PO q12hrs
0.05-0.1 µmol 5-10 mg/m2 PO q 12hrs
Adapted from Crom WR, Evans WE. Methotrexate. In: Evans WE, et al., eds. Applied Pharmacokinetics: Principles
of Therapeutic Drug Monitoring, 3rd ed.
Pentobarbital 60
PENTOBARBITAL
1. Time of Sampling
a. Relative to Dose
For example, a severe traumatic brain injury patient recently taken off of pentobarbital,
but still not demonstrating any neurologic motor function. A serum concentration
approximately 24-72 hours after discontinuation of the infusion should provide some idea
as to if the persistent lack of neurologic function is due to the patient’s injury or due to
continued neurologic suppression from pentobarbital.
3. Therapeutic Range*
This is a modified version of the Eisenberg protocol that combines the secondary
loading doses with the infusion rate to give the secondary load slower to avoid
hypotension & make the dosing easier & less error prone.
Pentobarbital 61
5. Dosage Adjustments
a. Relative to Dose
at ss ~ 3 – 5 weeks
initial level
initial level
repeat level, as dictated by changes in concurrent disease state/drug
therapy or the lack of adequate response to previously adequate
doses, or signs/symptoms of toxicity. Patients in status epilepticus
require more intensive monitoring.
3. Therapeutic Range
10 – 40 µg/ml
5 – 15 µg/ml (saliva)
a. Initial Dosing
C⋅V
Load: Xo* = V = 0.7 L/Kg (adults)
S ⋅F S = 0.9 (sodium salt)
F = 1.0
or
20 mg/kg Infusion rate should not exceed 65 mg/min.
Respiratory status should be closely monitored.
Phenobarbital 64
b. Maintenance Dose:
Usual adult dose: 1-3mg/kg/day in divided doses
It is common practice to give 25% of the total maintenance dose for one week, ↑ to
50% the second week, ↑ to 75% the third week, and ↑ to the full dose the fourth
week to minimize toxicity.
c (at ss) produced by any given maintenance dose is approximately 10 times the
daily dose in mg/kg (e.g. 2 mg/kg - 20 mcg/ml).
c. Dosing Adjustments
Pregnancy: ↑ PB Cls
6. Pediatric Guidelines:
Neonates
Loading Dose (Status epilepticus, neonatal seizures): 15-20 mg/kg/dose; Vd =
0.7-1.2 L/Kg – some patients may require additional bolus doses of 5-10
mg/kg/dose based on clinical response (max loading dose 40 mg/kg)
Other Considerations
Infusion rate should not exceed 1 mg/kg/min (30 mg/min maximum for
infants/children and 60 mg/min maximum for ≥ 60kg). Normal loading doses should
be administered over 15-20 min. Respiratory depression is more commonly seen in
patients who have recently received chloral hydrate or parenteral benzodiazepines
prior to initiation of phenobarbital therapy.
a. Relative to Dose
3. Therapeutic Range
a. Loading Dose
C⋅V
Xo* = V= 0.7 L/kg
S ⋅F S= 0.92 (sodium salt; caps, inject)
1.0 (acid; chewtabs, suspension)
F= 1.0 (oral - only if given in divided doses);
OR variable with suspension
b. Maintenance Dose
1. Initial
Dose
τ
(S)(F)(K m )
Css =
Dose
(Vmax ) - (S)(F)
τ
Phenytoin 69
3. Mini-loading
Used when concentration is too high, to determine how long (t) until patient
achieves concentration in therapeutic range (C); Co = measured concentration.
Co
[K m x (ln )] + (Co − C)
t = C
(days)
Vmax
Vd
(integrated form of Michaelis-Menten equation)
5. Pediatric Guidelines
The free fraction can also be adjusted using the following equation:
1
fub =
1 + (2.1 × alb)
Winter MG, Tozer TN. Phenytoin. In: Evans WE, Schentag JJ, Jusko WJ, eds. Applied
Pharmacokinetics. Principles of therapeutic drug monitoring. 2nd ed. Spokane: Applied
Therapeutics Inc.;1986.
↑ free fraction
↓ total concentration needed to achieve free phenytoin concentration
of 1-2 mcg/ml
c) Obesity
d) Elderly
e) Critically ill
↔ Vd unchanged
↔ Km unchanged
↑ Vmax increases over time in patients with brain injury, other critical
illness
↑ free fraction may increase with time (even when albumin is
unchanged)
↓ total and free conc. may decrease with time, warranting higher
maintenance doses.
APPENDIX 1
PHENYTOIN PHARMACOKINETICS
PARAMETERS
AGE Vmax Km Vd
(years) (mg/kg/day) (mg/L) (L/kg)
Adult
Pediatric
Absorption/Bioavailability
- IV: max concentrations achieved after at the end of infusion but
- IM: peak concs ~ 30min post dose
Distribution
- 95 – 99% protein bound, primarily albumin
- increases with dose/rate, ranges from 4.3 to 10.8L
Metabolism/Elimination
- phenytoin cleaved from the prodrug by phosphatase enzymes
- conversion t½ ~ 8-15 minutes
- complete conversion IV ~ 2hrs; IM ~ 4hrs
- NO drugs are known to interfere with the conversion
Dosing Guidelines & Monitoring
- Dosage similar to phenytoin BUT use PHENYTOIN EQUIVALENTS
- Because of risk of hypotension, NOT recommended to exceed 150 PE/min
and for pediatrics rate should not exceed 3 PE/kg/min (max 150 PE/min)
- Need to wait at least 2 hours after IV dose and 4 hours after IM dose for
complete conversion to measure serum concentrations
Suggested patient criteria for administration of fosphenytoin*:
1. Age: <7yo or >60yo
2. History of underlying cardiovascular problems or preexisting hypotension)
3. Chronic or acute debilitating illness, emaciation, hyponatremia, peripheral
vascular disease, hemodynamic instability, or sepsis
4. Poor intravenous access qualified by one of the following: size smaller than
the antecubital fossa vein, catheter size < 20 gauge, no preexisting central
venous catheter
5. Pain intolerance with phenytoin sodium recognized.
*Guidelines for Fosphenytion Use (Meek PD, et al. Arch Intern Med. 1999; 159:2639-2644)
Phenytoin, Free 74
FREE PHENYTOIN
Appendix II.
Free phenytoin concentrations should be reserved for the situations described below. For
example, a "normal" patient with normal albumin and normal renal function who is not on
concurrent medications that alter phenytoin protein binding or clearance would not
warrant a free phenytoin concentration.
1. The total phenytoin dosage is >7 mg/kg/day and the total concentration is <10
mcg/ml.
or
2. A patient is seizure-free at a total level of <10 mcg/ml and you need to determine
whether a dosage increase is necessary.
or
3. A patient is exhibiting signs of toxicity at a dosage of <7 mg/kg/day and has a total
concentration of <20 mcg/ml.
or
free
- Use Css , fub, Ko, and population Km to calculate Vm (mg/day) with equation #4.
free
- Use the desired Css (UKCMC range: 0.8-1.6mg/L), fub, Vm, and Km to calculate for
a new dosage, Ko (mg/day) with equation #3.
______________________________________________________
Derivation of the Modified Michaelis - Menten Equation:
Ko Vm ⋅ Css total
Vm ⋅ Csstotal
1.) = =
fub fub ⋅ (K m +Css total
) (fub ⋅ K m )+ (fub ⋅ Css
total
)
_____________________________________________________________
Rhoney DH, Leader WG, Chandler MHH. Modified Michaelis-Menten Equation for Estimating Unbound-
Phenytoin Concentrations. Clin Pharm. 1993:12:913-917.
Theophylline 76
THEOPHYLLINE
1. Time of Sampling
a. Relative to Dose
S-R preps:
tr within 1h prior to dose; any consistent time within dosing
interval is acceptable if S-R preparation.
Continuous infusion:
Single level
Intermittent injection
initial level
b. Use in Unstable Patients*
initial level
repeat level every 2 to 3 days
*The frequency of sampling is dictated by changes in concurrent disease state/drug therapy
or the lack of adequate response to previously adequate doses, or signs/symptoms of
toxicity. Patients in acute respiratory distress require more intensive monitoring.
3. Therapeutic Range
5-15 mcg/ml for asthma
6-12 mcg/ml for apnea of prematurity
a. Initial Dosing
Children (9 – < 12 years) & young adult 5.7 (4.6) 0.89 (0.71)
smokers
Initial Final
Age
Dosagea Dosagea
Premature neonates:
a. If trough concentrations are low before the next dose, then slow-release products may
decrease the fluctuation and permit longer dosing intervals.
b. Products containing an aminophylline salt should divide the listed dose by 0.8.
c. Children 1 – 15 years of age, the initial theophylline dose should not exceed 16 mg/kg/day
up to a maximum of 400mg/day in the presence of risk factors for reduced theophylline
clearance or if not feasible to monitor serum theophylline concentrations.
d. In adolescents ≥ 16 years, the initial theophylline dose should not exceed 400mg/day in the
presence of risk factors for reduced theophylline clearance or if not feasible to monitor
serum theophylline concentrations.
F ⋅ S⋅ X o
c=
Cl s ⋅ τ S = 1; F = 1
Continuous infusion
S • Ko
c=
Cls
(
1-e-Kt ) S = 0.8, if aminophylline
K = Cls/V
S • Ko
c= at ss
Cls
The Chiou equation may be used to calculate Cls, prior to reaching ss. Basic
assumptions: (1) known V; (2) true zero-order infusion between 2 sampling points
(C1 and C2). Obtain two levels at 1 and 9h after starting infusion (optimally, one t
1/2 apart).
2 ⋅ K o ⋅ 0.8 2 ⋅ V ⋅ (C 1 − C 2 )
Cl s = +
C1 + C 2 (C 1 + C 2 ) ⋅ ( t 2 − t 1 )
-Kτ S ⋅ F ⋅ Xo -Kτ 1
tr = Cpk ⋅ e
Css = ⋅e ⋅
ss
-Kτ
V 1-e
AGE
SMOKING
DRUG
DISEASE STATE
WEIGHT
Age:
Smoking:
Powell (1977) Am Rev Resp Dis 116:17
Jusko (1978) Clin Pharmacol Ther 24:400.
Drug:
Weight:
1. Time of Sampling
a. Relative to Dose
3. Therapeutic Range
50-100 mcg/ml
At times higher concentrations may be recommended by Neurology Service
Utility of serum concentration monitoring for valproic acid (VPA) has not
been fully determined. This is partially due to concentration-dependent
protein binding. It also may take several weeks to achieve a therapeutic
effect even after the patient has achieved ss within the therapeutic range.
Continued anticonvulsant effects are also seen even after VPA is
undetectable in the blood. Studies are controversial in determining an exact
relationship between serum concentration and therapeutic effect or toxicity.
a. Initial Dosing
IV Valproic Acid has been used in Europe since the 1980s; approved in USA in 1997.
Recommended doses from package insert: Complex partial seizures: 10-15 mg/kg/day,
incr. 5 – 10 mg/kg/week with usually max ~ 60 mg/kg/day. Simple and complex absence
seizures 15 mg/kg/day, increase 5 – 10 mg/kg/week.
Recommended infusion rate: Per package insert, no faster than 20mg/min. However,
infusion rate appears safe as high as 6mg/kg/min.
Wheless, 1998 Loading doses of 15-45mg/kg (1050 – 3150mg/70kg) infused over 1 hour (max
rate ~ 50mg/min) in epilepsy patients (n=25, ages 4-39 yrs) without active
seizures. Average Cpk 10min post infusion: 71-277 (mean, 135.3±59.5ug/ml).
No significant adverse effects observed except 1 patient with Cpk > 200ug/ml had
mild sedation.
Venkataraman, 1999 Loading doses of ~25mg/kg infused at 3-6mg/kg per min (82-319 mg/min) in
epilepsy patients (n=21, ages 2-54 yrs). Cpk 20min post infusion= 64-204.1ug/ml
(mean 132.6ug/ml). Five patients had pain at site of injection due to high
concentration of VPA in infusion fluid. Recommended minimal dilution 1:1 with
D5W, NS or LR.
Hovinga, 1999 Three pediatric patients. Pt#1: 10yo, LD: 20mg/kg followed by 2mg/kg/h infusion;
Cpk 1hr post = 69.2ug/ml; 4 hrs later = 40ug/ml. Pt#2: 8yo, LD 13.4mg/kg; Cpk
3hrs post = 33.3ug/ml. Pt#3: 34 months, LD = 20mg/kg over 30min; Cpk 7hrs
post = 49ug/ml.
Chez, 1999 Three pediatric patients with status epilepticus. Pt#1: 22 months, 30mg/kg over
60min (no side effects); Cpk = 74.9ug/ml. Pt#2: 13 months, 30mg/kg; Cpk 1hr
post = 33.9ug/ml additional 30mg/kg given; Cpk = 102.6ug/ml. Pt#3: 8yo: LD =
30mg/kg & MD = 30mg/kg IV q6; Cpk = 100ug/ml, then 2 hours post = 40ug/ml.
White, 1999 Case report in 11yo. LD = 30mg/kg (960mg) over 1hr. BP decr. (130/80 to
70/55) ~39min after start of infusion, respiratory depression, required intubation.
Cpk 5hrs post = 104 ug/ml. BP stabilized 14 hrs later after pressor therapy.
Naritoku, 1999 Loading doses ~19.4±5.4mg/kg (range 10.6-27.8), ~1420±540mg (range 700-
2800mg) at rates of 20-50mg/min in epilepsy patients (n=20, 52.8±23.5yrs).
Reported N/V in 2 patients; decr. BP in one patient. Recommended 0.23L/kg
(16.1L/70kg) for LD calculation.
Cloyd, 2003 Loading doses ~ 15mg/kg infused over 5 min (3mg/kg/min) or 10 min
(6mg/kg/min) in 112 patients with epilepsy (mean age = 36±16 yrs; wt = 76.6±25
kg). Mean Vd ~ 0.2 L/kg (range 0.12 – 0.30 L/kg, ~20% CV) but determined with
limited sampling strategy (6hrs post dose). Mean (%CV) Cmax at 1hr: Ctotal =
73.5 (22%) mg/L, Cfree = 8.3 (46%) mg/L. Authors recommend using
Vd = 0.2 L/kg to estimate loading dose.
b. Dosage Adjustments
5. Pediatric Guidelines
6. Drug Interactions
7. Dosage Forms
syrup 2 hours
capsules 3-4 hours
tablets 3-8 hours
8. Miscellaneous
elderly ↑f
↓ Cl
Valproic acid is an anticonvulsant commonly used for the acute treatment of seizures or migraine
headache. Intravenous valproate sodium is available for use, but the typical pharmacokinetics of this
formulation are somewhat problematic. The pharmacokinetic elimination half‐life of valproate is relatively
short and does not permit a constant serum concentration during intermittent dosing, particularly in
children or other acutely ill individuals who may have elevated metabolic capacity. Rather, due to rapid
elimination, there tends to be a peak and trough phenomenon. This phenomenon has the potential to
cause difficulty in establishing a safe and effective dose for an individual patient (peak concentrations
may be supratherapeutic when targeting goal trough concentrations).
The introduction of delivering valproate via continuous infusion has the potential to address this clinical
problem by providing a consistent serum concentration throughout the dosing interval and avoiding serum
concentration fluctuation. Thus, patients receiving continuous infusion valproate would be less likely to
have serum concentrations that are temporarily above or below the therapeutic range (50‐100 mcg/ml).
The area under the concentration‐time curve required to maintain concentrations in the recommended
therapeutic range should be less with continuous infusion. Administering valproate by continuous infusion
may diminish the dose requirement in some individuals because of the lack of frequent peak
concentrations that occur after intermittent bolus infusions. To this point, clinical experience with this new
dosing strategy thus far has indicated that normal daily doses are needed to achieve target
concentrations.[1] A more consistent serum concentration may also aid in transitioning patients from
intravenous to oral therapy, where an extended‐release formulation may be used to mimic continuous
delivery of drug. The current dosing of valproate typically includes a loading dose ranging from
20‐40mg/kg (infused no faster than 6mg/kg/min). The typical initial maintenance dose ranges from 10‐30
mg/kg/day.
UK Protocol
Loading Dose Maintenance Dose
20‐40mg/kg IV (< 6mg/kg/min infusion rate) Begin IV infusion at 0.5‐1mg/kg/hr (12‐24mg/kg/day)*
*Initial maintenance dose requirements may vary due to concomitant disease states or medications that may displace
valproate from albumin binding sites and/or alter metabolic clearance
Ordering Procedure
Prescriber Pharmacy Nurse
Enter COM‐valproic acid continuous Verify as 1000mg VPA in To run as continuous infusion
infusion 250ml NS (based on mg/kg/hr rate)
Dose (enter as mg/kg/hr)
Frequency = continuous infusion
Monitoring
• Obtain serum valproic acid concentration after loading dose (2 hours, for patients with active
seizures to ensure rapid achievement of target concentration)
• Obtain total serum valproic acid concentration approximately 24 hours after infusion
initiation
• Utilize continuous infusion equation to determine clearance rate and infusion rate required to
achieve desired concentration (Css = Xo/Cls)**
**where Css = steady state concentration (mg/L), Xo = infusion rate (mg/hr); Cls = systemic clearance (L/hr)
References
1. Taylor, L.M., et al., Clinical utility of a continuous intravenous infusion of valproic acid in pediatric patients.
Pharmacotherapy, 2007. 27(4): p. 519‐525.
Valproic Acid 88
FREE VALPROIC ACID
Policy:
1. The pharmacist should make sure that a total concentration, as well as the
free valproic acid concentration, is ordered.
Appendix I
Free valproic acid concentrations should be reserved for the situations described below.
For example, a "normal" patient with normal albumin and normal renal function who is not
on concurrent medications (that alter valproic acid protein binding or clearance) would not
warrant a free valproic acid concentration.
OR
6. A patient is seizure-free at a total level of <50 mcg/ml and you need to determine
whether a dosage increase is necessary.
OR
OR
Relative to Dose
- Trough within 30 min prior to dose
- Trough should be at steady-state (24 to 30 hours after initiation of therapy
with normal renal function; approximately after the fourth dose in adults)
- Peak at 1 h after end of 1h infusion (Note that peak concentrations have not
been shown to correlate well with toxicity or efficacy and not recommended
by 2009 ASHP/IDSA guidelines).
• For morbidly obese patients (> 90% over their IBW) with normal renal
function: 15-20 mg/kg/dose X ABW every 12 hours. Consider
maximum initial dose of 2000mg and assess concentrations to
determine dosing interval.
NOTE: Obese patients may require larger total daily doses at less frequent
intervals (i.e., q8hrs) in order to avoid low trough concentrations for
prolonged periods.
*Bauer LA; Black DJ; Lill JS. Vancomycin dosing in morbidly obese patients. Eur J
Clin Pharmacol 1998 Oct;54(8):621-5
0.693
3. Calculate t½: t½ =
K
6. Calculate Vd:
If doses have reached steady state (e.g., previous doses on time, concentrations
drawn appropriately), use:
If doses have NOT reached steady state AND there are at least 3 concentrations
after a multiple dose (e.g., trough, peak, & random) or 2 concentrations after the 1st
dose (e.g., peak and random or 2 random concentrations) use:
Vancomycin 93
K o (1-e-Kt ) Cmax
pk = peak extrapolated to END of infusion
Vd = t = time of infusion
K (Cmax
pk - Ctr e-Kt' ) t' = time between Ctr and Cpkmax
ln 1
Ctr Ctr1 = high Ctr; Ctr2 = desired Ctr
t' = Ctr2
t' = time required from Ctr1 to Ctr2
K
10. Round dose (FOR ADULTS: round dose to nearest 250mg) then recalculate the
actual Cpk:
- Briefly describe the rationale of the drug and determine if warranted based on clinical and
patient information. Refer to UK Hospital guidelines for appropriate use of vancomycin.
Vancomycin 94
- Document the current day of therapy and goal length of therapy (e.g., Day #2/14
vancomycin), and any concomitant antibiotics.
- Document the collect times of the reported concentrations and note if the samples were
obtained appropriately. For example, if actual Cpk was drawn late, also document the
estimated Cpk if drawn correctly.
- Include the calculate PK parameters: K (hr-1), t½ (hrs), Vd (L) and Vd (L/kg – DBW).
- Write a new dosage in mg and mg/kg-DBW/dose (e.g., vancomycin 1000 mg IV q12hrs,
15mg/kg/dose).
- When changing a dosage, include the start time of new dosing regimen with the order
(very helpful for the pharmacist entering the order and the nurse administering the drug).
- Include a range for the predicted concentrations with the new dosage recommendation:
(e.g., Cpk = 8-10mg/L; Ctr <2mg/L, ~1mg/L).
- Include other pertinent information used to assess the patient: weight (ABW, IBW, DBW),
height, BSA, Scr, Clcr, BUN, urine output, I/Os, cultures, Tmax, WBC, differential,
allergies, and other nephrotoxic medications (e.g., furosemide, amphotericin,
aminoglycosides).
- Refer to the sample note on the next page.
Vancomycin 95
Sample Note
9/2/20XX Patient is 40yo WM being treated with vancomycin 1000mg IV q12hrs (12.5 mg/kg/dose)
14:30 for staphylococcal bacteremia based on positive blood cultures (9/1, both bottles) for
Staphylococcus aureus. Current Tmax 102.5, WBC = 15K. Vancomycin therapy meets
ABW = 80kg approval criteria. ID service is following patient and recommends Cpk ~ 35-40mg/L and
Ht = 6’0” Ctr = 10-15 mg/L (discussed with ID resident).
IBW = 77.6kg
Scr = 1.2 (today) Vancomycin concs drawn around 3rd dose on 9/2:
Clcr = 93ml/min Trough = 8.7 mg/L C: 07:30
Dose = 1200 mg IV infused from 08:00 – 09:00
Peak = 22 mg/L C: 11:00
Recommendations:
XXXXXX, PharmD
Pager #
Vancomycin 96
1. Pediatric Recommendations
Dosing Pearls
Goal Trough 10-15 mcg/mL (uncomplicated infections)
15-20 mcg/mL (serious infections: endocarditis,
sepsis, osteomyelitis, CNS infections, S.
aureus pneumonia)
Renal Impairment Dosing interval should be extended
Creatinine Clearance Calculate with Bedside Schwartz equation
(refer to pg 18)
Obesity BMI >95th percentile, use actual body weight4,5
Consider obtaining peak and trough
concentrations
Infusion Time Infuse all doses over at least 1 hour
Administration Final concentration must be <5 mg/mL; may
use 10mg/mL through central line if fluid
restricted
Monitoring Renal function, UOP, strict ins/outs, infusion
reactions (i.e. Redmans requiring prolonged
infusion ±pre-medication), clinical status (fever
curve, WBC, culture results), drug interactions
*Gestational Age = weeks of pregnancy when patient is born
#Postnatal Age = Age after birth
1 Rainkie D, Ensom MH, Carr R. Pediatric assessment of vancomycin empiric dosing (PAVED): a retrospective
review. Paediatric Drugs 2015;17:245-53.
2 Eiland LS, English TM, Eilant EH. 3rd Assessment of vancomycin dosing and subsequent serum concentrations in
2014;19:182-8.
Vancomycin 97
2. Vancomycin- Hemodialysis
Dose
1. Loading dose of 15-20 mg/kg based on ABW
2. Enter “intermittent” vancomycin order as an active order between doses
Concentrations
1. Usually drawn 3-5 days post-dose ordered as a random level.
2. Redose when level is expected to be < 15 mg/L.
3. Levels drawn 10-12 hours following high-flux hemodialysis may be misleading.
Obtaining level prior to hemodialysis is preferred.
1. Rybak M., Lomaestro B., et al. Therapeutic monitoring of vancomycin in adult patients: A
consensus review of the American Health-System Pharmacists, the Infectious Diseases
Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health-Sys
Pharm 66; 2009:82-98.
2. Karam C., McKinnon P., et al. Outcome assessment of minimizing vancomycin monitoring
& dosing adjustment. Pharmacotherapy 9(3);1999:257-66.
3. Cohen E., Dadasher A., Drucker M., et al. Once daily vs. twice daily IV administration of
Vancomycin for infections in hospitalized patients. J. Antimicobial Chemotherapy 49;
2002:155-60.
Vancomycin 98
4. Zimmerman A., Katona B., Plaisance K. Association of vancomycin serum concentrations
with outcomes in patients with gram-positive bacteremia. Pharmacotherapy 15(1);1995:85-
91.
5. Cantu T., Yamanaka-Yuen N., Lietman P. Serum vancomycin concentration: reappraisal of
their clinical value. Clin Infect Dis 18;1994:533-43.
6. Moellering Robert Jr. Editorial: Monitoring serum vancomycin levels: Climbing the
mountain because it is there? Clin Infect Dis 18;1994:544-6.
7. Leader W., Chandler M., Castiglia M. Pharmacokinetic Optimisation of Vancomycin
Therapy. Clin Pharmacokinetics 28(4);1995:327-342.
8. Hammett-Stabler C., Johns T. Laboratory guidelines for monitoring of antimicrobial drugs.
Clin Chem 44;1998:1129-1140.
9. Palmer-Toy D. Therapeutic monitoring of vancomycin. Arch Pathol Lab Med
124;Feb2002:322-3.
10. Matzke GR, McGory RW, Halstenson CE, Keane WF. Pharmacokinetics of vancomycin in
patients with various degrees of renal function. Antimicrob Agents Chemother 1984
Apr;25(4):433-7.
Guidelines to Anticoagulation 99
UNIVERSITY OF KENTUCKY HOSPITAL POLICY NUMBER: PH-02-12
CHANDLER MEDICAL CENTER FIRST ISSUED: 1/04
Department of Pharmacy Policy CURRENT AS OF: 6/10
SEE ALSO: PH02-04 Guidelines for Writing Notes in Patient’s Chart; PH02-05 Clinical
Pharmacokinetics Service Policy/Procedures; PH02-08 Patient
Education-Inpatients; PH02-11 Prescribing Guidelines; HP-2-14
Discharge Medication Planning, Education, and Procurement, PH02-17
Role of the Pharmacist in the Electronic record, CN-08-01E Drug-Nutrient
Interactions
STAFF
AFFECTED: Clinical Pharmacist Specialists, Clinical Staff Pharmacists, Staff
Pharmacists, Pharmacy Residents, and Pharmacy Students under the
supervision of a licensed pharmacist.
Monitoring Responsibility
Within the pharmaceutical care process, the primary pharmacist/resident who attends rounds or
precepts pharmacy students on the primary medical team is responsible for providing
appropriate and cost-effective monitoring and provision of clinical anticoagulation evaluations.
Patients on a service without a rounding service will be identified and followed according to the
pharmacy monthly service coverage list. The pharmacist is available on a consultant basis as
well for assistance with anticoagulation issues via pager 330-4325 M-F 0800-1700 or pager
330-7400 (PharmD on-call) after-hours and weekends.
Ordering
Pharmacists consulted via pharmacist to dose orders within SCM are authorized to order lab
tests pertinent to the management of a patient’s anticoagulation. These orders must state “Per
Protocol”. Lab tests will be limited to those pertinent to the monitoring of the medication (i.e. PT,
INR, aPTT, anti-factor Xa concentrations, SCr, BUN, CBC, and Albumin). In addition,
pharmacists are able to order dosage adjustments for heparin, LMWH, direct thrombin
inhibitors, and warfarin in consultation with the prescribing physician.
Order Verification
Pharmacists involved in the order verification process will evaluate the following when verifying
a warfarin order:
1. Ensure that a recent INR is available for evaluation prior to order verification (INR within
72 hours prior to order)
Guidelines to Anticoagulation 100
2. Review the INR and ordered warfarin dose to ensure appropriateness of therapy
according to known previous dosing for that patient. For warfarin naïve patients, dosing
recommendation are available in the University of Kentucky Chandler Medical Center
Anticoagulation Guideline.
Education
The nurse and/or pharmacist will provide patient education for patients receiving anticoagulant
therapy prior to discharge. In addition, pharmacist provided patient counseling will be available
through consultation. This education will consist of the Krames warfarin education packet and
will include such items as importance of compliance with taking the medication and being
adherent with laboratory monitoring, drug-drug and drug-nutrient interactions, as well as
potential adverse reactions and increased risk for bleeding.
Mechanism of Action:
- Inhibits reduction of vitamin K epoxide, thereby limiting activation of vitamin K
dependent clotting factors: II (prothrombin), VII, IX, X. Antithrombotic effect primarily
due to reduction in prothrombin.
- Inhibits synthesis of anticoagulant proteins C and S (potential procoagulant effects).
Pharmacokinetics:
Warfarin is a racemic mixture of two active isomers, R and S. The S-isomer is approximately
five times more potent than the R-isomer.
Oral Administration
Absorption: rapidly and completely absorbed
Distribution: primarily intravascular, highly protein bound
Half-life: 36-42 hours
- Time to steady state = approximately 10 days
Half-lives of Clotting Factors:
Factor II = 60 hrs
Factor VII =6 hrs
Factor IX = 24 hrs
Factor X = 40 hrs
Baseline INR within 72 hours of warfarin initiation should be reviewed to assess sensitivity.
If an INR is not present, the pharmacist will contact the physician or enter an order to obtain
an INR prior to verification of the order. Collect INR daily in hospitalized patients being
initiated on warfarin until INR is within the desired therapeutic range, then two or three times
weekly.
- Consider holding warfarin therapy if INR > 4
Guidelines to Anticoagulation 102
Warfarin Anticoagulation Initiation Dosing for Warfarin Naïve Patients
Warfarin Warfarin Warfarin
High Moderate Low
Day INR Sensitivity* Sensitivity** Sensitivity***
1 Baseline INR 2.5-5 mg 5-7.5 mg 7.5-10 mg
4 <1.5 10 mg
1.5-1.9 5-7.5 mg
2-3 2.5-5 mg
>3 0-2.5 mg
5 <1.5 10 mg
1.5-1.9 7.5-10 mg
2-3 2.5-5 mg
>3 0-2.5 mg
6 <1.5 7.5-12.5 mg
1.5-1.9 5-10 mg
2-3 2.5-5 mg
>3 0-2.5 mg
Adverse reactions
Warfarin:
- Over Anticoagulation / Bleeding
INR Action/Recommendation
Greater than therapeutic but < 5 Continue with lower warfarin dose, OR omit a dose and
with no significant bleeding resume therapy at a lower dose.
5-9 (No significant bleeding) Omit 1 or 2 doses (monitoring INR more frequently), and
resume therapy at a lower dose when INR therapeutic,
OR
If patient is at risk of bleeding omit a dose and administer vitamin K1 1.25 to 2.5 mg PO
5-9 (Rapid reversal required for Administer vitamin K1 2.5 mg PO (INR to normalize in
urgent surgery)* 24 hours); if INR still high, administer additional 1.25 to
2.5mg of vitamin K1 PO.
>9 (No significant bleeding) Hold warfarin therapy AND administer vitamin K1 2.5-5
mg PO, administer additional vitamin K1 in 24-48 hours if
necessary; resume therapy at a lower dose when INR
therapeutic.
Significant bleeding at any INR value Hold warfarin therapy AND administer vitamin K1 10 mg
by slow IV infusion (1mg/min) diluted in D5W or NS; may
repeat every 12 hours if needed. (Supplement with fresh
frozen plasma, depending on urgency)
Life threatening bleeding Hold warfarin therapy AND administer fresh frozen
plasma AND administer vitamin K1 10 mg by slow IV
infusion (1mg/min) diluted in D5W or NS.
*For patients with INR >1.5 but <5 requiring reversal for urgent surgery administer
vitamin K1 2.5 to 5 mg PO, or for patients NPO, 1 mg IV. Reduction in INR may take 24hrs.
Indication INR
Atrial Fibrillation
Atrial Fibrillation with high risk factors 2-3 (chronic)
(age >75 years, history of TIA or stroke, hypertension,
history systemic embolus, mitral stenosis, bioprosthetic
cardiac valve, thyrotoxicosis, left ventricular dysfunction, CHF,
rheumatic mitral valve disease)
Atrial Fibrillation with > 2 moderate risk factors 2-3 (chronic)
(Age 65-75 years, diabetes mellitus, coronary artery disease)
Pre-cardioversion (for Afib >48 hours) 2-3 (3 weeks)
Post-cardioversion 2-3 (4 weeks)
Indication INR
Valvular Disease
Aortic valve disease
with concurrent mitral valve disease 2-3 (chronic)
with associated atrial fibrillation 2-3 (chronic)
Mitral annular calcification
with associated atrial fibrillation 2-3 (chronic)
with history of systemic embolization 2-3 (chronic)
Mitral valve prolapse
with associated atrial fibrillation 2-3 (chronic)
with history of systemic embolization 2-3 (chronic)
with history of TIA despite Aspirin therapy 2-3 (chronic)
s/p embolic event despite anticoagulation 2-3 (chronic)
plus ASA 325 mg
Patent foramen ovale/atrial septal anuerysm
with history of systemic embolization 2-3 (chronic)
with history of TIA 2-3 (chronic)
Rheumatic mitral valve disease
with left atrial diameter > 5.5 cm 2-3 (chronic)
with associated atrial fibrillation 2-3 (chronic)
with history of systemic embolization 2-3 (chronic)
s/p embolic event despite anticoagulation 2.5-3.5 (chronic) or
2-3 (chronic) plus
ASA 81 mg or
clopidogrel 75mg
Valve Replacement
Mechanical valve prosthesis 2.5-3.5 (chronic)
(tilting disk valves, bileaflet mechanical valves in the
mitral position or aortic position with atrial fibrillation)
Bileaftet aortic mechanical valve 2-3 (chronic)
(provided normal sinus rhythm, normal ejection fraction,
and normal sized atrium)
Mechanical valve following systemic embolization or risk factors 2.5-3.5(chronic)
(Concurrent atrial fibrillation, history of systemic plus ASA 81 mg
embolization left atrial thrombus,
severe left ventricular dysfunction)
Tissue valve prosthesis 2-3 (3 months)
Tissue valve with history of systemic embolization 2.5-3 (3-12 months)
Tissue valve with atrial fibrillation or pacemaker 2-3 (chronic)
Guidelines to Anticoagulation 107
Unfractionated Heparin
Mechanism of Action
- Binds to and causes conformational change in anti-thrombin III thereby accelerating
inactivation of activated clotting factors IIa (thrombin), IXa, Xa, XIa and XIIa,
subsequently halting coagulation.
- Low dose predominantly affects factor Xa (prophylaxis)
- Full-dose predominantly affects factor IIa (thrombin) (established clot)
Pharmacokinetics
Unfractionated Heparin (IV or SQ):
Absorption (SQ): completely absorbed (at treatment doses); peak concentrations at 2-4 hrs
Distribution: primarily intravascular
Half-life: 90 minutes (range 0.5-2 hours)
- Mean time to steady state = 6 hours (3-5 half-lives)
- Increases with larger doses (non-linear)
- Decreases with PE, massive thrombus, or new clot (increased clearance)
Metabolism: degraded by reticuloendothelial system
- No dose adjustment necessary for hepatic or renal dysfunction
- Not significantly affected by dialysis
Prophylaxis Dosing
General Surgery / Medicine Patients
- Unfractionated enoxaparin 40mg SQ q24hrs (preferable if eGFR > 30 mL/min) or heparin
(UFH) 5000 units sq q8h or q12h
Enoxaparin
Mechanism of Action
- Low molecular weight heparin (LMWH) derived from porcine heparin with an average
molecular weight of 4500 daltons.
- Both heparin and LMWH binds to and causes a conformational change in anti-thrombin
III thereby accelerating inactivation of activated clotting factors. Due to its smaller size,
enoxaparin preferentially inhibits factor Xa, with an anti-Xa:anti-IIa ratio of 3.6:1.
Pharmacokinetics
Absorption (SQ)
- 90% absorbed by subcutaneous route
- Peak anti-factor Xa activity 3-5 hours after injection
Distribution
- Similar to intravascular volume
Elimination
- Primarily renal, follows linear, first order kinetics
Half-Life (based on anti-factor Xa activity)
- 6 hours (multiple doses)
- Prolonged in patients with renal insufficiency due to decreased clearance
Prophylaxis Dosing
40 mg SQ every 24 hours
- General Surgery / Medicine patients
- Orthopedic hip replacement
30 mg SQ every 12 hours
- Orthopedic Trauma patients
- Orthopedic knee replacement
Treatment Dosing
Monitoring
Not generally necessary
- May be considered in special populations. Those at extremes of body weight or with
renal insufficiency (defined as Clcr < 30 ml/min).
- Limited data are available that correlate a specific anti-factor Xa range to antithrombotic
activity or bleeding risk. Appropriate surrogate marker of antithrombotic effect when the
clinical situation dictates monitoring.
Guidelines to Anticoagulation 109
Anti-factor Xa levels
- Concentrations measured by the clinical lab daily
- Collect peak concentration 3-5 hours after the subcutaneous dose
- Enoxaparin should be at steady state to account for accumulation, typically prior to third
dose
- Therapeutic Range (peak concentration):
o 0.6-1.2 Unit/ml (1mg/kg dosing)
Dosage adjustment
- Changes in dose can be calculated by using a ratio of dose and anti-factor Xa level
o Assumes current Xa level is at steady state
o Goal Xa level for treatment doses in therapeutic range
Renal Insufficiency
Enoxaparin is primarily eliminated renally. Its use in patients with severe renal dysfunction
will prolong the elimination half-life and may increase bleeding risk.
Inverse correlation exists between Clcr and anti-factor Xa levels. Patients with severe renal
impairment (Clcr < 30 ml/min) require dosage adjustment due to reduced clearance.
- Prophylaxis dosing: Enoxaparin 30mg SQ daily
- Treatment dosing: Enoxaparin 1mg/kg SQ daily
UFH is recommended for dialysis patients or patients with renal insufficiency at high risk of
bleeding.
Protamine
- Reverses the antithrombin activity of enoxaparin but ≤ 60% of the anti-Xa activity.
o No accepted method available to neutralize all effects of enoxaparin
- Reserved for patients with clinically significant bleeding episodes while receiving
enoxaparin therapy. Reversal may be incomplete due to lack of anti-factor Xa
neutralization. Use with supportive care of the patient and possible transfusion therapy.
- Dosing (within 8 hours of SQ dose)
o 1 mg of protamine will reverse approximately 100 anti-factor Xa units (1 mg of
enoxaparin = 100 anti-factor Xa units).
Guidelines to Anticoagulation 110
o Repeat dose of protamine 0.5 mg per 100 anti-factor Xa units may be given if
bleeding continues.
Direct Thrombin Inhibitors (Intravenous Therapy)
Argatroban
Mechanism of Action
- A direct, selective thrombin inhibitor. Reversibly binds to the active thrombin site of free
and clot-associated thrombin. Inhibits fibrin formation; activation of coagulation factors V,
VIII, and XIII; protein C; and platelet aggregation.
Pharmacokinetics
Immediate onset with IV infusion
Metabolism
- Hepatic
- requires initial dosage adjustment in patients with moderate to severe hepatic
dysfunction
Half-Life
- 40 minutes
- Prolonged in patients with hepatic insufficiency due to decreased clearance
Monitoring
Bivalirudin
Mechanism of Action
Specific and reversible direct thrombin inhibitor; it binds to the catalytic and anionic exosite of
both circulating and clot-bound thrombin. Inhibits coagulant effects by preventing thrombin-
mediated cleavage of fibrinogen to fibrin monomers, and activation of factors V, VIII, and XIII.
Pharmacokinetics
Immediate onset with IV infusion
Elimination
- Proteolytic cleavage
- Renal - requires initial dosage adjustment in patients with severe renal dysfunction, CrCl
< 30 ml/min
Half-Life
- 25 minutes
- Prolonged in patients with severe renal insufficiency
Kiser et. al. Safety, efficacy, and dosing requirements of bivalirudin in patients with heparin-induced
thrombocytopenia. Pharmacotherapy Vol. 28 (9), 2008 1115-1124
DTI Reversal
No antidote or reversal agent is available for direct thrombin inhibitors
- Bivalirudin and dabigatran are removed via hemodialysis/filtration and can be
considered in patients actively bleeding with elevated aPTT (Argatroban is not
significantly removed)
- Consider fresh frozen plasma (FFP), FEIBA, or Factor VII for refractory/life threatening
bleeding
Guidelines to Anticoagulation 113
Adult Heparin Induced Thrombocytopenia (HIT) Guidelines
HIT should be considered in patients exhibiting a decrease in platelet count after 5 days of
receiving a heparin/LMWH product (may be seen much sooner if previous exposure to heparin),
and one of the following:
o Platelet count of less than 150000/μL OR 50% drop in baseline platelet count
o Development of a new arterial or venous thrombus
o Inflammation or necrosis at heparin injection site
o Patient with previous documented HIT or heparin induced thrombocytopenia
thrombotic syndrome (HITTS) requiring treatment
The decision to administer DTI therapy for HIT is based on a clinical-pathologic diagnosis
Clinical probability can be assessed using the 4T scoring system below:
• Consider HIT in patients with intermediate to high probability
Laboratory tests for HIT should be interpreted within the context of the clinical probability
assessment obtained from the 4T scoring system :
o Collect HIT assay (ELISA)
o Positive – Possible HIT, consider direct thrombin inhibitor (DTI)
If available, consider optical density value in the interpretation of positive
ELISA
• Optical density (OD) value of 0.4-1.0 are associated with a
relatively low risk of HIT and should be interpreted within the
context of the clinical estimate for the probability of HIT
Guidelines to Anticoagulation 114
• OD value of >1 demonstrate nearly a 6-fold increased risk of
thrombosis over those less than 1.
o Negative – HIT diagnosis very unlikely consider other causes for
thrombocytopenia, DTI NOT INDICATED
o Serotonin release assay (SRA) should be sent to confirm ALL positive Elisa
Warfarin is not indicated as initial therapy and should be withheld until platelet count resolves.
<1.2x control increase rate by 40% <1.2x control increase rate by 40%
1.2-1.5x control increase rate by 20% 1.2-1.5x control increase rate by 20%
1.5 – 2.5x control No Change 1.5 – 2.5x control No Change
(upper limit 80) (upper limit 80)
2.5 – 4x control 2.5 – 4x control decrease rate by 20%
decrease rate by 20% (less than100)
(less than100)
Hold for 1 hour, reassess Hold for 1 hour, reassess
>4x control or >4x control or
aPTT; decrease rate by aPTT; decrease rate by
aPTT > 100 aPTT > 100
50% once aPTT < 100 50% once aPTT < 100
Initiation of warfarin:
o Should be held until platelet count returns to above 150000/μL
o Combined therapy of a DTI with warfarin should be continued for a minimum of 4 days and
until the INR is in the desired range
o Argatroban can cause an elevation in INR beyond that seen with warfarin alone (reversal
with vitamin K not necessary)
o Collect baseline INR on argatroban prior to initiation of warfarin
o Refer to argatroban to warfarin conversion guidelines
Guidelines to Anticoagulation 116
After patient is stabilized, check platelets; if within normal limits initiate warfarin
* Supratherapeutic aPTT may indicate Argatroban effects on INR are still present.
**Falsely elevated. Do not give Vit K for increased INR, only give if bleeding, s/s hemorrhage, etc.
DTIs directly interfere with PT/INR.
Guidelines to Anticoagulation 117
Bivalirudin:
o 1 mg/kg IV bolus, followed by 2.5 mg/kg/hr infusion for the duration of the procedure
o In addition, bivalirudin 50 mg is added to the pump prime
o Discontinue infusion 15 min prior to expected separation from CPB
o Goal to maintain ACT > 2.5-times baseline
o Administer additional 0.1-0.5 mg/kg boluses if subtherapeutic
* Infusion rate may need to be reduced by as much as 50% in patients with renal insufficiency
(Clcr < 30 ml/min) or critically ill patients
Bivalirudin:
o 0.75 mg/kg IV bolus, starting dose of 1.75 mg/kg/hr infusion for the duration of the
procedure
o Goal to maintain ACT above 300 seconds
o Adjust infusion rate by 0.25 mg/kg/hr increments to maintain ACT within desired
range
* Reduce initial infusion rate by 50% in patients with renal insufficiency (Clcr < 30
ml/min)
Patients required VTE prophylaxis with history of HIT or patients with resolved
HIT/HITTS:
Factor Xa Inhibitor:
o Fondaparinux 2.5 mg SC daily
o Caution in patients with a CrCl < 30 ml/min
o Monitor CBC daily to assess platelet count and evidence of bleeding
Guidelines to Anticoagulation 118
Direct Oral Anticoagulants (DOACs) - (apixaban, dabigatran, edoxaban,
rivaroxaban)
Apixaban 5mg twice BID; 2.5mg BID 10mg BID X 7 days then
(Eliquis) Dose adjusted to 2.5mg BID if the 5mg BID
patient is taking a strong dual Prevention: 2.5mg BID
inhibitor of CYP3A4 and P-gp, or has
two or more of: ≥80 years age, body
weight ≤60 kg, or Scr ≥ 1.5 mg/dL
Procedure:
VTE risk assessment completion
1. The physician will be prompted to complete the assessment upon patient
admission as a component of the admission order set.
2. Physician is ultimately responsible for completing initial assessment for every
patient with admission orders to the hospital.
Components of the risk assessment form: (user will be prompted to complete
each of the following)
1. VTE risk Category (See table below for risk assessment and suggested
therapies)
a. Low risk
b. Moderate Risk
c. High Risk
3. Admission order set will preselect therapies based on defined risk and
presence of any contraindications. Prescribers have the option to override
these selections prior to submission of the order.
a. Low risk = no selection of VTE prophylaxis
b. Moderate risk = heparin 5000 units SQ q8h
c. High risk = enoxaparin 30 mg SQ q12h (q24h if eGFR < 30 ml/min)
d. Selection of a contraindication will replace chemical prophylaxis
with an order for sequential compression devices
Guidelines to Anticoagulation 121
Risk Assessment Guideline for Medical Patients:
Patients with limited mobility and at least one additional risk factor: consider VTE
prophylaxis (moderate to high risk)
Contraindications
-Coagulopathy -Lumbar puncture, spinal injection, or epidural
-Severe liver disease catheter removal within past 2 hours
-Heparin induced thrombocytopenia -Multiple trauma with high bleeding risk
-Platelet count <20,000 without coagulopathy -Other (free text field)
-Enoxaparin 40 mg SQ -Enoxaparin 30 mg SQ
-No specific daily (preferred if eGFR q12h
recommendation > 30 mL/min
Suggested Therapy -Order for ambulation -Heparin 5,000 units SQ -Enoxaparin 40 mg SQ
-With SCDs q8h daily
-With or without SCDs -Heparin 5,000 units SQ
q8h
-With SCDs
Patients at moderate to high risk with bleeding risk should receive mechanical thromboprophylaxis.
Dosing adjustment should be considered for enoxaparin in patients with renal insufficiency (CrCl <30
mL/min) and should be considered in morbidly obese patients (BMI >40 kg/m2).
VTE=venous thromboembolism, SCDs=sequential compression devices, SQ=subcutaneously, q8h=every
8 hours, q12h=every 12 hours, CrCl=creatinine clearance, BMI=body mass index
Guidelines to Anticoagulation 123
Surgical Patient VTE Risk Assessment
Guidelines to Anticoagulation 124
References (Warfarin)
1. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: ACCP Evidence Based
Clinical Practice Guidelines. Chest 2012
2. Hirsh J, Fuster V, Ansell J, Halperin J. American Heart Association/American College of
Cardiology foundation guide to warfarin therapy. JACC 2003;41:1633-52.
3. Harrison L, Johnson M, Massicote MP, et al. Comparison of 5 mg and 10 mg loading doses
of warfarin therapy. Ann Intern Med 1997;126:133-6.
4. Kovacs M, Rodger M, Anderson D, et al. Comparison of 10 mg and 5 mg warfarin initiation
nomograms together with low-molecular-weight heparin for outpatient treatment of acute
venous thromboembolism. Ann Intern Med 2003;138:714-719.
5. Dager W. Initiating warfarin therapy. Ann Pharmacother 2003;37:905-8.
References (Heparin/Enoxaparin)
1. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: ACCP Evidence Based
Clinical Practice Guidelines. Chest 2012 141:2 suppl e24S-e43S
2. Brill-Edwards P, Ginsberg JS, Hirsh J et al. Establishing a therapeutic range for heparin.
Ann Intern Med. 1993; 119:104-109.
3. Weitz JI. Low-molecular-weight heparins. NEJM 1997; 337(10):688-98.
4. Fareed J, Hoppensteadt D, Sheikh T et al. Pharmacodynamic and pharmacokinetic
properties of enoxaparin. Clin Pharmacokinet 2003; 42(12):1043-57.
5. Chow SL, Zammit K, West K, et al. Correlation of antifactor Xa concentrations with renal
function in patients on enoxaparin. J Clin Pharmacol 2003; 43:586-90.
6. Kruse MW, Lee JJ. Retrospective evaluation of a pharmacokinetic program for adjusting
enoxaparin in renal impairment. Am Heart J 2004; 148:582-9.
7. Sanderink G, Liboux AL, Miro A. Pharmacokinetics and pharmacodynamics of enoxaprin in
obese volunteers. Clin Pharmacol Ther 2002;72:308-18.
Notes: