PharmaNote

VOLUME 25, ISSUE 1 OCTOBER 2009

25TH ANNIVERSARY OF THE PHARMANOTE

It is hard to believe it, but we are starting our 25th year of publishing the PharmaNote newsletter.
To all of our readers, we sincerely appreciate your support and look forward to continuing to provide
new and updated treatment information to assist you in the treatment of your patients.
ED Eel

PHARMACOKINETIC
VARIABILITY IN PREGNANCY
AND PROPOSED
LABELING CHANGES
Sarah K. Richardson, Pharm.D. Candidate

he issue of drug use in pregnancy continues to

be a perplexing topic for many practitioners.
The safe use of drugs in pregnant patients is a
dilemma because of the limited clinical trial data in-
volving these patients and the pharmacokinetic and
pharmacodynamic changes during pregnancy. This
issue is compounded by the increasing number of
women on chronic medications who are becoming
pregnant. This article will review pharmacokinetic
changes in pregnancy. It will also discuss the current
pregnancy categories and the new labeling changes
proposed by the Food and Drug Administration
(FDA).

EPIDEMIOLOGY

Prescription drug use in pregnancy is growing in
the United States. As the average age of pregnant
women increases, practitioners are faced with more

pregnant patients who require treatment for chronic
medical conditions. These medical conditions must
be addressed throughout their pregnancy. The main
problem with prescription drug use in pregnant pa-
tients is the potential teratogenic effects on the fetus.
Studies estimate that 10-15% of congenital anoma-
lies originate from maternal teratogen exposure.1
Practitioners must be aware of the potential risks of
drug exposure to the fetus and weigh these against
the potential benefits to the mother.

PHARMACOKINETIC CHANGES IN PREGNANCY

Understanding the pharmacokinetic changes that
take place during pregnancy provides practitioners
insight into the treatment of these women. Current
pharmacokinetic data, primarily from small observa-
tional studies, is summarized in Table 1.
Several important pharmacokinetic parameters
are altered in pregnancy. The first parameter is ab-

INSIDE THIS ISSUE:
PHARMACOKINETIC VARIABILITY IN PREGNANCY
AND PROPOSED LABELING CHANGES
INDEX FOR VOLUME 24 (OCT. 2008 SEP. 2009)

1 ---tf

mm
PharmaNoteVolume 25, Issue I I October 2009

Volume 25, Issue 1 I October 2009

PharmaNote

Table 1. Pharmacokinetic changes in pregnancy.2
PHARMACOKINETIC PARAMETER PHYSIOLOGICAL PARAMETER EFFECT EXAMPLES
Absorption t Gastric emptying time t or j Systemic absorption Ampicillin (theoretical) Cefa-
Gastric acid pH of medications zolin (theoretical)
1, GI motility

Distribution I Plasma volume t Volume of distribution Phenytoin, valproic acid
t Adipose tissue volume Plasma drug concentration
I Cardiac output

Excretion t GFR and renal blood flow I Clearance of drugs that are Digoxin, atenolol
cleared through the kidney
Protein Binding ,I/Albumin concentration t Free drug concentrations of Phenytoin, valproic acid
highly protein bound drugs

sorption. The interaction between absorption and cer- titioner is prescribing medications for pregnant pa-
tain antibiotics is theoretical since no studies have tients.
proven that this interaction leads to clinically signifi- Many drugs used in pregnancy are metabolized
cant changes. The second parameter is distribution, via the hepatic cytochrome p450 (CYP) system. The
The combined effects of an increase in cardiac output various CYP isoenzymes are altered to different ex-
and a decrease in plasma albumin concentrations can tents in pregnant patients. Consequently, altered
have a measurable effect on highly protein bound metabolic rates can result in substantial changes to
medications. This effect occurs in pregnant women drug concentrations. The changes to these metaboliz-
on anti-seizure medications such as phenytoin and ing enzymes can lead to a change in the clearance
valproic acid.3 The third parameter is an increase in and steady state concentration of drugs in patients.
the clearance of medications. The increase in glome- The pharmacokinetic changes in metabolizing en-
rular filtration rate (GFR) and renal blood flow can zymes are summarized in Table 2.
have an effect on drugs that are cleared extensively
by the kidneys. An increase in the elimination of CURRENT CLASSIFICATION SYSTEM
these drugs can lead to sub-therapeutic drug concen-
trations in pregnant patients. For example, In 1979, the FDA issued a classification system
the clearance of certain B-lactam antibiotics can be for drugs that serves as a guide to physicians in the
increased in pregnancy.4 A pooled analysis of several selection of drugs for use in pregnancy.8 The current
studies showed that the elimination of intravenous classification system is summarized in Table 3.
cefazolin in pregnant patients was twice that of cor- Some of these classes are based on the potential risk
responding non-pregnant patients.5 These pharma- of harm to the fetus, while others are a risk versus
cokinetic changes should be considered when a prac- benefit comparison. However, because this system

Table 2. Pharmacokinetic changes in metabolizing enzymes through the trimesters. 6, 7

ENZYME 1sT TRIMESTER (%) 2ND TRIMESTER (%) 3RD TRIMESTER (%) SUBSTRATES
CYP 1A2 33 50 65 Theophylline, Clozapine, Olanzapine
CYP 2A6 No Data 54 54 Nicotine
CYP 2C9 No Change No Change 20 Phenytoin, Losartan, Celecoxib
CYP 2C19 No Data 50 50 Omeprazole. Pantoprazole, Lansoprazole
CYP 2D6 No Data No Data 50 Metoprolol, Fluoxetine, Nortriptyline
CYP 3A4 No Data No Data t 50-100 Cortisol, Nifedipine, Ritonavir
CYP UGT 1A1 t 200 t 200 t 300 Lamotrigine

ri -a i i a i 1. 1.u IIrn

W U1110 QQUQ %ILU 01

ra ma ote

has caused significant confusion, a more evidence-
based model for classifying the risks and benefits of
medication use in pregnancy is needed.
Several deficits exist in the current system. First,
many practitioners and patients think that the risk
increases as you proceed from A to X; however, this
is not the case. Classifications A and B are only
based on the risk of harm to the fetus, while classifi-
cations C and D also consider the benefit of drug
therapy to the mother. This method of classifying
drugs differently in different categories contributes
to the confusion. There is no linear comparison be-
tween classifications A and B and classifications C
and D. In class C and D, the medicine is a risk to the
fetus, but the effects of the disease state on the fetus
and the mother are also considered. Finally, the vast
majority of drugs fall into category C. Since most of
these drugs have not been studied in pregnant
women or animals, the class C designation does not
help physicians determine the risk versus benefit of
the drug. If data became available for a class C drug,
it could move to any of the other classes. Class C
drugs are not necessarily any better than class D or X
drugs, or any worse than class A or B drugs. This

contributes to provider and patient confusion regard-
ing the safety of these medications. These deficits in
the current labeling of medications have prompted
the FDA to re-evaluate the current system. Last year,
a new system was proposed that will hopefully aid
clinicians and patients to better understand the risks
and benefits of medication use in pregnancy and lac-
tation.
Several deficits exist in the current system. First,
many practitioners and patients think that the risk
increases as you proceed from A to X; however, this
is not the case. Classifications A and B are only
based on the risk of harm to the fetus, while classifi-
cations C and D also consider the benefit of drug
therapy to the mother. This method of classifying
drugs differently in different categories contributes
to the confusion. There is no linear comparison be-
tween classifications A and B and classifications C
and D. In class C and D, the medicine is a risk to the
fetus, but the effects of the disease state on the fetus
and the mother are also considered. Finally, the vast
majority of drugs fall into category C. Since most of
these drugs have not been studied in pregnant
women or animals, the class C designation does not

Table 3. Pregnancy categories for prescription drugs.8

CATEGORY

DESCRIPTION

A Drugs in this category have controlled studies in pregnant women that have failed to demonstrate harm to the
fetus in the first trimester and have no evidence of further risk in later trimesters

. Examples: folic acid and vitamin B12

B Presumed safety is based on animal studies, but there are no controlled studies in pregnant women; OR ani-
mal studies have shown a risk, but controlled trials in pregnant women have not shown a risk.
Examples: acetaminophen, insulin aspart, metformin, and famotidine

C Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in preg-
nant women; OR no animal studies have been conducted and there are no adequate and well-controlled stud-
ies in pregnant women.
Examples: pseudoephedrine, fluconazole, ciprofloxacin, fexofenadine, escitalopram, fluoxetine, and bu-
propion

D Adequate well-controlled or observational studies have been done in pregnant women that have demon-
strated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk.
Examples: phenytoin, diazepam, and alprazolam

X Adequate, well-controlled or observational studies have been done in pregnant women or in animals and have
demonstrated positive evidence of fetal abnormalities. The use of the product is contraindicated in women
who are or may become pregnant.
Examples: warfarin, medroxyprogesterone, estrogens, methotrexate, and simvastatin

Volume 25, Issue I i October 2009

PharmaNote

help physicians determine the risk versus benefit of
the drug. If data became available for a class C drug,
it could move to any of the other classes. Class C
drugs are not necessarily any better than class D or X
drugs, or any worse than class A or B drugs. This
contributes to provider and patient confusion regard-
ing the safety of these medications. These deficits in
the current labeling of medications have prompted
the FDA to re-evaluate the current system. Last year,
a new system was proposed that will hopefully aid
clinicians and patients to better understand the risks
and benefits of medication use in pregnancy and lac-
tation.

PROPOSED NEW LABELING

The proposed system would discontinue the A, B,
C, D, and X categories. The new format for the preg-
nancy product labeling would include a summary of
information on fetal risk, clinical considerations, and
a summary of the available study data.9'10 Other sec-
tions on lactation would provide a risk summary,
clinical consideration, and any available lactation
data. Since the American Academy of Pediatrics
(AAP) recommends breastfeeding for at least the
first six months after birth, information on the effects
of medications on breastfeeding is needed now more
than ever." The proposed labeling changes for preg-
nancy and lactation are summarized in the following
sections and Figure 1.

Pregnancy
Fetal Risk Summary:
The fetal risk section would discuss the relation-
ship between drug use and the risk of developmental
abnormalities in humans. The four types of develop-
mental abnormalities that would be addressed in-
clude structural anomalies, fetal and infant mortality,
impaired physiologic function, and alterations in
growth. Any available data would also be differenti-
ated between animal and human data.12

Clinical Considerations:
Clinical considerations would address five main
topics. First, a statement would be made regarding
the potential risk in the event of an accidental expo-
sure. The manufacturer would also disclose the
known risks of both the drug and the disease. Infor-
mation about dosing adjustments in pregnancy and
any known adverse reactions that are unique to preg-

nant patients would be addressed. This statement
would also discuss potential complications and the
appropriate management if these complications arise.
A final statement would provide information on indi-
cations for use during the delivery process and the
drug effects during labor.

Data:
In the data section, the manufacturer would dis-
close pertinent aspects of the data that was used for
the approval process. First, the company would
elaborate on the study type, exposure levels, identi-
fied fetal abnormalities, and adverse events reported
during the trials. Secondly, human trial information
would include positive and negative outcomes, the
number of patients studied, and the duration of the
study. Additionally, animal trials would reflect
which species were included as the model, the doses
given to the animals, and the equivalent human
doses. If no data was available a statement would be
made to that effect.

Lactation
Risk Summary:
The lactation risk summary section would address
the potential effect the drug may have on maternal
milk production. Furthermore, it would disclose the
presence or absence of the drug in maternal milk. If
the drug is present in breast milk, then both the quan-
tity present and the concentration would be reported.
If the drug is not present in breast milk, then a dis-
closure of the limits of the assay would be reported.
A third statement would include the potential effects
of the drug on the nursing child, including the likeli-
hood and seriousness of the effects.

Clinical Considerations:
In the clinical considerations section, practitioners
would be provided with options that minimize the
exposure of the child to the drug, including informa-
tion about the timing of breast feeding or pumping to
coincide with troughs in the concentration of the
drug. Dosing adjustments appropriate for breastfeed-
ing mothers would also be included. Additionally,
this section would highlight the potential effects of
the drug on the breastfed child. This would include
recommendations for practitioners regarding the
monitoring of the child as well as possible responses
to the effects of the drug if they manifest in the child.

PhraoeVoue2,Isu ctbr20

Volume 25, Issue I I October 2009

PharmaNote

Fig 1. Fictitious example of revised pregnancy labeling.13

All pregnancies have a background risk of birth defect, loss, or other adverse outcome regardless of drug exposure. The
fetal risk summary below describes ALPHATHON's potential to increase the risk of developmental abnormalities above
the background risk.

Fetal Risk Summary
Based on animal data, the likelihood that ALPHATHON increases the risk of developmental abnormalities is predicted to
be high (see Data).

Clinical Considerations
Asthma complicates approximately 1% of all pregnancies resulting in higher perinatal mortality, low birth weight infants,
preterm births, and pregnancy-induced hypertension compared to outcomes for nonasthmatic women. Because of the
risks of even mild maternal hypoxia to the developing fetus, asthma should be clinically well-controlled during pregnancy.
There are no human studies evaluating ALPHATHON use in pregnant women. The time of gestation at which risk may be
greatest is unknown; therefore, risks of inadvertent exposure in early gestation cannot be evaluated. Animal data suggest
that ALPHATHON exposure may result in early fetal loss and anomalies of major organ systems. There are no data re-
garding dose adjustment needs in pregnancy. Given the lack of human data and the risks suggested by animal data, pre-
scribers should consider alternative treatments for asthma for pregnant women when possible (especially during the first
trimester) and women planning pregnancy.

Data
Human data:
There are no data on human pregnancies exposed to ALPHATHON.
Animal Data:
Reproductive studies performed during early pregnancy in rats at oral doses 0.75 to 1.0 times the recommended human
dose (adjusted for body surface area) showed implantation loss, fetal resorptions, and major congenital anomalies of
the cardiac, skeletal and renal systems without signs of maternal toxicity.
Reproductive studies performed in early pregnancy in rabbits at doses approximately 0.33 to 1.0 times the recom-
mended human dose (adjusted for body surface area) showed increased post-implantation loss. Studies at 3 times the
human dose showed significant fetal loss without signs of maternal toxicity.
The effects of ALPHATHON on fetal growth, labor, or post-natal complications were not evaluated in the animal studies.

Data:
The data section would provide an overview of the
studies that were used to support the labeling of the
medication. The addition of this section would pro-
vide clinicians with the information that was used to
draw conclusions regarding medication use in lactat-
ing patients. This would also state how relevant the
data presented is to lactating patients.

CONCLUSION

The topic of prescription drug use in pregnancy
continues to be a dilemma. Knowing the pharma-
cokinetic changes in pregnancy can help physicians
more effectively treat their patients; however it is
clear that more information about prescription drug
effects in pregnancy is needed. The current method
of classifying medications does not provide enough
information for health care providers to make in-
formed decisions about prescribing medications to
this subset of the population. A better classification
system is needed in an attempt to provide more accu-

rate information in an easily accessible format. If the
proposed labeling changes are accepted, the new la-
bels will provide clinicians and patients with more of
the information they need to better understand the
risks and benefits of prescription drug use in preg-
nancy.

REFERENCES

1. Coles LD, Eddington ND. Pharmacotherapy and
Pregnancy: The Dynamics of Pharmacokinetics,
Drug Metabolism, and Transporters. AAPS
Newsmagazine. April 2007.
2. Yerby MS, Friel PN, McCormick K, et al.

Pharmacokinetics

of anticonvulsants

pregnancy: alternations in plasma protein
binding. Epilepsy Res 1990;5:223-8.
3. Loebstein R, Lalkin A, Koren G. Pharmacoki-
netic changes: during pregnancy and their clini-

PharmaNote Volume 25, Issue I I October 2009

Volume 25, Issue I I October 2009

PharmaNote

* *

cal relevance. Cin Pharmacokinet 1997;33:328-
43.
4. Anderson GD. Pregnancy-induced changes in
pharmacokinetics: a mechanistic-based approach.
C/in Pharmacokinet 2005;44 (10):989-1008.
5. Allegaert K, van Mieghem T, Verbesselt R, et al.
Cefazolin pharmacokinetics in maternal plasma
and amniotic fluid during pregnancy. Am J Ob-
stet Gynecol 2009;200:170.el-170.e7.
6. Anderson GD, Carr DB. Effect of Pregnancy on
the Pharmacokinetics of Antihypertensive Drugs.
Clin Pharmacokinet 2009; 48 (3): 159-168.
7. Dunlop AL, Gardiner PM, Shellhaas CS,
Menard K, McDiarmid MA. The clinical content
of preconception care: the use of medications and
supplements among women of reproductive age.
Am J Obstet Gynecol 2008;199(6 supply 2):S367-
72.
8. Food and Drug Administration: http://
www.fda.gov [accessed May 25 ,2009].
9. Feibus KB. FDA's Proposed Rule for Pregnancy
and Lactation: Improving Maternal Child Health
Through Well-Informed Medicine Use. J Med
Toxicol 2008;4(4):284-8.
10. Proposed Pregnancy labeling: http://
www.fda.gov/cder/regulatory/
pregnancy labeling/default.htm [accessed May
25, 2009].
11. American Academy of Pediatrics: Policy http://
aappolicy.aappublications.org/cgi/content/full/
pediatrics; 115/2/496 [accessed May 28, 2009].
12. Proposed Pregnancy Labeling: http://
www.fda.gov/cder/regulatory/
pregnancy_labeling/default.htm [accessed May
25, 2009].
13. Fictitious Example of proposed Labeling: http://
www.fda.gov/downloads/Drugs/
DevelopmentApprovalProcess/
DevelopmentResources/Labeling/ucm093313.pdf
[accessed June 11, 2009].

,

Index for Volume 24 (Oct 2008 Sep 2009)

Topic

A-B-C-D
Antiepileptics: 2nd Gen Agents

E-F-G-H-I-J
Gestational Diabetes
Huntington's Disease
Hyperuricemia & Gout

K-L-M-N
Milnacipran

O-P-Q-R
Probiotics
RAAS Inhibitors & AF

S
Smoking Cessation
Statins: Unapproved Uses
Symbyax

T-U-V-W-X-Y-Z
Zoledronic Acid
Zygomycosis

Issue (Page)

Oct 2008 (01)

May 2009 (01)
Feb 2009 (01)
Apr 2009 (01)

July 2009 (01)

Nov 2008 (01)
Sept 2009 (01)

Dec 2008 (01)
June 2009 (01)
Aug 2009 (01)

Mar 2009 (01)
Jan 2009 (01)

PhraoeVoue2,Isu ctbr20

The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacotherapy and Translational
Research
University of Florida

John G. Gums Editor
PharmD, FCCP

R. Whit Curry, MD Associate Editor

Steven M. Smith Assistant Editor
PharmD

vwwww wwww yww I

Volume 25, Issue I i October 2009

PharmaNote