Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00018
 Material Information
Title: PharmaNote
Series Title: PharmaNote
Physical Description: Serial
Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: December 2003
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Bibliographic ID: UF00087345
Volume ID: VID00018
Source Institution: University of Florida
Rights Management: All rights reserved by the source institution and holding location.


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Christina N. Cao, Pharm.D. Candidate

Oral contraceptive (OC) agents are highly
reliable and effective methods of contraception.
Over 100 million women worldwide, and 12 mil-
lion women in the United States use oral OC agents
to prevent unwanted pregnancies. Most of the tra-
ditional OC regimens consist of a 28-day cycle
with 21 days of active pills followed by either a
pill-free week or a week of inactive pill use.2'3 This
cyclic 28-day regimen induces withdrawal bleeding
and mimics monthly menstruation.2'3 However, the
belief that a monthly period is normal and healthy
for women using contraception is being challenged.
Studies have suggested that extending the
use of active hormones continuously over several
cycles has offered a number of positive outcomes
from personal convenience to health benefits. A
survey of Dutch women found that the majority
would prefer an OC that eliminated menses com-
pletely or reduced the frequency to less than once a
month.5 Menstruation-related problems including
menorrhagia, anemia, dysmenorrhea, endometrio-
sis, and menstrual headache may improve with an
extended cycle OC regimen as well.6
Seasonale is a 91-day extended cycle regi-
men OC that can be taken continuously for 84 days
followed by 7 days of placebo. Each Seasonale

tablet consists of 30 mg ethinyl estradiol (EE) and
150 mg levonorgestrel (LNG), a synthetic progesto-
gen. Seasonale was evaluated at 47 study sites
throughout the United States and has shown to re-
duce the number of annual menstrual cycles from
the current norm of 13 to 14 per year to only four
per year.4 In September 2003, Barr Laboratories re-
ceived FDA approval to market Seasonale in the
U.S. This article will discuss the efficacy, safety,
and tolerability of EE/LNG-84.

Pharmacology and Pharmacokinetics
The primary action of the combination oral
contraceptive is to suppress the hypothalamic-
pituitary system, decreasing the secretion of gonad-
otropin-releasing hormone (GnRH)7 resulting in the
inhibition of ovulation. In addition, other modes of
action include changes in the cervical mucus, thus
preventing penetration of sperm into the uterus and
changes in the endometrium, which reduces the
likelihood of implantation.
The absolute bioavailability of EE/LNG-84
in humans has not been determined. However, stud-
ies have shown that following oral administration
in the third cycle of use, levonorgestrel is approxi-
mately 100% bioavailable and is not subject to
first-pass metabolism. Levonorgestrel is highly pro-
tein-bound, primarily to albumin and sex hormone-



I -rFi

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Volume 19, Issue 3 December 2003

Table 1. Reasons for discontinuation of contraceptive therapy3

Reason Extended cycle regimen Conventional regimen
N (%) N (%)
Adverse event 68 (14.9) 22 (9.7)
Patient decision 47 (10.3) 7 (3.1)
Lost of follow-up 39 (8.6) 21(9.3)
Other/unknown 31(6.8) 15 (6.6)
Total 185 (40.6) 65 (28.8)
N=number of patients.
Total number of patients 456. Total number of patients 226. lIncludes noncompliant, pregnant, investigator discretion and other/unknown.

binding globulin (SHBG). Ethinyl estradiol is rap-
idly and almost completely absorbed from the GI
tract, but after first-pass metabolism at the gut mu-
cosa and liver, the bioavailability of EE is approxi-
mately 43%. Ethinyl estradiol is highly but non-
specifically bound to albumin. The effect of food
on the rate and extent of absorption of LNG and EE
following oral administration has not been evalu-
Ethinyl estradiol is primarily metabolized in
the liver via CYP3A4 while sulfation is the major
metabolic pathway for LNG. Ethinyl estradiol is
excreted in the urine and feces and it undergoes en-
terohepatic recirculation. The terminal elimination
half-life of EE is about 16 hours after a single dose
of EE/LNG-84. Whereas about 45% of LNG and its
metabolites are excreted in the urine and about 32%
are excreted in feces. The terminal elimination
half-life of LNG after a single dose of EE/LNG-84
is about 30 hours.7

Clinical Trials
Anderson and Hait3 compared the 91-day
extended cycle OC Seasonale (30 ptg EE/150 tpg
LNG) to the 28-day conventional OC Nordette-28
(30 ptg EE/150 ptg LNG). This one-year, parallel,
multicenter, open-label trial randomized a total of
682 sexually active women (ages 18-40) of child-
bearing potential to EE/LNG-84 or Nordette-28
and was designed to assess the efficacy, safety, and
tolerability of EE/LNG-84. Over half of the pa-
tients in the study were continuous OC users
(60%), 30% had a history of prior OC use, and
about 10% had no prior history of OC use.
Bleeding, increased weight, mood swings,
and acne were reported as the most common ad-
verse events. Both treatment groups reported high
compliance rates (>93%) with 22 (4.8%) EE/LNG-

84 patients and nine (4.0%) Nordette-28 patients
discontinuing the study due to noncompliance. Af-
ter one year of therapy, 59.4% of patients (271/456)
in the extended cycle regimen (EE/LNG-84) and
71.2% (161/226) of patients in the conventional
regimen (Nordette-28) completed the study. Ad-
verse events, individual patient decision and "loss
to follow-up" were the most common reasons for
early discontinuation (Table 1).
The median number of days of withdrawal
bleeding was similar in both treatment groups on a
per-cycle basis, and the median percent of sched-
uled withdrawal bleeding and/or spotting and
bleeding-only days was similar in both treatment
groups as well. Among patients treated with the ex-
tended cycle regimen, more than half of the total
number of days were attributed to spotting. The
median observed total number of days (based on a
possible 364 days) of reported bleeding and/or
spotting for all patients enrolled in the study was 35
for the extended cycle regimen and 53 for the con-
ventional regimen (Table 2). As expected, extended
cycle regimen patients initially experienced more
breakthrough bleeding and/or spotting and bleed-
ing-only than did patients treated with the conven-
tional regimen, but the breakthrough bleeding was
comparable in the two treatment groups by the last
extended cycle (cycle 4).

Dosing and Administration
Patients should receive one active tablet of
EE/LNG-84 once daily for 84 days, followed by a
period of 7 days of inactive tablets to allow with-
drawal bleeding to occur. It must be taken exactly
as directed to achieve maximum contraceptive ef-
fectiveness and should be initiated on the first Sun-
day after the onset of menstruation. If it is initiated
at any other time during the cycle, the patient must

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Volume 19, Issue 3 December 2003

Table 2. Results of reports of observed days of bleeding and/or spotting versus bleeding alone3

Results Bleeding/Spotting Bleeding Only
Mean (SD) Median Mean (SD) Median
Total observed number of days
Extended cycle regimen (364 possible days) 48.2(44.0) 35.0 22.7(22.8) 16.0
Conventional regimen (364 possible days) 50.8 (27.0) 53.0 37.0 (19.6) 39.5

Scheduled withdrawal bleeding
Extended cycle regimen (28 possible days) 10.6 (8.2) 10.0 7.9 (6.6) 7.0
Conventional regimen (91 possible days) 32.4 (18.2) 36.0 27.0 (16.3) 29.0

Unscheduled (breakthrough) bleeding
Extended cycle regimen (336 possible days) 37.6 (38.8) 26.0 14.8 (19.1) 7.0
Conventional regimen (273 possible days) 18.3 (17.2) 13.0 9.9 (11.9) 5.5
SD standard deviation

use an alternative non-hormonal method to protect
herself from getting pregnant until she has taken the
active product for 7 consecutive days.
If spotting or breakthrough bleeding occurs,
the patient should continue on the same regimen
since this event might be transient. If the bleeding
is persistent or prolonged, the patient is advised to
consult her health care provider. Missing pills can
also cause spotting or light bleeding. Any time a
patient misses two or more active tablets, she
should use another method of non-hormonal back-
up contraception until she has taken an active tablet
daily for 7 consecutive days. The risk of pregnancy
increases with each active tablet that is missed.7

Toxicity and Safety
The risks of using EE/LNG-84 are similar
to the risks of other conventional oral contracep-
tives including an increased risk of venous throm-
boembolism, heart attack, and stroke. Based on the
results of SEA 301 trial, the incidence of adverse
events is similar across the treatment groups. The
most common adverse events reported were those
associated with sinus and respiratory tract infection,
headache and "unacceptable" bleeding including
intermenstrual bleeding and/or spotting (Table 3).
The incidence of headache was lower in the ex-
tended cycle regimen than in the conventional regi-
men patients (21% vs. 28%), but higher rates of
bleeding-reported events were noted in extended
cycle regimen subjects compared to conventional
regimen subjects (12% vs. 3%). There were no sig-
nificant differences with changes in triglycerides

and low-density lipoprotein cholesterol between the
two treatment groups as well as changes in other
laboratory values, body weight, vital signs (systolic
and diastolic blood pressure, heart rate or tempera-
ture) from baseline to end of study. There were
three cases of serious adverse events reported in-
cluding a pulmonary embolism (PE) event in the
extended-cycle regimen and cholecystitis, and an
exacerbation of preexisting depression in the con-
ventional regimen.3

The retail costs for one EE/LNG pack (3
month supply) and two EE/LNG packs (6 months
supply) are listed in Table 4.

Seasonale is the first extended regimen OC
agent approved in the U.S and represents a change
in the paradigm of OC therapy. It contains a combi-
nation of ethinyl estradiol and levonorgestrel and
appears to be as safe and effective as conventional
OC pills. Seasonale may help prevent anemia and

Table 4. Cost comparison of EE/LNG-849
Pharmacy 3-month supply 6 months supply
(1 pack) (2 packs)
Retail (chain) $111.69 $216.69
Internet $142.00 $ 275.00
Mean Price $126.85 $245.85

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Volume 19, Issue 3 December 2003

Table 3. Percent of subjects with intermenstrual bleeding and/or spotting3

Regimen Subjects with Intermenstrual Bleeding/Spotting*
= 7 days = 20 days
Cycle 1 (N=385) 65% 35%
Cycle 4 (N=261) 42% 15%
28-day regimen
Cycles 1-4 (N=194) 38% 6%
Cycles 10-13 (N=158) 39% 4%
*Based on spotting and/or bleeding on days 1-84 of a 91 day cycle in the Seasonale subjects and days 1-21 of a 28 day cycle over 4 cycles in the 28-day dosing

endometriosis, a common cause of pelvic pain and
infertility, by decreasing the frequency of menstrual
cycles. However, Seasonale users may experience
a higher incidence of break-through bleeding than
women taking conventional OC agents. Short-term
studies have shown that extending the menstrual
cycle to 91 days has no negative impact on the
quality of life patients. Nevertheless, the long-term
effects are still unknown. Seasonale appears to be
a safe and effective OC regimen allowing women
the option for fewer menstrual periods.

1. Smallwood GH, Meador ML, et al. Efficacy and safety of
a transdermal contraceptive system. Am J Obstet Gynecol
2001;98: 799-805.
2. Anderson FD. The safety and efficacy of Seasonale a
novel 91-day extended oral contraceptive regimen. Obstet
Gynecol 2002; 99(suppl):26S.
3. Anderson FD, Hait H. The Seasonale-301 Study Group: A
multicenter, randomized study of an extended cycle oral
contraceptive. Contraception 2003 (68): 89-96.
4. FDA Approves Seasonale Oral Contraceptive. Available
at URL: http://www.fda.gov/bbs/topics/ANSWERS/2003/
5. de Tonkelaar I, Oddens BJ. Preferred frequency and char-
acteristics of menstrual bleeding in relation to reproductive
status, oral contraceptive use, and hormone replacement
therapy use. Contraception 1999; 59:357.
6. Miller L, and Notter KM. Menstrual reduction with ex-
tended use of combination oral contraceptive pills: Ran-
domized controlled trial. Am J Obstet Gynecol 2001;98:
7. Seasonale Prescribing Information. Available at URL:
http://www. seasonale.com/pdfs/
Seasonale prescribing info.pdf
8. Seasonale Birth Control Pill Prescription Pricing Infor-
mation. Available at URL: http://www.bcmethods.com/.


Alfuzosin (UroxatralTM) is a selective al-
antagonist approved for the treatment of
benign prostatic hyperplasia (BPH). The
recommended dose is one 10-mg extended-
release tablet given by mouth once daily. It
should be used with caution in patients
taking drugs that can inhibit or induce the
cytochrome P450 3A4 isozyme and drugs
which prolong the QT interval. Common
adverse reactions include postural
hypotension, dizziness, headache, fatigue, GI
upset, and impotence.

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

John G. Gums Editor

R. Whit Curry, M.D. Associate Editor

John M. Tovar Assistant Editor

Pha rma Note Volume 19, Issue 3 December 2003


Volume 19, Issue 3 December 2003

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