Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00049
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Title: PharmaNote
Series Title: PharmaNote
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Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: February 2007
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Rong Wang, Pharm.D. Candidate

Digoxin may be the oldest drug in cardiovas-
cular medicine.' In 1875, Sir William Withering pub-
lished his famous paper on the use of foxglove.2
Withering reported the use of a preparation of fox-
glove leaves to treat "dropsy".3 Digoxin is the active
ingredient in the extract of foxglove leaves. Digoxin
has played an important role in treating heart failure
and arrhythmias for over 100 years since Withering's
findings. Digoxin is a member of a group of drugs
known as cardiac glycosides which have in common
some specific effects on the myocardium. Digoxin
has been used in the treatment of certain cardiac dis-
orders for many years and labeled for use in chonic
heart failure (CHF), atrial fibrillation, atrial flutter,
and paroxysmal atrial tachycardia. Digoxin is avail-
able for oral and intravenous administration. The first
commercially available digoxin product was ap-
proved by the FDA in 1952. Digitek, Lanoxin,
Lanoxincaps and Lanoxin pediatric are the brand
names of digoxin.4Digoxin was approved for treat-
ing heart failure in 1998 by FDA on the basis of the
PROVED, RADIANCE and DIG clinical trials.1 The
neurohormonal hypothesis in the pathophysiology of
heart failure increases use of medications which
block the excessive neurohormornal activation such
as ACEI, beta-blockers, ARBs and aldosterone an-
tagonists.5-7 Improved survival in patients with heart
failure using angiotensin-converting enzyme inhibi-

tors (ACEI)8'12, angiotensin receptor blockers (ARB)
13,14, beta blockers15'8 and aldosterone antagonists19
has been published. The controversy of digoxin use
in patients with heart failure was ignited when the
DIG trial showed no mortality improvement even
though there was a decrease in hospitalization rates.20
Although digoxin use is declining, there has not been
a similar decrease in cases of digoxin toxicity.21 This
paper intends to discuss the pharmacologic effects,
pharmacokinetic characteristics, and toxicity of di-
goxin and some key clinical trials regarding its use in
heart failure patients.

Effects of Digoxin
The pharmacologic actions of digoxin re-
mained obscure for a long time. Digoxin was first
considered to have diuretic properties. In 1938, Cat-
tle and Gold found that digoxin has direct inotropic
effects and this became the accepted mechanism of
action. However, recognition of digoxin's effect has
changed drastically with the enhanced understanding
of the pathophysiology of heart failure.22 Digoxin has
multiple pharmacologic effects in addition to its
positive inotropic function.



ll ^ I




Volume 22, Issue 5 February 2007


Positive Inotropic Effect
Digoxin reversibly binds to and inhibits the
alpha subunit of sodium-potassium ATPase which
pumps sodium out and potassium into cells. Thus,
transmembrane sodium gradient is reduced. Since a
low intracellular sodium concentration drives the ac-
tion of the sodium-calcium exchanger, by inhibiting
sodium-potassium ATPase, digoxin indirectly inhibits
the action of the sodium-calcium exchanger. This
leads to higher intracellular calcium, which increases
myocardium contractility.22 Based upon this mecha-
nism, digoxin should benefit patients with systolic
heart failure characterized by impaired ventricular

Neurohormonal Effect
Previous studies demonstrated that digoxin
significantly decreased serum norepinephrine, renin
and aldosterone concentration in heart failure pa-
tients.23 24 These effects are beneficial to heart failure
patients in whom neurohormonal activation is fre-
quently present.

Autonomic Effect
Chronic heart failure is characterized by in-
creased sympathetic activity and decreased parasym-
pathetic activity.25 Long term use of digoxin sensi-
tizes cardiac and aortic baroreceptors.26'27 Along with
decreased norepinephrine, sensitized baroreceptors
lead to decreased sympathetic tone.2830 In addition,
digoxin increases parasympathetic tone.31

Diuretic Effect
Digoxin inhibits sodium-potassium ATPase in
the kidney which leads to inhibition of sodium reab-
sorption. Digoxin indirectly improves renal perfusion
by increasing cardiac contractility.32' 33

Electrophysiological Effect
Digoxin has vagomimetic action on the si-
noatrial (SA) and atrioventricular (AV) nodes. It
slows heart rate and decreases conduction velocity
through the AV node.34

Pharmacokinetics of digoxin
Oral digoxin is absorbed by passive diffusion
in the upper small intestine.35 Food may delay the
absorption of digoxin, but does not affect the extent
of absorption. The bioavailability of digoxin varies
slightly in terms of formulation. The bioavailabilty of

the elixir is 75-85%, the tablet is 70-80%, while the
capsule is 90-100%.35 The distribution phase is 6-8
hours long. Approximately 30% of digoxin is protein
bound. Digoxin is concentrated in tissue and there-
fore has large volume of distribution. The volume of
distribution (Vd) of digoxin is 6-7L/Kg in patients
with normal renal function.35 But age, renal impair-
ment, concomitant drug use and some disease states
could affect the Vd of digoxin, which in turn alters
the effects and toxicity of digoxin (Table 1). Only
16% of a digoxin dose is metabolized. The end me-
tabolites, which include 3 1-digoxigenin, 3-keto-
digoxigenin, and their glucuronide and sulfate conju-
gates, are polar in nature and are postulated to be
formed via hydrolysis, oxidation, and conjugation.
Digoxin is not known to induce or inhibit the cyto-
chrome P-450 system.36 In about 10% of population,
gut bacteria may convert up to 40% of oral digoxin
dose to inactive product. As a result, some antibiotics
may affect the serum concentration of digoxin by
inactivating the gut bacteria. Fifty to seventy percent
of a digoxin dose is excreted unchanged in the urine.
The elimination half-life is dependent on age, renal
and cardiac function. Cardiac disease, advanced age
and kidney disease are associated with diminished
creatinine clearance and with decreased renal clear-
ance of digoxin. Digoxin has a half-life of 38-48
hours in patients with normal renal function and ex-
tends to 4-6 days when patients have compromised
renal function.35
Digoxin interacts with many medications
through different mechanisms. Some medications,
such as magnesium and potassium-depleting diuret-
ics, can precipitate digoxin toxicity by decreasing
serum potassium. Beta-adrenergic blockers or non-
dihydropyridine calcium channel blockers may have
an additive effect on heart rate when used in combi-

Table 1. Volume of distribution of digoxin in different pa-
tient groups
Patient groups Vd (L/Kg)
Adults with normal renal function 6-7
Neonates 7.5-10
Children 16
Adults with chronic renal failure 4-6
Hyperthyroidism T Vd
1 distribution to the
Hyperkalemia and Hyponatremia distribution to the
heart and muscle
Hypokala distribution to the
heart and muscle
Concomitant quinidine therapy I Vd

PharmaNote Volume 22, Issue 5 February 2007

Volume 22, Issue 5 February 2007


nation with digoxin. Some antibiotics such as mac-
rolides and tetracyclines increase digoxin serum lev-
els by inhibiting conversion to inactive product by
gut bacteria. Many medications affect digoxin serum
level by disturbing its absorption. Rifampin can de-
crease digoxin serum levels by increasing its non-
renal clearance. Amiodarone increases digoxin serum
levels. When starting amiodarone in patients taking
digoxin, an immediate reduction of digoxin dose by
50% is warranted. Quinidine displaces digoxin from
tissue binding sites and inhibits its renal clearance,
which leads to increased digoxin concentration.37
There are also many medications which affect di-
goxin concentration with undefined mechanisms
(Table 2).35,36
When dosing digoxin, there are several fac-
tors to be considered. Dose should be calculated
based upon lean body weight. Age, renal function,
diseases and concomitant drug use are all likely to
change the pharmacokinetic and pharmacodynamic
profiles of digoxin (Table 3).38 Establishing the opti-
mal dose of digoxin is very important since digoxin
has a narrow therapeutic range. The digoxin concen-
tration of 0.125 mg 0.25 mg/day is often used to
achieve a serum concentration of 0.5-1.0 ng/ml in
patients with heart failure.1 Serum concentration
should be monitored due to its high risk of toxicity.
Since the half-life of digoxin is about 2 days in pa-
tients with normal renal function, the steady state
concentration is obtained after approximately 10
days of initiation. Any serum concentration obtained
sooner than 8 hours after the last dose is uninter-
pretable because this time period reflects the distri-

bution phase of digoxin, which is not appropriate for
clinical decision making.1 If steady state concentra-
tion is therapeutic, frequent serum concentration
monitoring is unnecessary unless signs and symp-
toms of toxicity are suspected, the patient's renal
function changes, or an interacting drug is added or

Adverse Reactions of Digoxin
Among all digoxin adverse reactions, cardiac
adverse events account for 50%, gastrointestinal dis-
turbances for about 25%, and CNS and other toxicity
for the remaining 25%.36 Cardiac events include tar-
chycardia, bradycardia, AV block and ventricular fib-
rillation. Gastrointestinal manifestations include nau-
sea, vomiting, diarrhea and anorexia. CNS reactions
include visual disturbances, hallucination, headache,
dizziness and confusion. Gynecomastia, thrombocy-
topenia and skin reactions have also been observed,
but incidences are rare.36

Treatment of Digoxin intoxication
When toxicity of digoxin is suspected, a valid
serum concentration should be measured to confirm
toxicity. If the elevated concentration is thought to
cause toxicity, digoxin should be discontinued. If hy-
pokalemia or hypomagnesemia are identified, the
electrolyte disturbances should be corrected. Patients
with sympatomatic bradyarrhythmias should be
treated with atropine.' Patients with life-threatening
ventricular arrhythmias or heart block should be ad-
ministered Digibind to reverse toxicity. Digibind is
purified antidigoxin Fab fragments from digoxin-

Table 2. Medication interactions with digoxin
Increased effects or toxicity of digoxin Decreased effects of digoxin
Mechanism Medications Mechanism Medications
Precipitate hypokalemia HCTZ, loop diuretics Interfere with small intestine Antacids, kaolin-
Additive effects on HR, AV Beta-adrenergic blockers, absorption pectin, sulfasalazine, neomy-
blockade DHP-calcium channel block- cin, cholestyramine, certain
ers anticancer drugs, metoclopra-
mide, and food
Decreased conversion to inac- Macrolides, tetracyclines Increase non-renal clearance Rifampin
tive products by gut bacteria
Decrease GI motility Propantheline, diphenoxylate
Increase risk of arrhythmia Succinylcholine Increase metabolism rate Synthroid in patients with
Reduce renal clearance or vol- Quinidine, verapamil, amio- hypothyroidism
ume of distribution darone, propafenone,
indomethacin, itraconazole,
alprazolam, and spironolac-

HR-Heart Rate; AV-Atrium Ventricle; GI-Gastrointestinal; HCTZ-Hydrochlorathiazide; DHP-Dihydropyridine.

PharmaNote Volume 22, Issue 5 February 2007

Table 3. Situations in which digoxin dose requires adjustment.
Situation Dose adjustment
Concomitant use with amiodarone Reduce digoxin dose by 50%
Concomitant use with quinidine Reduce digoxin dose by 33-50%
Clcr 10-50mL/min Administer 25-75% of dose or dose every 36 hours
Clcr <10mL/min Administer 10-25% of dose or dose every 48 hours
ESRD Reduce digoxin dose by 50%
Concomitant use with Synthroid Increase digoxin dose when initiating Synthroid
Switching from oral digoxin (tablets, elixir) to IV digoxin Reduce IV digoxin dose by 20-25%
Clcr creatinine clearance; ESRD end stage renal disease; IV intravenous.

specific antisera. Reinitiation of digoxin may be con-
sidered when the symptoms of toxicity resolve and
the underlying factors are addressed.1, 39

Major Clinical Trials
In spite of its long history in cardiovascular
medicine, the FDA approval of digoxin for treating
heart failure was relatively recent. The approval was
on the basis of several clinical trials: the Prospective
Randomized Study of Ventricular Function and Effi-
cacy of Digoxin (PROVED), Randomized Assess-
ment of Digoxin on Inhibitors of the Angiotensin
Converting Enzyme (RADIANCE), and Digitalis
Investigators Group (DIG). The trials provide com-
pelling evidence in favor of digoxin use in the treat-
ment of symptomatic chronic heart failure.20' 40-41
Prior to these three trials, several controlled
studies conducted in the 1980's demonstrated that
digoxin improved the symptoms and exercise toler-
ance of patients with normal sinus rhythm whose
ventricular systolic function is impaired.4244 Using a
randomized, double-blind, crossover protocol, Lee et
al. found that long-term digoxin therapy is clinically
beneficial in patients with heart failure, unaccompa-
nied by atrial fibrillation, whose symptoms persist
despite diuretic therapy.44 In another randomized,
double-blind, crossover trial, the digoxin treatment
group showed greater improvement in patients with
CHF and normal sinus rhythm regarding dyspnea,
walking test score, ejection fraction and clinical as-
sessment of CHF compared to placebo group.42 A
multicenter, double-blind, placebo-controlled study
was conducted by the Captopril-Digoxin Multicenter
Research Group in 1988. Patients with mild to mod-
erate heart failure received maintenance diuretic
therapy. Captopril significantly improved exercise
time (mean increase, 82 s vs 35 s) and New York

Heart Association class (41% vs 22%) compared to
placebo, while digoxin therapy did not. However,
digoxin treatment achieved greater left ventricular
ejection fraction increase (4.4%) than captopril
(1.8% increase) or placebo (0.9% increase).43
PROVED was a prospective, placebo-
controlled, double-blind digoxin withdrawal trial.
The aim was to determine whether digoxin is effec-
tive in patients with chronic, stable, mild to moderate
heart failure. Patients were in normal sinus rhythm
and received long-term treatment with diuretics and
digoxin. Digoxin withdrawal resulted in worsening
of maximal exercise capacity, an increased incidence
of treatment failure, and decreased time to treatment
failure compared with continuation of digoxin.40
In RADIANCE, patients were receiving not
only diuretic and digoxin, but also and ACE inhibitor
(ACEi)(captopril or enalapril). Similar to PROVED,
patients in RADIANCE had New York Heart Asso-
ciation class II or III heart failure and left ventricular
ejection fractions of 35% or less in normal sinus
rhythm. Digoxin discontinuation was associated with
lower quality of life scores, decreased ejection frac-
tion, and increases in heart rate and body weight. The
digoxin withdrawal group had a 5.9-fold higher risk
of worsening heart failure. In addition, maximal ex-
ercise tolerance and submaximal exercise endurance
were reduced in patients discontinuing digoxin.41
A meta analysis of PROVED and RADI-
ANCE was conducted. Data suggested that worsen-
ing heart failure occurred more often in patients on
an ACEi plus diuretic therapy, digoxin plus diuretic
therapy, or diuretic alone compared to triple therapy
(ACEi, diuretic, and digoxin).45
The DIG trial was a large, international, pla-
cebo-controlled trial that included two sub-studies,
DIG-Main and DIG-Ancillary.20 A total of 7,788 pa-

PharmaNote Volume 22, Issue 5 February 2007

Volume 22, Issue 5 February 2007


Table 4. Baseline characteristics and clinical outcomes of PROVED40, RADIANCE41 and DIG trials.20
Patients baseline or clinical outcomes with digoxin PROVED TRIAL RADIANCE TRIAL DIG TRIAL
ACEI (95%) or
Concomitant therapy Diuretics ACEI and diuretics e ( o
Diuretics (82%)
Treatment Digoxin withdrawal Digoxin withdrawal Add digoxin
Patients NYHA class II-III and NYHA class II-III and NYHA class -
Patients NYHA class I-IV
LVEF <35% LVEF <35%
Duration of study (weeks) 12 12 148
Average Serum Digoxin Level 1.2 1.2 0.9
Incidence of worsening HF Decreased Decreased Decreased
Incidence of hospitalization for HF Decreased Decreased Decreased
Exercise time Increased Increased NA
LVEF Higher Higher NA
Time to treatment failure Increased Increased NA
Body Weight Decreased Decreased NA
Heart Rate Decreased Decreased NA
All cause Mortality NA NA No effect
Mortality due to Heart failure NA NA Slightly decreased

LVEF left ventricular ejection fraction
New York Heart Association (NYHA) Classification:
Class I: patients with no limitation of activities; they suffer no symptoms from ordinary activities.
Class II: patients with slight, mild limitation of activity; they are comfortable with rest or with mild exertion.
Class III: patients with marked limitation of activity; they are comfortable only at rest.
Class IV: patients who should be at complete rest, confined to bed or chair; any physical activity brings discomfort and symptoms occur at rest.

tients were enrolled in the trial, including 6,800 pa- pected digoxin toxicity (11.9% vs 7.9%) and were
tients in the main trial, and 988 in the ancillary trial, hospitalized due to the toxicity (16.5% vs 11.4%)
The DIG-Main study determined the effect of di- compared to the placebo group. The most common
goxin on all-cause mortality in patients with clinical manifestations of digoxin toxicity included ventricu-
heart failure who were in sinus rhythm and whose lar fibrillation, tarchycardia, supraventricular ar-
ejection fraction was less than 45%. The DIG- rhythmia, and second- or third degree atrioventricu-
Ancillary study examined the effect in those with an lar block.20
ejection fraction greater than 45%. Secondary out- In a comprehensive pos-hoc analysis of the
comes evaluated in this large trial included hospitali- DIG trial, the effect of digoxin on outcomes was
zation for worsening heart failure, cardiovascular studied as a function of the serum digoxin concentra-
mortality, deaths due to progressive heart failure and tion (SDC). Lower SDCs (0.5-0.9 ng/ml) were asso-
hospitalizations for all other causes, including di- ciated with reduced all-cause mortality (29.3% vs
goxin toxicity.20 32.9%), cardiovascular mortality (24.1% vs 25.5%)
In the DIG trial, digoxin had no effect on and HF hospitalization compared to placebo (8.8%
overall mortality or cardiovascular mortality. Di- vs 12.1%), whereas high SDCs (> 1.0 ng/ml) were
goxin treatment was associated with a modest reduc- associated with increased risk in all three outcomes
tion in all-cause hospitalizations (6%), substantial (41.7%, 33.2% and 13.6%). Low SDCs did not re-
reductions in HF hospitalizations (27%) and in HF duce all-cause mortality in some subgroups of pa-
mortality or hospitalizations (24%).20 Digoxin was tients, including women or non-white patients, pa-
more beneficial in patients with lower ejection frac- tients not receiving ACE inhibitors, patients with
tions (< 25%), enlarged hearts, and NYHA func- NYHA I or II functional class, or ejection fraction >
tional classifications III or IV.20 With respect to tox- 45%. In this study, predictors of high SDC were
city, more patients in the digoxin group had sus- identified as advanced age, female gender, renal dys-

PharmaNote Volume 22, Issue 5 February 2007

function, use of non-potassium sparing diuretics, and
pulmonary congestion. This study suggested that low
concentration digoxin would be most beneficial in
men with moderate to severe systolic heart failure
receiving ACE inhibitors.38 Table 4 summarizes the
main characteristics and outcomes in the three major

Controversy in Digoxin Trial Cohorts
Women with heart failure tend to be more
symptomatic than men with similar ejection frac-
tions.46 The majority of deaths attributable to heart
failure occur in women.47 Although women made up
22% of the study population1, digoxin did not pro-
vide benefit in women with heart failure. One post-
hoc study suggested that digoxin was associated with
an increased risk of death, death from cardiovascular
causes or death from worsening heart failure in
women. Digoxin had a small impact on reduced hos-
pitalizations for worsening heart failure in women.48
In another post-hoc analysis of DIG trial, female
gender was a risk factor for high serum digoxin con-
centrations and even low SDCs did not decrease
With age, the incidence and prevalence of
heart failure increase substantially. In the DIG trial,
although advanced age is a predictor of higher
SDC38, it is not associated with an increased occur-
rence of digoxin toxicity.48 The findings of reduced
all-cause hospitalizations, reduced HF hospitaliza-
tions and a neutral effect on mortality are consistent
in all age groups.48 Digoxin remains a useful treat-
ment in elderly patients with heart failure. Due to
reduced lean body mass and declining renal function,
a lower dosage of digoxin would be appropriate.

Although digoxin had no effect on mortality
in patients with heart failure, it reduced hospitaliza-
tions. Digoxin remains a useful agent in treating
heart failure. Digoxin could be used as adjunct ther-
apy in patients who still have symptoms while taking
an ACEI or ARB and/or a beta-blocker. Digoxin can
reduce hospitalizations and decrease the risk of death
when dosed at a lower concentration (0.5-0.9 ng/ml).
Digoxin may be more beneficial in patients whom
have lower ejection fractions (< 25%), enlarged
hearts, and are NYHA functional class III or IV.
Women with heart failure seem to have reduced
benefit from digoxin compared to men.


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MC, Jolly MK. Randomized study assessing the effect of
digoxin withdrawal in patients with mild to moderate
chronic congestive heart failure: results of the PROVED
trial. PROVED Investigative Group. J Am Coll Cardiol
1993; 22: 955-62.
41. Packer M, Gheorghiade M, Young JB, Costantini PJ, Ad-
ams KF, Cody RJ, et al. Withdrawal of digoxin from pa-
tients with chronic heart failure treated with angiotensin-
converting-enzyme inhibitors. RADIANCE Study. N Engl
J Med 1993; 329: 1-7.
42. Guyatt GH, Sullivan MJ, Fallen EL, Tihal H, Rideout E,
Halcrow S, et al. A controlled trial of digoxin in congestive
heart failure. Am J Cardiol 1988; 61: 371-5.
43. Comparative effects of therapy with captopril and digoxin
in patients with mild to moderate heart failure. The Capto-
pril-Digoxin Multicenter Research Group. JAMA 1988;
259: 539-44.
44. Lee DC, Johnson RA, Bingham JB, Leahy M, Dinsmore
RE, Goroll AH, et al. Heart failure in outpatients: a ran-
domized trial of digoxin versus placebo. N Engl J Med
1982; 306: 699-705.
45. Young JB, Gheorghiade M, Uretsky BF, Patterson JH, Ad-
ams KF,Jr. Superiority of "triple" drug therapy in heart
failure: insights from the PROVED and RADIANCE trials.
Prospective Randomized Study of Ventricular Function
and Efficacy of Digoxin. Randomized Assessment of Di-
goxin and Inhibitors of Angiotensin-Converting Enzyme. J
Am Coll Cardiol 1998; 32: 686-92.
46. Lindenfeld J, Krause-Steinrauf H, Salerno J. Where are all
the women with heart failure? J Am Coll Cardiol 1997; 30:
47. Rathore SS, Wang Y, Krumholz HM. Sex-based differ-
ences in the effect of digoxin for the treatment of heart
failure. N Engl J Med 2002; 347: 1403-11.
48. Rich MW, McSherry F, Williford WO, Yusuf S, Digitalis
Investigation Group. Effect of age on mortality, hospitali-
zations and response to digoxin in patients with heart fail-
ure: the DIG study. J Am Coll Cardiol 2001; 38: 806-13.

Phrm~oe olme22 sse Fbrar 20

Volume 22, Issue 5 February 2007



Michael Babbitt, PharmD Candidate

More than 10 million American women use
oral contraceptives annually. With over 40 brands
on the market, patients and practitioners have options
when selecting "The Pill" that is right for them.
When choosing an oral contraceptive agent, the goal
is to select a pill that will provide the lowest effec-
tive dose with the least amount of side effects.
While the progestin component of combined oral
contraceptives (COC) varies greatly, the estrogen
component, ethinyl estradiol (EE), is available in es-
sentially two categories: traditional (> 30 mcg/24 hr
EE) or low-dose (< 30 mcg/24 hr EE). Currently
marketed low-dose regimens are displayed in Table
1. The introduction of low-dose estrogen pills has
raised the question of whether they offer any signifi-
cant advantage over traditional pills.
The accepted dose of estrogen has changed
over time. Enovid 10, the first birth control pill,
contained 105 mcg of ethinyl estradiol (EE) equiva-
lent when it was introduced in 1960. Traditional
COC's, similar in dosing to what is used today, were
introduced in 1967 with Ortho-Novum 1/50, which
contained 35 mcg EE equivalent. Low-dose pills,
often thought of as a new concept, actually originate
back to 1973 with Loestrin 1/20, which contained
20 mcg of EE/24 hr.
Despite low-dose and traditional pills being
available for decades, there is continued debate
among practitioners and patients regarding which
dose of EE is "better". This is evident when observ-
ing that in 2005, of the two most commonly pre-
scribed oral contraceptive agents, one is a traditional
pill (Yasmin), the other a low-dose (Ortho Tri-
Cyclen Lo).1 The objective of this article is to com-
pare traditional oral contraceptive pills to low-dose
pills, discussing their respective efficacies and side
effect profiles.

PharmaNote Volume 22, Issue 5 February 2007

Numerous comparative studies have found
that efficacy rates of 20 mcg preparations are similar
to those of 30/35 mcg preparations. The Pearl Index,
an industry standard measure of efficacy that corre-
sponds to number of births per 100 woman years, is
similar for both EE strength preparations, ranging
from 0.2 1.02.2-8 Overall it appears that preg-
nancy is prevented at similar rates with both regi-
mens; however, variation in follicle size has been
For a follicle to reach adequate size for ovu-
lation it must reach a diameter of > 16 mm.9 Folli-
cles > 10 mm are considered "dominant follicles"
and have a greater potential for ovulation.10 Follicu-
lar diameter length has been correlated with the EE
content in COC's. Heusden et al. found that women
taking 20 mcg EE pills had an 18-27% greater pro-
duction rate of dominant follicles compared to
women taking 30 mcg pills.10 A recent study involv-
ing Triphasil (30-40 mcg EE), Alesse (20 mcg
EE), and Ortho Tri-Cyclen (35 mcg EE), found that
the low-dose pill, Alesse, resulted in statistically
significant larger follicle sizes, compared to the other
OC agents, in each of the four cycles studied.11 In
addition, a study of 209 women compared 30 mcg
EE to 20 mcg EE and found follicular development
to be twice as frequent in the 20 mcg EE arm and
concluded that "reducing the dose to 20 mcg is asso-
ciated with a significant increase in follicle size".12
Low-dose pills provide acceptable rates of
contraception, but may increase a women's ability to
produce a dominant follicle. If these regimens are
taken exactly as prescribed, follicle size may not be
as critical and contraception would sustain. Unfortu-
nately, compliance is an existent burden accompany-
ing oral contraceptives that cannot be overlooked.

Compliance is a major concern with all oral
contraceptive agents, with irregular use estimated to
be as high as 60%.13 The 1995 New Survey for
Family Growth reported that 15.5% of COC users
reported missing one pill and another 13.3% reported
missing two or more pills in the past three months.14
Evidence suggests that missing pills adjacent to the
seven day pill-free interval is associated with an in-
creased risk of ovulation regardless of EE dose.15'16
However, more follicular activity has been associ-
ated with a pill-free interval extension of low-dose

Volume 22, Issue 5 February 2007


Table 1. Low-dose oral contraceptives
Product Progestin Component Manufacturer Price/Cycle ($)a
20 mcg ethinyl-estradiol
Levlite (B) 0.1 mg levonorgestrel Berlex 38
Aviane (G) 0.1 mg levonorgestrel Barr 33
Alesse (B) 0.1 mg levonorgestrel Wyeth 38
Lutera (G) 0.1 mg levonorgestrel Watson 27
Lessina (G) 0.1 mg levonorgestrel Barr 33
Loestrin 1/20 FE (B) 1 mg norethindrone acetate Warner Chilcott 55
Microgestin 1/20 FED (G) 1 mg norethindrone acetate Watson 25
Junel 1/20 FE (G) 1 mg norethindrone acetate Barr 28
Yaz (B) 3 mg drospirenone Berlex 50
10/20 meg ethinyl-estradiol
MircetteD (B) 0.15 mg desogestrel Duramed/Organon 42
Kariva (G) 0.15 mg desogestrel Barr 39
25 meg ethinyl-estradiol
Cyclessa (B) 0.1/0.125/0.15 mg desogestrel Barr 43
Ve i cl (G) 0.1/0.125/0.15 mg desogestrel Barr 30
Ortho Tri-Cyclen Lo (B) 0.25/0.215/0.18 mg norgestimate Ortho-McNeil 46
aCosts as of 12/06, taken as average from: drugstore.com and walgreens.com
b (B) = brand; (G) = generic

users.15 In one study, a 10-day pill-free interval re- Therefore, decreased compliance, particularly
sulted in follicles >18 mm in 40% of women on 20 near the pill-free interval, results in increased follicle
mcg EE while the same follicle size was noted in size and therefore increased risk of ovulation and
only 24% of women on 30 mcg EE.17 pregnancy. This risk is increased in women taking
The increased follicular activity after missed low-dose birth control pills compared to traditional
pills adjacent to the pill-free interval among users of pills.
low-dose formulations suggests that the margin of
contraceptive safety, or the "degree of forgiveness," Cycle Control
may be decreased in women using these formula- Lack of cycle control is a major contributor
tions.15 The transient interruption of traditional regi- to patient dissatisfaction and a resultant decrease in
mens in a location other than adjacent to the pill-free compliance.20 Estrogen dose clearly affects cycle
interval appears to be less significant.15 Multiple control, but the severity difference of this effect be-
studies show that missing up to four consecutive pills tween low-dose and traditional formulations is am-
has not resulted in signs of ovulation.18 However, biguous. In addition to estrogen, individual patient
similar studies have not been completed using low- characteristics, progestin dose and type, and the ratio
dose formulations. Due to the limited evidence on of progestin and estrogen doses can all cause signifi-
the result of transient interruptions with low-dose cant variation in cycle control. While inter-
pills, the World Health Organization Selected Prac- individual characteristics may not be easily repli-
tice Recommendations for Contraceptive Use cated in a clinical trial, progestin formulations can.
(WHOSPR) updated its recommendations to include Unfortunately, there is limited comparative data in-
a more cautious approach when 20 mcg EE or less volving different estrogen strengths with similar pro-
pills have been missed.19 These recommendations are gestin types and doses.
summarized in Table 2. Akerlund et al. compared 150 mcg of deso-
gestrel with both 20 mcg EE and 30 mcg EE. In the

PharmaNote Volume 22, Issue 5 February 2007

Table 2: Advice for women missing OC'sa

Missed ONE or TWO 30-35 mcg/24 hr pill She should take a pill as soon as possible and then continue
or taking pills daily, one each day.
Missed ONE 20 mcg/ 24 hr pill She does not need any additional contraceptive protection

She should take a pill as soon as possible and then continue
taking pills daily, one each day.
She should also use condoms or abstain from sex until she
has taken pills for 7 days in a row.
Missed THREE or more 30-35 mcg/ 24 hr pills If she missed the pills in the third week, she should finish
the pills in her current pack and start a new pack the next
Missed TWO or more 20 mcg/24 hr pills day. She should not have a pill-free interval. If the pill-free
interval is avoided in this way, she does not need to use
emergency contraception.
If she missed the pills in the first week (effectively extend-
ing the pill-free interval) and had unprotected sex (in week
1 or in the pill-free interval), she may wish to consider the
use of emergency contraception.

aAdapted from The World Health Organization SelectedPractice Recommendationsfor Contraceptive Use (WHOSPR)19

8,573 cycles analyzed, significantly more irregular
bleeding patterns and amenorrhea occurred with the
low estrogen formulation.21 Another study, which
compared 75 mcg of gestodene with both 20 mcg EE
and 30 mcg EE, found significantly more spotting
among low-dose users, with the largest difference,
22.6% versus 13.8%, occurring during the first cycle
of use.22
Studies involving different progestin compo-
nents have provided similar results. A 2001 study
comparing two low-dose pills with different pro-
gestin components and a reference pill of 30 mcg
EE, found that the two low-dose pills resulted in con-
siderably more episodes of spotting and break-
through bleeding than the 30 mcg EE pill.20 The inci-
dence of breakthrough bleeding during the third cy-
cle for the three regimens was 18.4% (EE/LNG
20/100), 39.8% (EE/NET 20/500), and 2.5% (EE/
LNG 30/150).20 In a study comparing 20 mcg EE
and norethindrone acetate 1 mg to 30 mcg EE and
levonorgestrel 150 mcg, the low-dose pill fared
worse in frequent, infrequent, and prolonged bleed-
ing incidences.23
All of these trials show low-dose oral contra-
ceptives to have poorer irregular bleeding outcomes
than their traditional dose counterparts. However,
different progestin doses and types, the ratio of pro-
gestin to estrogen doses, small sample sizes, and/or
varying criteria to define bleeding outcomes con-

found most of the comparative trials involving these
regimens. 24
While a clear picture of the difference be-
tween low-dose and traditional pills' relationship to
irregular bleeding patterns is not available, it is as-
sumed that low-dose regimens may provide less cy-
cle control for some patients.

Side Effects
Side effect rates raise significant concerns for
oral contraceptive users. Estrogenic side effects,
such as breast tenderness and nausea, can affect pa-
tient satisfaction and compliance. Breast tenderness
and nausea are dose-dependent, relating directly to
the amount of estrogen each pill contains.25 A study
comparing Alesse (20 mcg EE), Mircette (20 mcg
EE), and Ortho Tri-Cyclen (35 mcg EE) found that
women using the traditional dose pill experienced
breast tenderness, nausea, and bloating at an inci-
dence rate 50% higher than their low-dose counter-
Unfortunately, the clear benefit involving a
decrease in side effect incidences with low-dose pills
stops there. Oral contraceptive use is associated
with an increased risk of venous thromboembolism
(VTE), stroke, hypertension, and breast cancer.
These results may be a product of estrogen dose, pro-
gestin dose and type, and inter-individual character-
istics. Long-term studies comparing traditional and
low-dose regimens with these endpoints have not


Volume 22, Issue 5 February 2007


been completed. Some studies have compared inter-
mediate markers (i.e. coagulation factors, renin sub-
strates, etc.) and found low-dose pills to have more
favorable profiles.24 These studies are preliminary at
best, and not predictors of clinical events. Whether a
further decrease in estrogen from traditional regi-
mens results in a decrease in these adverse events
remains to be seen. However, it can be reasonably
hypothesized that a decrease in estrogen will not re-
sult in an increase in these outcomes.

Selecting an Appropriate Regimen
The "best" regimen is ideally the one that is
the most effective with the least amount of side ef-
fects. However, all pills are not created equal for all
women, and the needs and concerns of each patient
should be fully assessed before determining the most
appropriate regimen. For a woman confident with
regard to compliance and no history of cycle control
problems, a low-dose pill is an acceptable choice.22
For a woman whose primary concern is contracep-
tion and who may have issues with compliance, a
traditional dose pill may be a better option. A
woman with a history of cycle control problems or
who experienced such problems with a 20 EE pill,
would likely benefit from a 30 mcg EE pill with
similar type and strength of progestin.22
Contraception may not be the most important
feature of oral contraceptives for some women.
Non-contraceptive benefits of COC's include re-
duced acne and hirsutism, reduced pre-menstrual
symptoms, decreased incidence of endometrial and
ovarian cancers, and reduced incidence of benign
breast disease.26 Women primarily interested in non-
contraceptive benefits may choose to start with a
low-dose formulation.

Combined oral contraceptives have been
available for nearly half a century. Today there are
over 40 brands on the market. Low-dose pills were
introduced over 30 years ago and yet their niche in
the marketplace remains ambiguous. Although more
research is necessary to determine a difference be-
tween traditional and low-dose oral contraceptives,
certain facts are becoming evident. Low-dose pills
are associated with similar efficacy rates with proper
compliance, but an increase in cycle control and ir-
regular bleeding patterns. In addition, certain side
effect rates (breast tenderness, nausea, bloating) are

decreased with low-dose pills, while the effect of de-
creased estrogen on other negative outcomes (VTE,
stroke, hypertension, etc.) remains unclear. With no
guidelines currently available, the most appropriate
regimen varies with each patient and should be deter-
mined on a case-by-case basis.

1. http://www.drugtopics.com/drugtopics/data/
articlestandard/drugtopics/102006/3 11294/
article.pdf Accessed: 11/2006
2. Rosenberg MJ, Meyers A, Roy V. Efficacy, cycle
control, and side effects of low- and lower-dose
oral contraceptives: a randomized trial of 20[tg
and 35[g estrogen preparations. Contraception.
3. Reisman H, Martin D, Gast MJ. A multicenter
randomized comparison of cycle control and
laboratory findings with oral contraceptive agents
containing 100 microg levonorgestrel with 20
microg ethinyl estradiol or triphasic norethin-
drone with ethinyl estradiol. Am J Obstet Gyne-
col. 1999;181(5 pt 2):45-52.
4. Dando TM and Curran MP. Low dose ethinyles-
tradiol and levonorgestrel. Drugs 2005; 65 (16):
5. Bassol, et al. A 13-month multicenter clinical
experience of a low-dose monophasic oral con-
traceptive containing 20 microg ethinylestradiol
and 75 microg gestodene in Latin American
women. Contraception. 2003 May;67(5):367-72
6. Archer, et al. Efficacy and safety of a low-dose
monophasic combination oral contraceptive con-
taining 100 microg levonorgestrel and 20 microg
ethinyl estradiol (Alesse). North american
Levonorgestrel Study Group (NALSG). Am J
Obstet Gynecol. 1999 Nov;181(5 Pt 2):39-44.
7. The Mircette Study Group. An open-label, multi-
center, noncomparative safety and efficacy study
of Mircette, a low-dose estrogen-progestin oral
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8. Bannemerschult R, Hanker JP, Wunsch C, Fox P,
Albring M, Brill K. A multicenter, uncontrolled
clinical investigation of the contraceptive effi-
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Volume 22, Issue 5 February 2007


9. Elomaa K and Lahteenmaki P. Ovulatory Poten-
tial of Prevovulatory Sized Follicles During Oral
Contraceptive Treatment. Contraception 1999:
(60) 275-297
10. van Heusden AM and Fauser B. Activity of the
Pituitary-Ovarian Axis in the Pill-Free Interval
During Use of Low-Dose Combined Oral
Contraceptives. Contraception 1999 (59) 237-
11. Ortho EvraTM/EvraTM versus oral contraceptives:
follicular development and ovulation in normal
cycles and after an intentional dosing error. Fer-
tility and Sterility 2003; 80: 34-42.
12. Teichmann AT, et al. The influence of the dose
of ethinylestradiol in oral contraceptives on folli-
cle growth. Gynecol Endocrinol. 1995 Dec;9
13. Potter L, Oakley D, Leon-Wong E, Canamar R.
Measuring compliance among oral contraceptive
users. Fam Plann Perspect. 1996;28:154- 8.
14. Abma JC, Chandra A, Mosher WD, Peterson LS,
Piccinino LJ. Fertility, family planning, and
women's health: new data from the 1995 Na-
tional Survey of Family Growth. Vital Health
Stat 1997;23: 1- 114.
15. Creinin MD, et al. The effect of extending the
pill-free interval on follicular activity: triphasic
norgestimate/35 mcg ethinyl estradiol versus mo-
nophasic levonorgestrel/20 mcg ethinyl estradiol.
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16. Hamilton CJCM and Hoogland HJ. Longitudinal
ultrasonographic study of the ovarian suppressive
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17. Elomaa K, Rolland R, Brosens I, et al. Omitting
the first oral contraceptive pills of the cycle does
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18. Curtis KM., et al. Effective use of hormonal
contraceptives Part I: Combined oral contracep-
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19. World Health Organization. Selected Practice
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[update] http://www.who.int/reproductive-health/
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20. Endrikat J., et al. Multicenter, comparative study
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The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida

John G. Gums Editor

R. Whit Curry, M.D. Associate Editor

Shawn Anderson Assistant Editor



Volume 22, Issue 5 February 2007


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