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HUMAN PAPILLOMAVIRUS
(HPV) AND CERVICAL CANCER:
IMPLICATIONS OF HPV
VACCINES

Patricia R. Louzon, Pharm.D. Candidate


On June 8, 2006 the FDA announced ap-
proval of Gardasil guard a sil), Quadrivalent Hu-
man Papillomavirus (HPV) recombinant vaccine
manufactured by Merck. This vaccine, along with
Cervarix (sar var' iks) which is in Phase III clinical
trials by GlaxoSmithKline, has implications for the
prevention of cervical cancer, genital warts and pre-
cancerous or dysplastic lesions. This article will dis-
cuss HPV and its' relation to cervical cancer, as well
as the efficacy, duration of protection and place in
practice of the HPV vaccine.

Cervical Cancer
According to the American Cancer Society, it
is estimated that in 2006 over 9,700 women in the
United States will be diagnosed with cervical cancer
and 3,700 will die.1 Worldwide, the numbers of
women affected are much greater. Cervical cancer is
the 2nd most diagnosed cancer in underdeveloped
countries, with approximately 470,000 cases/year,
and a 50% mortality rate.2 After the addition of rou-
tine PAP screening, the incidence of cervical cancer
has been on a downward trend in the US. Addition-
ally, the economic burden of disease is large: the
costs of screening cervical cancer are estimated at $6
million/year and approximately $2 billion/year are
spent on treatment.2


HPV
HPV is a small, double-stranded, circular
DNA virus that infects human basal epithelial cells
and is transmitted sexually.1-3 Approximately 20 mil-
lion people in the US at any time are infected with
HPV.2'7 Over 100 types of HPV have been identified.
Some types, such as type 16 and 18, are higher risk
for causing cervical cancer. Low risk types such as
HPV 6 and 11 cause 90% of genital warts.3'6'0 Cervi-
cal cancer and HPV infection are highly correlated,
with at least 99% of cervical cancers containing HPV
of certain high risk types, and approximately 70%
containing HPV types 16 or 18.2,6,9,12 HPV leads to
cervical cancer by infecting the cervical epithelium
during sexual intercourse. Infection by the virus
leads to viral replication and shedding that results in
epithelial changes. HPV oncogenes E6 and E7 act to
deregulate the cell cycle of normal cells and can lead
to cancerous lesions by offering infected cells a
growth advantage, introducing defects in differentia-
tion, increasing the probability of mutation and creat-
ing genomic instability.2'5 A vaccine that would pro-
tect against high risk types of HPV would be benefi-
cial in reducing the incidence of cervical cancer.

ri,. .,il


mm


SPharmaNote


VOLUME 22, ISSUE 3 DECEMBER 2006


INSIDE THIS ISSUE:

HUMAN PAPILLOMAVIRUS (HPV) AND CERVICAL
CANCER: IMPLICATIONS OF HPV VACCINES

IlIl'I \\0\ :A REVIEW


,*


Volume 22, Issue 3 December 2006


PharmaNote







HPV Vaccines


Pharmacology
The vaccines that are on the market or in
Phase III clinical trials are classified as prophylactic
vaccines. They work by utilizing the major capsid
protein of the HPV virus (LI), which self-assembles
into virus-like particles (VLP's) that are empty cap-
sids. The VLP's contain no viral DNA and are thus
noninfectious. VLP's are so similar to HPV virions
that they are effective in stimulating an antibody re-
sponse. Gardasil is the first HPV vaccine approved
to prevent cervical cancer and genital warts. It is a
quadrivalent vaccine that targets HPV types 6, 11, 16
and 18 by containing VLP's of each HPV type. It
contains amorphous aluminum hydroxyphosphate
sulfate as an adjuvant.4Cervarix is a bivalent vac-
cine targeting HPV 16 and 18. It contains a new ad-
juvant, aluminum hydroxide with 3-decylated mono-
phosphoryl lipid A, that may offer an advantage by
producing higher antibody titers than the aluminum
salt alone, leading to an enhanced immune response.7
Phase II studies compared the new adjuvant to the
aluminum salt formation and found a 1.6 to 3.2 fold
increase in antibody response with the new formula-
tion. 17

Clinical trials

Efficacy trials
Gardasil was evaluated in 4 placebo-
controlled, double-blind, randomized Phase II and III
clinical trials. The Phase III trials were termed FU-
TURE I and FUTURE II (Females United to Unilat-
erally Reduce Endo/Ectocervical Disease.) FUTURE
I administered Gardasil or placebo to 5,455 women,
and FUTURE II evaluated 12,157 women. In both
trials, women aged 16-26 received vaccination or
placebo on day 1 and at months 2 and 6. Co-primary
endpoints were combined incidence of HPV 6,11,16
or 18-related cervical dysplasia, adenocarcinoma in
situ (AIS), and combined incidence of HPV 6,11,16
or 18-related condyloma (genital warts), vulvar intra-
epithelial neoplasia (VIN), vaginal intraepithelial
neoplasia (VAIN), and vulvar or vaginal cancer.
Presence was detected by PAP smears taken at day 1,
month 7, month 12, and 6 month intervals up to
month 48. Genital tract specimens were also obtained
at day 1 and months 3 and 7. The per-protocol popu-
lation included subjects who received all 3 vaccina-
tions within 1 year of enrollment, had no major pro-


tocol deviations, and were HPV naive. FUTURE I
and II found 100% efficacy (p<0.001) in preventing
HPV 16 or 18 related CIN or AIS. FUTURE I found
Gardasil to be 100% effective (p<0.001) in prevent-
ing HPV 6,11,16 or 18-related CIN, AIS, condy-
loma, and vaginal/vulvar lesions, and FUTURE II
found 90.7% efficacy (p<0.001) for this endpoint.16,4
It is unknown why FUTURE II had lower efficacy
than previous phase II and III trials that showed
100% efficacy. In a combined analysis of the pla-
cebo groups in phase II and III studies, 83 of 7861
subjects experienced HPV 6,11,16,or 18 related CIN
or AIS as opposed to 4 of 7853 subjects in the treat-
ment group.4
A double-blind, multi-center, randomized,
placebo-controlled trial was performed to assess the
efficacy of the bivalent HPV 16 and 18 vaccine Cer-
varix. The study administered the vaccine at day 1,
month 1 and month 6 and included women aged 15-
25. Cervical samples for HPV testing were collected
at months 6, 12 and 18, and immunogenicity was as-
sessed at months 0,1,6,7,12 and 18.The primary end-
point was effectiveness at preventing infection with
HPV 16 or 18 in patients not infected at baseline.
Secondary outcomes were prevention of persistent
HPV 16 and 18 infection, squamous epithelial le-
sions, cancer or adenocarcinoma.15 Follow-up contin-
ued until month 18 and extended follow-up was per-
formed until month 27. In the per-protocol analysis,
study results found 100% efficacy (p<0.0001) of the
vaccine against persistent HPV 16 and 18 infection.
The vaccine was also effective at preventing 93.5%
of HPV-related cytological abnormalities.15 An inten-
tion-to-treat (ITT) analysis was performed in partici-
pants who did not follow study protocol but received
at least 1 dose of the vaccine. In the ITT analysis,
84.5% (p<0.0001) of patients were protected against
HPV 16 and 91.1% (p=0.003) effective against HPV
18. Efficacy in preventing cervical HPV 16 or 18
persistent infection was 95.1% (p<0.0001) and ab-
normal cytology was prevented in 92.9% (p<0.0001).
15
Both HPV vaccines are considered prophy-
lactic. In Gardasil trials, there was no evidence that
the HPV vaccine provided any protection against
HPV types covered by the vaccine that study sub-
jects had already contracted.4 However, if a subject
was infected with one particular HPV type at base-
line, the vaccine offered protection against other
types of HPV included in the vaccine.4 Thus, while
individuals not yet exposed to HPV benefit most


PharmaNote Volume 22, Issue 3 December 2006


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PharmaNote






Table 1. Summary of clinical trials evaluating HPV vaccines
Study FUTUREa 1 16 FUTURE II 4 Harper 15 Harper followup 8
HPV subtypes in vac-
HPV subtypes invac- 6, 11, 16, 18 6, 11, 16, 18 16, 18 16, 18
cine
Randomized, Dou- Randomized, Double- Randomized, Double- Randomized, Double-
Design ble-blind, controlled blind, controlled blind, controlled blind, controlled
Age (N) 16-26 (5455) 16-26 (12157) 15-25 (1113) 15-25 (776)
Aluminum hydroxy- Aluminum hydroxy- Aluminum hydroxide and Aluminum hydroxide and
Adjuvant phosphate sulfe phoshe sul 3-decylated monophos- 3-decylated monophos-
phosphate sulfate phosphate sulfate
phoryl lipid (ASO4) phoryl lipid (ASO4)
Schedule 0,2, and 6 months 0,2, and 6 months 0,1 and 6 months 0,1 and 6 months
Median follow-up 29 months 24 months 27 months 42 months
%Efficacy vs. HPV
100% 100% 100% 100%
16/18

%Efficacy vs. prevent-
ing cytological abnor- 100% 90.7% 93% 92.6-100%
malaties
% Efficacy preventing 100% 98.3% NR NR
genital warts
Adverse Events Nonsignificant Nonsignificant Nonsignificant Nonsignificant
aFUTURE= Females United to Unilaterally Reduce Endo/Ectocervical Disease HPV= Human Papillomavirus; NR=Not Reported; N=number of subjects


from receiving the vaccine, there is still an indication
for its' use in those who have already been exposed.
A summary of the clinical trials is presented in Table
1.

Duration ofprotection
Trials have assessed the efficacy of the HPV
vaccine in the short term, therefore it is possible that
individuals will need booster shots over the years to
maintain high antibody titers. A follow-up study of
the multicenter, double-blind, randomized, placebo-
controlled trial evaluating Cervarix was performed
to assess vaccine efficacy over an extended period of
time.8Women that originally received all three doses
of the vaccine were included in the extended follow-
up (393 in the vaccine group and 383 in the placebo
group.) Cervical samples were collected every 6
months. The primary endpoint was long-term vac-
cine efficacy in the prevention of HPV 16 and 18
infection. Secondary endpoints assessed were HPV
16 or 18 infections persistent for 6 and 12 months,
and squamous intraepithelial lesions, atypical
squamous cells, and atypical glandular cells. Analy-
sis of antibody titers showed over 98% of women
remained seropositive for HPV 16 and 18 at all time
points during the follow-up period of 42 months. The
study found that 100% vaccine efficacy remained


against all HPV 16 and 18 related histological abnor-
malities. This follow-up study demonstrates that the
vaccine can be effective against incident and persis-
tent infections of HPV 16 and 18 for a period of at
least 4.5 years.
Gardasil trials also assessed antibody titers
through 36 months. A study assessing immunologic
responses in the first phase II trial was performed. At
36 months post-dose, 94%, 96%, 100%, and 76% of
women in the per-protocol population remained sero-
positive for HPV types 6, 11, 16 and 18, respec-
tively.14 While the geometric mean titers (GMT) of
all subjects decreased for each time point (months 7,
24, and 36), titer levels became more stable between
months 24-26 and remained positive through 36
months.4'14 It was also noted that antibody levels
post-vaccination were comparable to those of a natu-
ral infection.14
While it is possible that the novel adjuvant in
Cervarix may offer a titer advantage over the adju-
vants of other vaccines, GMT's were not reported in
the Cervarix trial so a direct comparison is not pos-
sible. Also, minimum antibody levels needed for dis-
ease protection have not been established because
there were few disease cases in those seronegative at
baseline. Since women will be receiving the vaccine
at a very young age, continued follow-up and more


PharmaNote Volume 22, Issue 3 December 2006


Volume 22, Issue 3 December 2006


PharmaNote







clinical trials will be needed to confirm duration of
protection.

Dosage and Administration
Gardasil is administered intramuscularly in
a series of three 0.5 ml doses. The second and third
doses are given 2 and 6 months after the first dose.4
Cervarix is administered in 3 doses, with the second
and third doses given at 1 and 6 months after the first
dose.
Clinical trials studied women aged 15-26, yet
the vaccine is indicated for girls ages 9-26. Younger
ages were included as a result of a study that com-
pared anti-HPV titers one month after the last Gar-
dasil dose in 9-15 year old girls and 16-26 year
olds.4 It found that anti-HPV responses in ages 9-15
were non-inferior to responses of 16-26 year olds, so
efficacy of Gardasil in ages 9-15 is inferred. The
Advisory Committee on Immunization Practices re-
cently recommended its' addition to the vaccination
schedule for all girls ages 11-12.

Toxicity and Safety
Adverse reactions to Gardasil were mild
compared to placebo, with the most common reac-
tions consisting of injection site reactions, pyrexia,
nausea, nasopharyngitis and dizziness. Injection-site
reactions were judged by 94.3% of patients as mild
or moderate intensity. The incidences of overall ad-
verse reactions were low and comparable to placebo.
(Table 2) Gardasil is not recommended for use in
pregnancy, and is rated pregnancy category B. It is
unknown if the vaccine is excreted in breast milk,
and thus it is recommended that caution should be
used when administering the vaccine to nursing
mothers.4

Cost
Gardasil is currently the most expensive
vaccine on the market, twice the cost of other 3-dose
vaccines.13 Each dose is $120, for a total of $360 for
the series. Cost data is not currently available for
Cervarix. Due to the recent approval and high cost,
it is uncertain when insurance companies will begin
covering the vaccine. Some major insurance carriers
already offer coverage, but most companies have yet
to make a decision. It is expected that many will be-
gin offering coverage in the next year.13If officially
included in the CDC's routine vaccination schedule,
Gardasil will be automatically included in the fed-


Table 2. Most common vaccine-related adverse reactions 4
Adverse Reactions Gardasil (%) Placebo (%)
Injection Site
Pain 83.9 75.4
Swelling 25.4 15.8
Erythema 24.6 18.4
Pruritis 3.1 2.8
Fever 10.3 8.6
Nausea 6.7 6.6
Nasopharyngitis 6.4 6.4
Dizziness 4.0 3.7
Diarrhea 3.6 3.5
Vomiting 2.4 1.9
Myalgia 2.0 2.0
Cough 2.0 1.5

eral Vaccines for Children Program that provides
vaccines free to uninsured children or those on Medi-
caid. Many private insurers also use the recom-
mended vaccination schedule to make coverage deci-
sions.

Summary
HPV is a highly prevalent sexually transmit-
ted virus with low risk subtypes that result in up to
90% of genital warts, and high risk subtypes that can
result in cervical cancer. Cervical cancer is highly
correlated with the presence of the HPV virus as in-
dicated by the presence of HPV in approximately
99% of all cervical cancers. Gardasil, a new preven-
tative HPV vaccine was recently approved by the
FDA. Another HPV vaccine, Cervarix, is currently
in Phase III clinical trials. These vaccines show up to
100% efficacy at preventing HPV 16 and 18 related
cervical cancer and have a favorable safety profile.
With the introduction of these vaccines, there is
promise for decreasing HPV infection and cervical
cancer death rates.

References
1. Speck LM and Tyring SK. Vaccines for the Pre-
vention of Human Papillomavirus Infections.
Skin Ther Lett 2006; 11(6):1-9
2. Mahdavi A and Monk BJ. Vaccines against Hu-
man papillomavirus and cervical cancer: Prom-
ises and challenges. Oncologist 2005; 10;528-
538
3. Kahn J and Bernstein DI. Human papillomavirus
vaccines and adolescents. Curr Opin Obestet
Gynecol 2005; 17:476-482
4. Gardasil packagee insert]. Whitehouse Station,
NJ; Merck & Co. 2006


PharmaNote Volume 22, Issue 3 December 2006


Volume 22, Issue 3 December 2006


PharmaNote







5. Stanley M. HPV and the pathogenesis of cervi-
cal cancer. Eur J of Obstet & Gynecology and
Reproductive Biology 2006
6. Dunne EF and Markowitz LE. Genital Human
Papillomavirus infection. Clinical Infectious
Diseases 2006; 43:624-9
7. Schmiedeskamp MR and Kockler DR. Human
Papilomavirus Vaccines. Ann Pharmacother
2006; 40:1344-52
8. Harper DM, et al. Sustained efficacy up to 4.5
years of a bivalent L1 virus-like particle vaccine
against human papillomavirus types 16 and 18:
follow-up from a randomized controlled trial.
Lancet 2006; 367:1247-55.
9. Ault KA. Vaccines for the prevention of human
papillomavirus and associated gynecologic dis-
eases: A review. Obstetrical and Gynecological
Survey 2006; 61(6): S26-S31
10. Giles M and Garland S. Human papillomavirus
infection: an old disease, a new vaccine. Austra-
lian and New Zealand Journal of Obstetrics and
Gynecology 2006; 46:180-185
11. American Cancer Society. Cancer Facts and Fig-
ures 2006. Atlanta: American Cancer Society;
2006
12. Munoz N, et al. Epidemiologic Classification of
Human papillomavirus types associated with cer-
vical cancer. N Engl J Med 2003; 348:518-27
13. Tanner L. New Cervical Cancer Vaccine in
Short supply. Associated Press; August 30, 2006
14. Villa et al. Immunologic responses following ad-
ministration of a vaccine targeting human papil-
lomavirus Types 6, 11, 16, and 18. Vaccine
2006; 24:5571-5583
15. Harper et al. Efficacy of a bivalent L1 virus-like
particle in prevention of infection with human
papillomavirus types 16 and 18 in young women:
a randomized controlled trial. Lancet 2004;
364:1757-65
16. Garland SM. Efficacy of a Quadrivalent HPV
(Types 6, 11, 16, 18)L1 VLP Vaccine Against
External Genital Disease: FUTURE 1 analysis.
6th European Research Organization on Genital
Infection and Neoplasia (EUROGIN), Paris,
France. Apr 23-26,2006:26-4
17. Ginannini SL. Enhanced humoral and memory B
cellular immunity using HPV 16/18 L1 VLP vac-
cine formulated with the MPL/aluminum salt
combination compared to the aluminum salt only.
Vaccine 2006; 24:5937-5949


IMPLANON: A REVIEW


Poonam Patel, Pharm.D. Candidate


Contraceptive use in the United States is virtually
universal among women of reproductive age. Statis-
tics show that 98% of all sexually experienced
women had used at least one contraceptive method.
The leading method of contraception in the United
States in 2002 was the oral contraceptive pill. It was
being used by 11.6 million women 15-44 years of
age. The second leading method was female sterili-
zation or tubal ligation; used by 10.3 million
women.1'2 Choosing a method of birth control is a
highly personal decision, based on individual prefer-
ences, medical history, lifestyle, and other factors.
Although there are many options for contraception
use, implantable devices are one of the least used
methods due to lack of knowledge, fear of side ef-
fects, or an existing satisfaction with current tech-
niques.
Until now, there was one implantable contracep-
tive device in the United States. Norplant, a
levonorgestrel implantable device, approved by the
FDA in December of 1990, consisted of six, 36mg
slow release capsules that provided protection for 5
years. Due to problems with removal of the implants
and high numbers of reported ADRs, it was discon-
tinued in 1996.
Etonogestrel implant (Implanon[im' pla n6n]) is
the newest progestin-only implantable contraceptive
device that was approved by the FDA on July 17,
2006. Unlike Norplant, etonogestrel implant (ENG
implant) consists of a single rod; each containing
68mg of etonogestrel. ENG implant achieves a con-
traceptive effect by mechanisms that include sup-
pression of ovulation, increased viscosity of the cer-
vical mucus, and alterations in the endometrium.4 It
is manufactured by Organon USA Inc. and is ex-
pected to be widely available in the U.S. by 2007.
This article will review the pharmacology, admini-
stration, safety, and efficacy profile of the ENG im-
plant.


Phama~te olue 2, Isue3 Dcemer 00


Volume 22, Issue 3 December 2006


PharmaNote







Pharmacology/Pharmacokinetics
ENG implant is a single nonbiodegradable rod,
about the length of a toothpick (4 cm x 2 mm), con-
sisting of 40% ethylene vinyl acetate (EVA) and
60% ENG, containing a total of 68 mg of ENG.
Each rod is surrounded by an EVA copolymer mem-
brane (0.06 mm thick) that controls the rate of re-
lease of ENG over a span of 3-years. Throughout the
first two years, 100% bioavailability is achieved by a
constant release of ENG. The 68 mg of ENG con-
tained in the rod is initially absorbed at a rate of 60
[tg per day, slowly declining to 30 [tg per day after 2
years. Peak serum concentrations (266 pg/mL) of
ENG are achieved within 1 day after insertion, effec-
tively suppressing ovulation (which requires 90 pg/
mL ENG or more). The steady release of ENG into
the circulation avoids first-pass effects in the liver.
The elimination half-life of ENG is 25 hours and is
mainly excreted in the urine and to a lesser extent in
feces.4 After removal of the device, serum ENG con-
centrations become undetectable within 1 week, and
ovulation resumes in 94% of women within 3 to 6
weeks.5 Similar to other contraceptive steroids, cyto-
chrome P450 inducing drugs, such as rifampin,
griseofulvin, phenylbutazone, phenytoin, and car-
bamazepine, may decrease serum levels of ENG, de-
creasing efficacy.

Administration

Timing
Timing of the ENG implant insertion depends on
the patient's recent history of contraceptive use. The
most important rule before inserting the implant is to
rule out pregnancy. For women who have not been
using contraception or who have been using a non-
hormonal method, the implant is inserted between
days 1 and 5 of menses. For women changing from a
combination or progestin-only oral contraceptive, the
implant is inserted any time during active treatment.
If a woman is changing from an injectable contracep-
tion, the implant is inserted on the date of the next
scheduled injection. Lastly, for women using an in-
trauterine device (IUD), insertion can take place at
any time.5

Insertion and Removal
ENG implants will be available to all patients
seeking a more convenient and discreet form of birth
control, however; only physicians who undergo spe-


PharmaNote


cialized training will be able to administer the de-
vice. Subdermal placement is imperative for efficacy
and easy removal, therefore; the implant comes pre-
loaded with all equipment necessary to reduce the
risk of accidental placement in muscle tissue. The
insertion process takes on average 1.4 + 1.7 min-
utes.9 Once inserted, the implant may not be visible
but must remain palpable to ensure the 4 cm rod is
correctly in place. In addition, it is important to ad-
vise all patients to use a second form of birth control,
such as a condom or spermicide, for 7 days follow-
ing insertion to protect against any failure of the im-
plant.5
The ENG implant can be removed at any time,
but will remain effective for 3 years if left in place.
Removal requires a 2-mm incision at the distal tip of
the implant and takes about 2.5 to 5.5 minutes.3
Common reactions that may occur after insertion or
removal of the procedure are pain, swelling, redness,
and hematoma. Because ovulation resumes rapidly
following removal, women still desiring contracep-
tion should begin another method immediately or
have a new rod inserted through the removal inci-
sion.5

Clinical Trials
The efficacy of the ENG implant has been stud-
ied in various trials. Trials have been performed
studying the effects of ENG implant on metabolic
processes; including lipid profiles and liver function
tests, and against a similar progestin-only implant.

Lipids
The effects of Implanon and Norplant implants on
serum lipids over 2 years of use was assessed in an
open, randomized study. Study subjects (N=80), di-
vided into 2 groups, were sexually active between
the ages of 18 and 40 years old. Serum lipids were
obtained preinsertion and after 6, 12, and 24 months
of use. The lipid parameters evaluated were: TC,
HDL, LDL, TGs, apolipoprotein A-i and B. At the
end of 2 years, TC, HDL, and LDL were signifi-
cantly decreased in the Implanon group (p-values
0.000, 0.026, 0.027 respectively); whereas TC, LDL,
and TGs were significantly reduced in Norplantus-
ers (p-values 0.000, 0.020, 0.000 respectively). TGs
were slightly increased by 2.25% in Implanon us-
ers, but was not statistically significant. In both
groups, there was a significant increase in apolipo-
protein B at the end of the 24 month period. Overall,


Volume 22, Issue 3 December 2006







the study showed reductions in all lipid parameters
for each group; however, there was no significant
difference between the implant groups at any time
period (Table 1).6 Since the study population in-
cluded subjects with higher BMIs and preinsertion
lipid levels, we can presume these implants have a
beneficial effects on lipid parameters in hyperlipi-
demic patients.

Liver Function Tests
In the same 2-year open, randomized, compara-
tive study (N=80), change in liver function parame-
ters: total bilirubin, unconjugated bilirubin, albumin,
AST, ALT, GGT, and lactate dehydrogenase (LDH)
were assessed on subjects receiving either implant.
Blood samples were taken preinsertion and after 6,
12, and 24 months. In both implant groups, the most
significant change was in total bilirubin and unconju-
gated bilirubin levels. At the end of 2 years, the
mean unconjugated bilirubin levels were more than
seven fold greater than the mean preinsertion levels
for users of both types of implants (Implanon: 1.17
tmol/L vs. 8.32 tmol/L, p < 0.000; Norplant: 1.25
kmol/L vs. 8.25 kmol/L, p < 0.000). However, the
total and unconjugated bilirubin levels did not ex-


ceed the normal range at any point during the study.
In the Norplant group, ALT levels were signifi-
cantly decreased (23.80 U/L vs. 18.93 U/L, p <
0.008) while AST and LDH levels were significantly
increased in the Implanonsubjects during the first
year of use, which gradually returned to baseline at
the end of 2 years. In both groups, the GGT levels
were significantly raised during treatment period
(Implanon: 25.05 U/L vs. 33.10 U/L, p < 0.000;
Norplant: 18.60 U/L vs. 24.83 U/L, p < 0.000).8
There were no significant changes in serum albumin.
To a healthy user of either implant, there are no ad-
verse effects related to hepatic dysfunction, however,
caution should be used in patients with preexisting
liver disease (Table 2).

Bleeding Patterns
Irregular bleeding problems tend to be the most
common adverse effect among progestin-only meth-
ods of contraception. The efficacy and bleeding pat-
terns of Implanon and Norplant were studied in an
open, comparative, randomized, multicenter trial.
Two hundred healthy, sexually active women re-
ceived either a single-rod Implanon or six capsule
Norplant for 2 years. The study was extended up to


Table 1. Changes in serum lipids between Implanon and Norplant users.6
ParamImplanon" (N= 41 1) Norplant (N= 41- 1 Group Com-
Parameter
(mmol/L) Mean % change from p-value Mean % change from p-value prison of mean
(mmol/L) baseline (mmol/L) baseline (p-value)
Total Chol.
Baseline 5.36 5.49 0.198
6 months 4.88 -7.16 0.000 4.63 -14.75 0.000 0.206
12 months 4.82 -8.27 0.000 4.69 -14.07 0.000 0.470
24 months 4.72 -8.85 0.000 4.78 -10.65 0.000 0.786
HDL
Baseline 1.38 1.30 0.278
6 months 1.24 -9.24 0.000 1.14 -9.1 0.000 0.051
12 months 1.23 -9.59 0.001 1.12 -11.94 0.000 0.050
24 months 1.27 -5.78 0.026 1.21 -3.24 0.087 0.246
LDL
Baseline 3.55 3.75 0.397
6 months 3.38 -2.58 0.049 3.25 -11.73 0.000 0.581
12 months 3.40 -2.48 0.232 3.36 -9.43 0.000 0.811
24 months 3.19 -5.87 0.027 3.35 -6.9 0.020 0.698
Triglycerides
Baseline 0.88 1.09 0.013
6 months 0.82 -1.55 0.065 0.73 -26.89 0.000 0.444
12 months 0.78 -6.09 0.014 0.73 -30.25 0.000 0.201
24 months 0.86 2.25 0.795 0.80 -22.27 0.000 0.265

PharmaNote Volume 22, Issue 3 December 2006







4 years after data showed ovulation remained sup-
pressed after 2 years. Overall results showed fewer
frequent bleeding patterns in the Implanon group.
The incidence of amenorrhea and infrequent bleed-
ing, defined as < 2 bleeding/spotting episodes per
reference period (90 days), was higher in the Im-
planon group. In a given reference period, amenor-
rhea occurred in 2.0%-18.6% of the women in the
Implanon vs. 1.0%-6.2% of women in the Nor-
plant group. Results of infrequent bleeding in the 2
groups were 8.4%-26.0% (Implanon) and 5.0%-
13.7% (Norplant). In general, lower incidence of
frequent bleeding, > 4 bleeding/spotting episodes,
were observed in the Implanon group. Frequent
bleeding ranged between 1.3% 10.4% in the Im-
planon group compared to 2.3% 13.0% in the Nor-
plant group. The mean overall incidence of pro-
longed bleeding, > 1 bleeding/spotting episode last-
ing > 10 days, fell dramatically during the study,
with Implanon ranging from 66% in the first refer-
ence period to 27% in period 16, and with Norplant
from 69% to 22% (Figure 1). Efficacy was based on
the occurrence of in-treatment pregnancies, which
was zero in both treatment groups.10

Safety and Efficacy
Safety of the ENG implant has been investigated
in several trials. In one study, the most common ad-
verse event reported in patients was infrequent bleed-
ing, defined as less than three bleeding/spotting epi-
sodes in a reference period (90 days), excluding
amenorrhea. The least common pattern was frequent
bleeding, or more than five episodes of bleeding in a


reference period. Infrequent, prolonged and frequent
bleeding patterns were most common during the first
8 months of the study and declined thereafter. During
months 4-24, the incidence of amenorrhea ranged
from 14% to 20%. Forty-three subjects (13%) with-
drew from the study because of bleeding pattern
changes and 76 subjects (23%) discontinued because
of other AEs: emotional liability (6.1%), weight in-
crease (3.3%), depression (2.4%) and acne (1.5%).7
Side effects that have been reported from a combina-
tion of clinical trials (942 subjects) include headache
(24.9%), vaginitis (14.5%), breast pain (12.8%), and
upper respiratory tract infection (12.6%).4

Cost
The cost of Implanonhas not yet been deter-
mined; however it is assumed that it will be compa-
rable to the monthly cost of other contraceptive
methods.

Summary
Overall, the ENG implant is a highly acceptable,
excellent contraceptive alternative in patients who
are searching for a long term, disguisable birth con-
trol method.11 By maintaining a sustained release of
progestin, it is independent of user compliance,
which is a factor in the efficacy of most contracep-
tive methods.10 In clinical trials, the implants have
minimal metabolic effects and decreased bleeding
episodes over time.6,8,10 By providing 3 years of con-
traception and a rapid return of fertility after re-
moval, the ENG implant is a tolerable and effective
contraceptive alternative.10


Table 2. Changes in Liver Function Tests between Implanon4 and Norplant" users.8
Implanon" (N= 41i) Norplant" (N= 41i) Group Com-
Parameter Sample % change % change prison of
times Mean from base- p-value Mean from base- mean (p-value)
value
line line
Total bilirubin Baseline 3.42 2.25 0.001
(umol/L) 24 mo. 9.32 196.01 0.000 9.26 317.20 0.000 0.975
Unconjugated Baseline 1.17 1.25 0.794
bilirubin (umol/L) 24 mo. 8.32 720.09 0.000 8.25 758.33 0.000 0.975
Baseline 23.80 23.80 0.546
ALT (U/L)
24 mo. 22.89 2.60 0.687 18.93 -15.83 0.008 0.041
Baseline 21.30 21.60 0.334
AST (U/L)
24 mo. 20.59 5.23 0.402 21.77 4.67 0.749 0.367
Baseline 25.05 18.60 0.039
GGT (U/L)
24 mo. 33.10 36.06 0.000 24.83 38.28 0.000 0.229
Baseline 449.35 387.97 0.006
LDH (U/L)
24 mo. 436.05 2.43 0.441 401.90 2.74 0.890 0.010

PharmaNote % Volume 22, Issue 3 December 2006







Implanon


3-- a Anenonea
&- Inf wnt
k Frequent
)*---- Prdlanged


0 2 4 6 8 10 12 14 16
Reference Perlod


% of Women
70 1


0- -a Amenornea
&--a Ir~rraqwnt
h-& Frequent
*-4c Prolmged


6 B 10
Relerence Period


Figure 1. Percentages of women reporting amenorrhea, infrequent, frequent, and prolonged bleeding in the Norplant" and Im-
planon groups.10


References
1. Mosher WD et al., Use of contraception and use
of family planning services in the United States:
1982-2002, Advance Data from Vital and Health
Statistics, No. 350. 2004
2. Contraceptive Use. The Alan Guttmacher Insti-
tute, 2006
3. Smith A, Reuter S. An assessment of the use of
Implanon in three community services. J Fam
Plann Reprod Health Care. 2002;28:193-196
4. Implanon [package insert]. Roseland, NJ: Or-
ganon; 2006
5. Darney, Philip D., MD, MSc. Everything you
need to know about the contraceptive implant.
September 2006 Vol. 18, No. 9
6. Biswas A, Viegas OA, Roy AC. Effect of Im-
planon and Norplant subdermal contraceptive
implants on serum lipids-a randomized compara-
tive study. Contraception. 2003;68:189-193
7. Funk S, Miller MM, Mishell DR Jr, et al. Safety
and efficacy of Implanon, a single-rod implant-
able contraceptive containing etono-
gestrel. Contraception. 2005;71:319-326
8. Biswas A, Viegas OA, Roy AC. Effect of etono-
gestrel subdermal contraceptive implant
(Implanon) on liver function tests- a random-
ized comparative study with Norplant im-
plants. Contraception. 2004;70:379-382


9. Shulman LP., Gabriel H. Management and local-
ization strategies for the nonpalpable Implanon
rod. Contraception. 2006;73:325-330
10. Zheng, Shu-Rong et al. A Randomized Multi-
center Study Comparing the Efficacy and Bleed-
ing Pattern of a Singl-Rod (Implanon) and a
Six-Capsule (Norplant) Hormonal Contracep-
tive Implant. Contraception. 1999;60:1-8
11. Rekers H. et al. The pharmacodynamics and ef-
ficacy of Implanon. An overview of the data.
Contraception. 2004 Nov;70(5):433



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
Pharm.D.

R. Whit Curry, M.D. Associate Editor

Shawn Anderson Assistant Editor
Pharm.D.
:. WWK^WS WS~y ^WSW S^KX


Pharm~oteVolum 22,Issu 3 Deembe 200


% of Women


Norplant*


PharmaNote


Volume 22, Issue 3 December 2006




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