8
TUESDAY, NOVEMBER 16', 2004
Drug arouses UNC studies
BY ELIZABETH BLACK
STAFF WRITER
Until recently, two options have
been available for male contracep
tion condoms and vasectomies.
But new research stemming from
UNC laboratories has discovered
that a natural protein produces an
immune reaction in the male repro
ductive system that, when made into
an immunization, could work as a
nonhormonal male contraceptive.
The shot would allow men to
regain fertility after stopping treat
ment, and would not force them to
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ruth Giveaways!
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KHtravell,
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I STUDENT TRAVEL & BEYOND |
ORTHO EVRA®
(NORELGESTROMIN / ETHINYL ESTRADIOL
TFtANSDERMAL SYSTEM)
Patents stxxrtd be counseled that ttis product does not protect against HIV intec
ten (AIDS) and otter malady transmitted diseases.
ffeonty
ORTHO EVRA* Is a combination transdermai contraceptive patch with a contact surface area
of 20 cm ; . It contains 6.00 mg ncrelgestromh and 0.75 mg efhryt estradiol (EE), and releases
150 micrograms of norelgestromin and 20 micrograms of EE to the bloodstream per 24 hours.
IMPORTANT NOTE - This Information la a BRIEF SUMMARY of the complete prescribing
information provided with the product and therefore should not be used as the bails for
prescribing the product This summary was prepared by deleting frosnfhe complete pre
scribing Information certain text tables and references. The physldan shoultf be thorougNy
tamHlar wtth the complete prescribing Information before prescribing the product
INDICATIONS AND USAGE: ORTHO EVRA* Is indicated for the prevention of pregnancy.
Lke oral contraceptives. ORTHO EVRA* s highly effective if used as recommended ti this INjel.
ORTHO EVRA ® Ass not been studied tor and Is not Indicated tor use In emergency
contraception.
CONTRAINDICATIONS: ORTHO EVRA* 1 should not be used in women who cuTently have the
folowng conditions: t. Thrombophlebitis, thromboembolic disorders 2. A past history of deep
veil thrombophlebitis or thromboembolic disorders 3. Cerebrovascular or coronary artery
disease (curent or pest history) 4. Valvular heart disease wth complications 5. Severe hyper
tension 6. Diabetes with vascular nvolvement 7. Headaches with focal neurological symptoms
S. Major surgery wlh prolonged immobilizaticn 9. Known or suspected carcinoma of Die breast
or personal history of breast cancer 10. Carcinoma of the endometrium or other known or
suspected estrogen-dependent neoplasia 1 UJndiagwsed abnomal genital bleedhgl 2. Cholestatc
jaundice of pregiancy or jaundice with prior hormcnal contraceptive use 13. Acute or chronic
hepatocellular disease with abnormal liver Auction 14. Hepatic adenomas or carcinomas
15. Known or suspected pregnancy 16. Hypersensitivity to any component of tils product
WARNMGS
~cigarette smoking Increases the risk of serious cardiovascular side effects
from hormonal contraceptive use. This rtsk increases wtti age and wtth heavy
smoking (15 or more cigarettes per day) and Is quite marked in women
over 35 years of age. Women who uee hormonal contraceptives, Including
ORTHO EVRA* should be sfronjy advised not to smoke.
ORTHO E\RA® and other contraceptives that contain bobi an estrogen and a progestin are
called combination hormonal contraceptives. There Is no epidemiologic data available to
determrvr whether safety and efficacy wlh the transdermai route ot admiilstratkfi would be
different han the oral route Practitioners prescribrig ORTHO EVRA* should be tamiiar wlh
the foHming Information relating to risks.
The use c( combination hormonal contraceptives is associated with increased risks of several
serious rondltlons including myocardial infarction, thromboembolism, stroke, hepatic
neoplasi i, and galbladder disease, although the risk of serious moitxdity or mortality Is very
small n healthy women without underlying nsk (actors. The risk of mottxdly and mortality
ncreases significantly In the presence ol dher underlyng rtsk (actors such as hypertension,
hypertif idemlas, obesity and diabetes.
The Information contaned m the package nsert s principally based on studies canted out In
women who used combination oral contraceptives with higher formulations of estrogens and
progestins than those in commcxi use today. The effect ot long-term use of combiiation
hormonal contraceptives with lower doses of both estrogen and progestin admiiistered by any
route remaps to be determined.
Throughout this labeling, epidemiological studies reported are ot two types: retrospective or
case control studies and prospective or cohort studies. Case control studies provide a meas
ure ot the relative risk ot a disease, namely, a ratio ot the Incidence of a disease among oral
contraceptive users to that among non users The relative risk does not provide Intormation
on the actual clinical occurrence ot a disease. Cohort studies pnwkte a measure ot attributa
ble risk, which Is the Merence In the Incidence of disease between hormonal contraceptive
users and nonusers. The attributable risk does provide intormation about the actual occur
rence ot a dsease in the population (adapted from rets. 2 and 3 with the author's permission).
For further intormation, the reader Is referred to a text on epidemiological methods,
t. Thromboembolic Disorders And Other Vascular Problems: a. Thranboambollam: An
increased risk ot thromboembolic and thrombotic disease associated with the use of hormonal
contraceptwes Is well established. Case control studies have fcund the relative risk ot users
compared to nonusers to be 3 tor the first episode ot superficial venous thrombosis, 4to 11 ■
tor deep ven thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposng
conditions for venous thromboembolic disease. Cohort studies have shown the relatwe risk to
be somewhat lower, about 3 tor new cases and about 4.5 ter new cases regurng hospitaliza
tion. The risk of thromboembolic disease associated wlh hormonal contraceptives Is not
related to length ol use and disappears alter hcxmonal contraceptive use is stopped. A two- to
four-told increase n relative risk ol post-operative thromboembolic complications has bean
reported with the use ot hotmonal contraceptives. The relative risk ot venous thrombosis in
women who have predisposing cond lions is twice that ot women without such medical con
ditions. If feasible, hormonal contracejrtives should be discontinued at least tax weeks prior
to and tor two weeks attar elective surgery ot a type associated with an increase rt risk of
thromboembolEm and during and following prolonged immobilization. Since the immediate
postpartum period Is also associated wlh an Increased risk ot thromboembolism, hormonal
contraceptwes should be started no earlier than tour weeks after delivery it women who elect
not to breast-feed In the large clinical trials (N= 3.330 with f ,704 women-years of eqto6tre),
one case ot non-tatal pulmonary embolism occurred during ORTHO EVRA* use, and one case
ot post-operative non-fatal pulmonary embolism was reported following ORTHO EVRA® use. 1
is unknown it the risk ot venous thromboembolism with ORTHO EVRA® use Is different than
wfh use ot combnation oral contraceptives. As with any combination hormonal contracep
tives, the clinician should be alert to the earliest manifestations ot thrombotic disorders (throm
bophlebitis, pulmonary embolism, cerebrovascular disorders, and retital thrombosis). Should
any of these occur or be suspected, ORTHO EVRA® should be discontiiued immediately,
b. Myocardial Infarction: An ncreased risk ot myocardial Infarction has been attributed to
hormonal contraceptive use. This risk Is primarily n smokers or women with other underlyng
risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid
obesity, and diabetes The relatwe risk ot heart attack tor current hormonal contraceptive users
has been estimated to be two to sec compared to non-users. The risk Is very low under the age
ot 30. Smoking in combination with oral contraceptive use has been shown to contrtjute stc
stantalfy to the incidence ot myocardial Infarctions n women In their mid-thirties or older wfh
smokng accounting tor the majority ol excess cases. Mortality rates associated with circula
tory dsease have been shown to ncrease sub6tantialy in smokers, especially n those 35 years
ot age and older among women who use oral contraceptwes. Hcxmonal contraceptwes may
compound the effects of well-known risk factors, such as hypertension, diabetes, hypertpi
demias, age and obesity. In particular some progestins are known to decrease HDL choles
terol and cause glucose intolerance, while estrogens may create a state of hyperinsullnlsm.
Hormonal contraceptwes have been shown to ncrease blood pressure among some users (see
Section 9 n WARNINGS). Sim far effects on risk (actors have been associated wtth an increased
rtsk ol heart disease. Hormonal contraceptives. Including ORTHO EVRA®, must be used wfh
caution m women with cardiovascular disease risk factors. Norgestimate and norelgestromh
have mmmal androgenic activity (see CUN CAL PHARMACOLOGY in ful Presenting hformatxxi).
There is some evidence that the risk ot myocardial infarction associated with hormonal
contraceptwes Is tower when the progestin has minimal androgenic activity than when the
activity Is greater, c. Cerebrovaicutar diseases: Hormonal contraceptives have been shown
to ncrease both the relative and attrtutable risks ot cerebrovascular events (thrombotic and
hemorrhagic strokes), although, In general, the risk Is greatest among older (>35 years),
hypertensive worn en wtio also sm*e. Hypertension was found to be a risk (actor tor both users
and nonusers, tor both types ot strokes, and smoking interacted to ncrease the risk ot stroke.
In a large study, the relative risk ot thrombotic strokes has been shown to range trom 3 tor
normotensne users to 14 tor users wfh severe hypertension. The retatwe risk ot hemorrhagic
stroke is reported to be 1.2 tor non-smokers who used hormonal contraceptives, 2.6 tor smok
ers vfio did not use hormonal contraceptives, 7.6 tor smokers who used hormonal cotrtra
cefrtives. 1.8 lor normotensive users and 25.7 tor users with severe hflKrtension. The attributable
risk is also greater ti older women and. Don-related flak of macular dlnaae trom hormonal
contraceptives: A posfive association has been cbseived between Hie amount ot estrogen
and progestin r hormonal contraceptwes and the risk ot vascular disease A decline r setum
hjgh-densrty lipoproteins (HDL) has been reported with many progestaticnal agents. A decline
n seram high-density Ipoprotems has been associated with an Increased incidence of ischemic
heart disease. Because estrogens mease HDL cholesterol, the net effect ot a hormonal con
traceptwe depends on a balance achieved between doses ot estrogen and progestin and the
activity ot the progestin used n the contraceptives. The activity and amount ot both hotmeras
should be considered in the choice ot a hormonal ccnfraceptive a. Parti stance ol rtsk ot vas
cular disease: There are two studies that have shown persistence of risk ol vascular disease
tor eve-users ot combination hormonal contraceptives. In a study in the United States, the risk
ot developing myocardial infarction afte disconthuhg combination hormonal contraceptives
persists tor at least 9 years tor women 40-49 years who had used combination hotmonal con
traceptwes tor five or more years, but this increased risk was not demonstrated to other age
grou|* In another study in Great Britain, the risk ot developing cerebrovascular disease
persisted tor at least 6 years after discontruation ot combination hormonal contraceptives,
alhough excess rtsk was very small However, both studies were performed with combiiation
hormonal contraceptive formulations contahiig 50 micrograms or hitfier ot estrogens. It is
unknown whether ORTHO EVRA® is distinct from other combination hormonal contraceptives
wlh regard to the occurrence ot venous and arterul thrombosis. 2. Estimates Of Mortality
From Combination Hormonal Contraceptive Use: One study gathered data from a variety
of sources that have estimated the mortality rate associated wfh different methods ot
rely on taking pills daily, wearing
condoms, or getting a vasectomy
which usually proves irreversible.
“We’ve been interested in immu
no-contraception for many years,”
said Michael O’Rand, a profes
sor in the Department of Cell and
Developmental Biology who led the
project “Since it works in monkeys,
there should be no theoretical rea
son why it shouldn’t work in men.”
The experiment immunized
male macacas monkeys with a form
of eppin, a protein produced in the
testis and epididymis. Monkeys that
contraception at different ages. These estimates include the combned risk of death associ
ated with contracefrtiue methods plus the risk attributable to pregnancy in the event ot method
failure. Each method of contraception has its specific benefits and risks. The study concluded
that wilh the exception ot combnation oral contraceptwe users 35 and older who smoke, and
40 and older who do nut smoke, mortality associated wlh all methods ot birth control is low
and below that associated wtth chidbirth.
The obeetvatkn of a posstte Increase In risk ot mortally wth age for combination oral con
traceptwe users Is based on data gathered In the 1970* but not reported until 1983. Cuirent
dnical recommendation involves the use of lower estrogen dose formulations and a careful
consideration of rlskfactors. h 1989, the Fertility and Maternal Health Drags Advisory Commltee
was asked to review (he use ot combination hormonal contraceptwes it women 40 years of
age and ewer. The Commltee concluded that although cardiovascular disease risks may be
ncreased wlh combnation hormonal contraceptive use alter age 40 n healthy non-smokng
women (even with the newer low-dose formulations), there are also greeter potential health
risks associated wlh pregnancy m older women and with the alternative surgical and medical
procedures fiat may be necessary it such women do not have access to eftectwe and acceptable
means of contraception. The Committee recommended that the benefits ot low-dose combi
nation hormonal contraceptive use by healhy non-smoking women over 40 may outweigh the
possible risks. Although the data are mainly obtained wlh oral contraceptives, this Is likely to
apply to ORTHO EVRA® as wel. Women ol all ages who use combination hormonal contra
ceptives. should use the lowest possible dose formulation that Is effective and meets the hdl
vidual patient needs a Carcinoma Of The Reproductive Organs And Breasts: Numerous
epidemiological studies give conflicting repots on the relationship between breast cancer and
COC use. The rtsk of havitg breast cancer diagnosed may be slightly ncreased among cuirent
and recent uaers of combination oral contraceptwes. However, this excess risk appears to
decrease over tine alter COC dlscantlnuaticn and by 10 years after cessation the Increased
risk disappears. Some studies report an Increased risk with duration of use while other stud
ies do not and no consistent relationshp* have been tound with dose o type of steroid. Some
studies have tound a small increase it risk tor women who first use COCs betore age 20. Most
studies show a similar pattern of risk wfh COC use regardless of a woman's reproductive
history or her family breast cancer history. In addition, breast cancers diagnosed in current or
ever oral confraceptlve users may be less clinically advanced then in never-usets. Women who
currently have or have had breast cancer should not use hormonal contraceptives because
breast cancer Is usualy a hormonally sensitive kimor. Some studies suggest that combination
oral contraceptwe use has been associated with an increase it the risk of cervical intraep
ithelial neoplasia in some populations of women. However, mere continues to be controversy
abort the extent to which such fitdiigs may be due to differences n sexual behavior and other
factors, it spie ot many studies of the relationshp between oral cartraceptive use and breast
and cervical cancers, a cause-and-effect relationshp has not been established. It Is not known
whether ORTHO EVRA® Is distinct from oral contraceptwes with regard to the above state
ments. 4 Hepatic Naoplaata: Benign hepatic adenomas are associated with hormonal con
traceptive use. alhough the Incidence ot benign tumore Is rare P the United States. Indirect
calculations have estimated the attributable risk to be P the range of 3.3 cases/1 00,000 for
usere, a risk that ncreases after tour or more years of use, especially with hormonal contra
ceptives contaPPg 50 micrograms or more ol estrogen. Rupture of benign, hepatic adenomas
may cause death through irtra-abdomPai hemorrhage Studies from Britan and the US have
shown an ncreased risk of developing hepatocelPlar carcinoma it long term (a 8 years) oral
contraceptwe users. However, these cancets ere extremely rare in the U.S. and me attrtuta
ble risk (the excess ncktence) of her cancers P oral contraceptive usere approaches less than
one per milion users. I Is ipknown whether ORTHO EVRA® Is distitet from oral contraceptives
P this regard. 5 Ocular Laatonc There have been dnical case reports of retinal thrombosis
associated with the use of hormonal contraceptwes. ORTHO EVRA® should be discontinued If
there is unexplained partial or complete loss of vision: onset ot proptosis or diplopia;
papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures
should be undertaken Immediately 6 Hormonal Contraceptlw Use Before Or During Earty
Pregnancy: Extensive epidemiological studies have revealed no increased risk ot birth defects
P women who have used oral contraceptives prior to pregnancy. Studies also do not indicate
a teratogenic effect, paitfcularty p so tar as cardiac anomalies and (mb reduction detects are
concerned, vPen oral cartracepiives are taken inadvertently during early pregnancy. Combination
hormonal contraceptives such as ORTHO EVRA® should not be used to induce wilhdrawa I bleed-
Pg as a test tor pregnancy. ORTHO B/RA® should not be used duPg pregnancy to treat threat
ened or habrtualabortton.lt is recommended that for anypatient who has missed two consecutive
periods, pregnancy should be rated out. It the patient has not adhered to the presorted sched
ule tor the use ot ORTHO EVRA® the possPilty ot pregnancy should be considered at the time
ot the tret missed period. Hormonal contraceptwe use should be discontinued pregnancy is
confirmed. 7. Gallbladder Dlnaae Earlier studies have reported an Increased lifetime rela
tive risk ot gallbladder surgeiy P uaers ot hormonal contraceptives and estrogens. More re
cent studies, however, have shown that the relative risk otdevekippg galbladder disease among
hormonal contraceptive users may be mPhtal. The recent findings of minimal risk may be re
lated to the use ot hormonal contraceptive formulations contaPPg Pwer hormonal do6es ot
estrogens and progestPs. Combination hormonal contraceptives such as ORTHO EVRA® may
worsen existing galbladder disease and may accelerate the development of this disease P
previously asymptomatic women. Women with a history of combination hormonal
contracepitwe-related cholestasis are more Ikely to have the condition recur with subsequent
combnation hormonal contraceptive use. ft Carbohydrate And Llgld Metabolic Enacts:
Hormonal contraceptives have been shown to cause a decrease p glucose tolerance P some
usere. However, P the non-diabetic woman, combmatior hormonal contraceptwes appear to
have no effect on tastng bktod glucose. Prediabetic and diabetic women P particular should
be carefully mm ibred while takng combnation hormonal conpaceptives such as ORTHO EVRA®.
P dnical trials wlh oral contraceptives contaPPg elhhyl e6tradbl and norgestimate there
were no ethically sPnlkant changes P tastng blood glucose levels. There were no dnically
significant changes P glucose levels over 24 cycles of use. Moreover, glucose tolerance tests
showed no clinically significant changes from baseline to cycles 3,12 and 24. P a 6-cyde
dnical trial wth ORTHO EVRA® there were no clinically significant changes P tastng blood '
glucose from baselne to end ot treatment. A small proportion of women will have persEtent
hypertriglyceridemia while takpg hormonal contraceptives. As discussed earlier (see WARN
INGS 1a and 1 and), chargee P seram triglycerides and (poproten levels have been reported P
hormonal confraceptlve usere. ft Banted Blood Pressure: Women wlh significant hyper
tension should not be started on hormonal contraception. Women with a history of hyperten
sion or hypertension-related diseases, or renal disease should be encouraged to use another
method of contraception. I women eted to use ORTHO EVRA®, they should be monitored closely
and It a dnically signlicant elevation ot blood pressure occurs, ORTHO EVRA® should be
dlsconthued. For moet women, elevated blood pressure wll refrxn to normal after stopppg
hormonal contraceptives, and there is no difference P the occurrence ot hypertension between
former and never users. An Increase P blood pressure has been reported P women taking
hormonal contraceptives and this Pcrease Is more Ikely P older hormonal axrtraceplive users
and with extended duration of use. Data from the Royal College of General Practitioners and
subsequent randomized trials have shown that be pcidence ot hypertension ncreases wib
increasing progestational activity. 10. Headache The onset or exacetbation of migraine
headache ot the development and headache wib anew pattern batis recunent, perstetemor
severe requres discontinuation of ORTHO EVRA® and evapation of be cause. 11. Blooding
Irregularities: Breakthrough bleeding and spotthg are sometimes encountered P women uspg
ORTHO EVRA®. Non-hormonal causes should be considered and adequate diagnostic meas
ures taken to rale out malignancy, other pathology, ot pregnancy P be event cf breakthrough
bleeding, as p the case ot any abnormal vagpal bleedhg. It pathology has been excluded, tree
or a change to another contraceptwe product may resolve be bleeding. P the event ot amen
onhea, pregnancy should be rated out betore initiating use ot ORTHO EVRA®. Some women
may encounter amenonhea or oligomenorrhea attar discontinuation ol hormonal contracep
tive use. especialy vPen such a condition was pre-existent. Bteedmo Patterns: h the dnical
trials most women started belr withdrawal bleeding on be fourth day ot the drag-tree
interval, and be median duration of withdrawal bleeding wassto6days.on average 26% ot
women per cycle had 7 or more total days ot bleedng and/or spotting (bis hcludes bob wib
drawal flow and breakthrough bleedpg and/or spotting). 12 Ectopic Pregnancy: Ectopic as
well as PtrauterPe pregnancy may occur P contraceptwe failures.
PRECAUTIONS: Women should be counseled that ORTHO EVRA* does not prefect agalnit
HIV Infection (AIDS) and other texually tranemitted Infections 1. Body Weight *196 IDs.
(90 kg): Resuts ot dPlcal trials suggest that ORTHO EVRA® may be less effective in women
wth body weight *l9B t*. (90 kg) ban P women wth tower body weights. 2. Physical
Examination And Follow-Up: t Is good medical practice tor women ushg ORTHO EVRA®, as
lor all women, to have annuel medical evaluation and physical examhations. The physical
examination, however, may be deferred until after initiation ot hormonal contraceptives it
requested by be woman and judged appropriate by be clPician. The physical examination
should Pdude special reference to blood pressure, breasts, abdomen and pelvic organs,
xidudpg cervical cytology, and relevant laboratoty tests, P case ot undiagnosed, persistent or
recurrent abnormal vagpal bleedpg, appropriate measures should be competed to rate out
malignancy or other pathology. Women wib a strong family history ot breast cancer or who
have breast nodules should be monitored wib particular care. 3. Lipid Dtaortiers: Women
who are being treated tor hyperlipidemias should be followed closely It bey elect to use
ORTHO EVRA®. Some progestins may elevate LDL levels and may render be control of hyper-
Itpidemias more difficult. 4. Uvar Function: It jaundice develops in any woman using
ORTHO EVRA®, be medication should be dlsconthued. The hormmes P ORTHO EVRA® may
be poorly metabolized P patents wrth impaired liver (unction, 5. Fluid Retontkxi: Steroid hor
mones Ike bore p ORTHO EVRA® may cause some degree ot fluid retention. ORTHO EVRA*
should be presorted wib caution, and only wrth careful monitoring, p patients wrth conditions
which might be aggravated by fluid retention. 6. Emotional Diaordare: Women who become
significantly depressed while using comb Patton hormonal contraceprtives such as
ORTHO B/RA® should stop the medication and use another method ot contraception P an at
tempt to determPe whether be symptom s drag related. Women wrth ahistory ot depression
should be carefully observed and ORTHO EVRA® discontPued If significant depression occure.
7. Contact Lantat: Contact tens wearers vho develop visual changes or changes P lens tol
erance should be assessed by an ophthalmologst ft Drug interactions: Changes p Contraceptive
Effectiveness Associated wib Co-Admnistration ot Other Drugs: Contraceptive efleettreness
may be reduced when hormonal contraceptives are co-admPistered wib some antibiotics,
developed an immune response to
the protein were not able to fertil
ize a female egg.
The protein causes the body’s
defense mechanism to disable the
sperm. This occurs because the
protein never enters the blood
stream, so when it is injected for
the first time, the immune system
does not recognize it and produces
antibodies to fight it.
Stan Beyler, director of embry
ology and andrology laboratories,
said this idea has been around for
a while.
“The concept is not something
brand new,” he said. “It’s just find
ing the right molecule. This could
be the one.”
Finding a way to help provide
male contraception, Beyler said,
also might help identify people
with infertility disorders.
Sally Perreault, director of the
reproductive toxicology division
at the Environmental Protection
Agency, said there have not been
many reliable methods of birth
Judicial system faces scrutiny
BY MARK PUENTE
STAFF WRITER
Legal observers probably would
say justice was served after three
men received a death sentence and
three life sentences for murder and
rape in North Carolina.
But lawyers said it represents
a serious problem when the three
men spend a combined 48 years
behind bars —and are later
released after courts determine
that the evidence used to prosecute
them was flawed.
“I am certain that there are
many more innocent people behind
News
control for men other than barrier
methods such as condoms.
“I think this would serve a great
need, allowing men to take respon
sibility and give couples more
choice,” Perreault said.
If the method is proven safe,
effective and reversible, scientists
could invent a safe male contra
ceptive.
However, the treatment will not
be placed on the market anytime
soon. “This is a long process,” she
said. “Clinical trials could take sev
eral years.”
Beyler said that it is difficult to
predict when the treatment will
be placed on the market, and that
much depends on funding.
“It needs to be recognized as
something that is important and
needs a substantial amount of fund
ing and support,” he said. “These
are areas that we need to continue
to strive to fund and research.”
Contact the University Editor
at udesk@unc.edu.
bars,” said Roy Trest, an attorney in
Brunswick County.
Alan Gell, Darryl Hunt and
Sylvester Smith are three of a grow
ing number of inmates who were
wrongly convicted in North Carolina
—and freed when new evidence
surfaced years after their trials:
■ Gell was freed from death row
in February after 10 years and given
anew trial when a judge ruled that
prosecutors withheld key evidence
during his 1995 trial in the murder
of Allen Ray Jenkins. The prosecu
tors have since been reprimanded.
■ Hunt served about 18 years of
antltungals, anticonvulsants, and other drags that ncrease metaboism ot contacepdue steroids.
This could result In unintended pregnancy or breakthroutft bleedng. Examples Include barbi
turates, griseofuMn. rifampin, phenybutazone. pltenyton, carbamazepne, tebamate, oxcar
bazepne, topiramate and possibly wrth ampidin. The propoeed mechanism ot Interaction of
antbtodcs Is different from that of Irt/er enzyme-inducing drags. Literature suggests possible
interactions wrth the concomitant use of hormonal contraceptives and ampidin or tetracy
cine. n a pharmacokinetic efrug interaction study, oral admnistratlon ot tetracydne HCL
500 mg q.i.d. tor 3 days prior to and 7 days during wear ot ORTHO B/RA® did not significantly
affect the pharmacoknetics ol norelgesfromn or EE Several ot the anti-HIV protease hhbitors
have been studied wrth co-adminisfration ot oral combination hormonal contraceptives;
significant changes (increase and decrease) In the mean AUC of the estrogen and progestn
nave been noted it some cases The efficacy and safety of oral contraceptwe products may be
affected; rt Is unknown whether this applies to ORTHO EVRA®. Healthcare professionals shcxtld
refer to the label ot the ndlvidual anti-HIV protease inhibtors tor further drag-drag hteraction
intormation. Herbal products contahhg St. John's Wort (hypericum perforatum) may itduce
hepatic enzymes (cytochrome P 450) and p-glycoprotein transporter and may reduce the
effectiveness ol contraceptive steroids. This may also result it breakthrough bleeding, fricrease
in Plasma Hormme Levels Associated with Co-Administered Drags: Co-adminisfration ot
atorvastatm and certain oral contraceptives containng ethinyl estradiol Increase AUC values
for ethinyl estradiol by approximately 20%. Ascrxbic acid and acetaminophen may ncrease
plasma ethinyl estradiol levels, possbly by inhibition ot conjugation. CYP 3A4 Inhibitors such
as itraconazole or ketoconazole may ncrease plasma homtone levels.Chanoesn Plasma Levels
ol Co-Admnistered Drags: Combnation hormonal contraceptives contaniig some synthetic
estrogens (e.g., ethinyl estradiol) may inhibit the metabolism ot other compounds, horeased
plasma concentrations of cyclosporine, prednisolone, and theophylline have been reported wrth
concomitant administration ot oral contraceptives, n addition, oral contraceptives may hduce
me conjugation ot other compounds. Decreased plasma concentrations of acetaminophen and
increased clearance ot temazepam, salicylic add, morphine and ckrtbric add have been noted
when these drags were admiiistered wlh oral contraceptives. Although norelgestromii and
its metabolites inhibft a variety ot P 450 enzymes h human liver mcrosomes, me clinical
consequence ol such an Interaction on the levels of other concomitant medications Is Ikely to
be insignificant. Under the recommended deeirtg regimen, the In vivo concentrations of norelge
stromit and Its metabolites, even at the peak seram levels, are relatively low compared to the
mhbtory constant (Ki) (based on results ot In vitro studies). Hearth care professionals are
advised to also refer to prescribing Information of co-admiiistered drugs tor recommendations
regardiig management ot cencomtamtherapy. ft Intancttons With Laboratory Teats: Certah
endocrine and liver function tests and blood components may be affected by hormonal
contraceptives: a. Increased prothrombin and factors VII, VII, K, and X; decreased antithrom
bit 3; Increased norepiiephrtne-mduced platelet aggregability. b. Increased thyroid binding
gtobuki (TBG) leading to increased doubting total thyroid hormone, as measured by protem
bound up he (PBI). T 4 by column or by radioimmunoassay. Free T3 resin uptake Is decreased,
reflecting the elevated TBG, free T 4 concentration Is unaltered, c. Other binding proteins may
be elevated it seram. and. Sex hormone balding globulins are ncreased and result h elevated
levels of total cremating endogenous sex steroids and corticolds; however, free or biologically
active levels either decrease or remain unchanged, e. Triglycerides may be ncreased and
levels ot various other Ipids and Ipxprotens may be affected, f. Glucose tolerance may be
decreased, g. Seram folate levels may be depressed by hormonal contraceptwe therapy. This
may be of clinical significance it a woman becomes pregnant shortly after discontinuing
ORTHO EVRA®. Ift Carcinogenesis: No carcinogenicity studies were conducted wth norelge
sfromn. However, bridghg PK studies were conducted ushg dues of NGM/EE Witch were
used previously h the 2-year rat carcinogenicity study and 10-year monkey toxicity study to
support the approval ot ORTHO-CYCLEN and ORTHO TRI-CYCLEN under NDAs 19-653 and
19-697, respectively. The PK studies demonstrated that rats and monkeys were etposed to 16
and 8 times the human exposure, respectively, wth the proposed ORTHO B/RA® transdermai
contraceptive system. Norelgesfromn wastested h h-vitro mutagenicity assays Ojacterialpbte
Incorporation mutation assay, CHO/HGPRT mutation assay, chromosomal abeiration assay
ushg cu lured human peripheral lymphocytes) and In one h-vWo test (rat mkaonudeus assay)
and tound to have no genotoxicpotentlal. See WARNINGS Section. It.Preonancy: Pregnancy
Categmy X. See CONTRANDtCATIONS and WARNNGS Sections. Norelgesfromn wastested lor
its reproductwe toxicity in a rabbit developmental toxicity study by the SC route ot administra
tion. Doses of 0,1,2,4 and 6 mg/kg body weight, which gave systemic exposure of approxi
mately 25 to 125 times the human exposure wrth ORTHO EVRA®, were administered dally on
gestation days 7-19. Malformations reported were paw hypertletdon at 4 and 6 mg/kg and
paw hyperextension and cleft palate at 6 mg/kg. 12 Nursing Mothers: The effects of
ORTHO EVRA® In nursing mothers have not been evaluated and are unknowt. Small amounts
ot combiiation hormonal contraceptwe steroids have been Identified at the mik of nursing
mothers and a tew adverse effects on the chid have been reported, Induing jaundice and
breast enlargement at addition, combination hormonal contraceptwes gWen n the postpartum
period may intertere with lactation by decreasiig the quantity and quality <4 breast mik. Long
term (ol tow-up of infants Wtoee mothers used combnation hormonal contraceptives Write breast
feedng has shown no deleterious effects. However, the nursing mother should be
advised not to use ORTHO EVRA® but to use other torms of contraception until she has com
plertely weaned her chid. 13. Pediatric Use Safety and efficacy ot ORTHO EVRA® have been
established n women of reproductwe age. Safety and efficacy are etqteded to he the same tor
post-pitoertal adolescents under the age of 16 and tor usere f 6 years and older. Use cf this
product before menarche Is not Indicated. 14 Geriatric Uee This product has nef been stud
ied n women ewer 65 years ot age and is not ndicated n this population. 15. Sexually
Transmitted Disease* Patients should be counse ted that this product does not protect against
HIV niechon (ADS) and other sexuah transmitted diseases. 16. Patch Adhesion: Experience
with mere than 70,000 ORTHO EVRA® patches worn tor contracepf lon tor 6-13 cycles showed
that 4.7% ot patches were replaced because they either tel off (1.6%) or were patty detached
(29%). Sim (arty, n a smal study ot patch wear under conditions of physical exertion and vari
able temperature and humidity, less than 2% ot patches were replaced tor complerte or partial
detachment. It the ORTHO EVRA® patch becomes partially or completely detached and
remans detached, Insufficient drag delivery occure. Apatch should not be re-applied rt I is no
lenger sticky, If it has become stuck to Itsof or another surface, It rt has other material stuck
to t, or rt rt has become loose or fallen off betore. Ia patch cannot be re-appSed, anew potch
should be applied immediately. Supplemental adheswes or waps should not be used to hold
the ORTHO EVRA® patch h place. If a patch is partially or completely detached tot more than
one day (24 hours or more)oß f the woman Is not sure how long the patch has been detached,
she may not be protected from pregnancy. She should stop the cument contraceptive cycle and
start anew cycle immediately by applying anew petch. Back-up contraception, such as con
doms, spermicide, or diaphragm, must be used tor the first week of the new q/cte.
INFORMATION FOR THE RATtENE See Patient Package Insert.
ADVERSE REACTIONS: The most common adverse events reported by 9 to 22% ot women
ushg ORTHO EVRA® in dnical trials (N= 3,330) were the tollowng, n order of decreashg
incidence: breast symptoms, headache, application site readlon. nausea, upper respiratory
infection, menstrual cramps, and abdominal pan.
The most frequent adverse events leading to dlscmtinuation n 1 to 2.4% and women usng
ORTHO EVRA® h the trials included the tallowing: nausea and/or vomiting, application site
readlon, breast symptoms, headache, and emotional lability.
Lsted below are adverse events that have been associated with the use of combination
hormonal contraceptives. These are also likely to apply to combination transdermai hormonal
contraceptives such as ORTHO EVRA®.
An ncreased risk of the folowng serious adverse readlons has been associated wrth the use
ot combnation hormonal contraceptives (see WARNINGS Section): 1 Thrombophteblis and
venous thrombosis wrth or without embolism 2. Arterial thromboembolism 3. Pulmonary
embolism 4. Myocardial rtfardton 6. Cerebral hemorrhage 6, Cerebralthrombosis 7. Hypertension
8. Gallbladder disease 9. Hepatic adenomas or benign liver tumors
Rtete Is evidence ot an association between the foltowng conditions and the use ot combda
tkn hormonal contraceptives: 1. Mesenteric thrombosis 2. Rethal thrombais
The tallowing adverse reactions have been reported n users of combination hormonal con
traceptwes and are believed to be drug-related: 1. Nausea 2. Vomiting 3. Gastrointestinal symp
toms (such as abdomral cramps and bloatng) 4. Breakthrough bleeding 5. Spotting 6. Change
r mensfrual (tow 7. /Vnenonhea 8. Temporary nterfiy after dtscontnuatton cf treatment 9. Edema
10. Melasma which may persist 11. Breast changes: tenderness, enlargement secretion
12, Change in weight (increase or decrease) 13. Change n cervical erosion and secretion
14. Diminution n lactation when given immediately postpartum 15. Cholestatic jaundice
16. Migraine 17. Rash (allergic) 18. Mental depression 19. Reduced tolerance to carbohydrates
20. Vagnal candidiasis 21. Change n comeal curvature (steepenng) 22. Intolerance to
contact tenses
The tallowing adverse reactions have been reported n users ot combination hormonal
contraceptives and a cause and effect association has teen neither confirmed nor refuted:
1. Pre-menstraal syndrome 2. Cataracts 3. Changes in appetite 4. Cystitis-llke syndrome
5. Headache 6. Nervousness 7. Dizziness 8. Hirsutism 9. Loss of scalp hair 10. Erythema
' multitorme 11. Erythema nodosum 12 Hemontragic eruption 13. Vaginitis 14. Porphyria
15. Impaired renal function 16 Hemolytic uremic syndrome 17. Acne 18. Changes In Ibido
19. Colitis 20. Budd-Chiari Syndrome
OVERDOSAGE: Serious 111 effects have not been reported tallowing accidental ngestlon ot large
doses ol hormonal contraceptives. Overdosage may cause nausea and vomiting, and withdrawal
bleedng may occur m tamales. Given the nature and design ot the ORTHO EVRA® patch, rt Is
unlikely that overdosage will occur. Serious 111 effects have not been reported tallowing acute
ngestlon of large doses of oral contraceptives by young children. In case ot suspected overdcee,
all ORTHO EVRA® patches should be removed and symptomatic treatment given.
ORTHg^cNEIL
ORTHO-McNEIL PHARMACEUTICAL, INC.
Raritan, New Jersey 08869
© OMP 2001 Revised: May 2003 631-10-660-2 B
State commission
to revamp voting
CHARLOTTE A state study
commission will convene as early as
this week to decide how to overhaul
North Carolina’s voting machines
including the one that lost about
4,500 votes in Carteret County.
Other problems included
an Election Day miscount in
Mecklenburg County and the
delayed discovery 0f13,200 ballots
in Gaston County.
Despite all 100 counties’ report
ing unofficial results in North
Carolina’s Nov. 2 election, the out
come of two statewide races won’t
be known for days.
Protests and requests for recounts
have been filed by candidates for
agriculture commissioner and state
superintendent, forcing election
workers to again labor over the more
than 3 million ballots cast. They
have until Wednesday to finish.
As recounts and protests go on,
the quest to restore voter confi
dence is taking center stage.
“The legal system never changes overnight.
It is a problem for the entire system. But
we’re seeing the beginnings of change.”
RICH ROSEN, unc law professor
a life sentence for a crime he always
denied committing. In December
2003, Willard Brown confessed
to the 1984 rape and murder of
Deborah Sykes after DNA testing
linked him to the crime.
■ Smith was freed Nov. 5 after 20
years, when the two children who
(% oaUg (Ear
Federal auditing officials will
meet today to review a request
from six congressional Democrats,
including U.S. Rep. Mel Watt of
Charlotte, for an investigation of
voting problems in North Carolina
and other states.
“The objective ultimately is to
get to a system where people vote
and feel that their vote is being
counted,” Watt said.
National experts call Carteret
County’s lost votes one of the worst
election flubs this year. There, out
dated software lost 4,500 ballots,
which could induce a statewide re
vote for agriculture commissioner.
Carteret County officials had
been assured the machine would
take 10,000 ballots, but the soft
ware had not been updated. When
the machine hit its limit, the
screen said “voter log full,” said
UniLect president Jack Gerbel,
whose California company made
the machine.
accused him of raping them recant
ed their testimony and implicated
a family member. Smith received
three life sentences based primar
ily on the testimony of a 4-year-old
girl and her 6-year-old cousin.
Rich Rosen, professor of law at
UNC, said officials are aware that
people are incarcerated based on
misidentifications.
“That is the single greatest factor
to wrongful prosecutions,” he said.
“The DNA cases have convinced us.
... We want to lessen the number of
times in the future.”
On the national level, there
have been 117 people exonerated
from death row since 1973 because
DNA testing showed them to be
innocent, according to the Death
Penalty Information Center in
Washington, D.C.
But the process is slow, and attor
neys are inundated with letters from
inmates proclaiming innocence.
“The legal system never changes
overnight,” Rosen said. “It is a prob
lem for the entire system. But we’re
seeing the beginnings of change.”
Wrongful convictions also are
being blamed on lawyers who lack
training in capital punishment
cases.
“One of the biggest problems
is poor lawyering,” said Richard
Dieter, executive director of the
DPIC. “That results in things not
being caught.”
N.C. Supreme Court Chief
Justice Beverly Lake formed the
N.C. Actual Innocence Commission
in February 2003 to recommend
solutions to the problems.
The group comprises legislators,
judges, prosecutors, police officers
and law professors who review how
innocent people are convicted and
how to free them when it happens.
“We have looked at pretrial iden
tification procedures,” said Rosen,
a member of the commission. “We
have made recommendations to a
number of police departments.”
As of Monday, there were 36,292
inmates behind bars and 183 on
death row in the state, according to
the N.C. Department of Correction
Web site.
A number of innocent people get
convicted, Rosen said. But there is
no way to determine how many
people actually are innocent with
out scientific proof.
Attorneys also are concerned
about prosecutors relying on children
to testify in many capital cases.
Edwin Colfax, executive direc
tor of the Center on Wrongful
Convictions at the Northwestern
University School of Law, said the
legal system needs revamping when
it comes to interrogating children.
“Child witnesses are problemat
ic. There are major problems with
them being manipulated.”
In the Smith case, the girls’
grandmother, who is now deceased,
was covering up for her grandson
and coaxed the girls into implicat
ing Smith.
“The main villain is no longer
here to be prosecuted,” said Trest,
Smith’s attorney. “Any time you rely
on children’s testimony, everyone
should look at it with a critical eye.”
Trest said the jurors who con
victed Smith were convinced by
the girls’ testimony.
“There is such an emotional
reaction when sex crimes and kids
are involved,” he said.
The system doesn’t work per
fectly. But there is a quest to seek
the truth.”
Contact the State National
Editor at stntdesk@unc.edu.