Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/23
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NuvaRing (Insert, Extended Release)
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To achieve maximum
contraceptive effectiveness, NuvaRing' must be used as directed (see
When to
Start NuvaRing' below). One NuvaRing' is inserted in the
vagina. The ring is to remain in place
continuously for three weeks. It is removed for a one-week
break, during which a withdrawal bleed usually occurs. A new ring is
inserted one week after the last ring was removed. The user can choose
the insertion position that is most comfortable to her, for example,
standing with one leg up, squatting, or lying down. The ring is to be
compressed and inserted into the vagina. The exact position of NuvaRing'
inside the vagina is not critical for its function. The vaginal ring
must be inserted on the appropriate day and left in place for three
consecutive weeks. This means that the ring is removed three weeks later
on the same day of the week as it was inserted and at about the same
time. NuvaRing' can be removed by hooking the index finger under the
forward rim or by grasping the rim between the index and middle finger
and pulling it out. The used ring should be placed in the sachet (foil
pouch) and discarded in a waste receptacle out of the reach of children
and pets (do not flush in toilet). After a one-week break, during which
a withdrawal bleed usually occurs, a new ring is inserted on the same
day of the week as it was inserted in the previous cycle. The withdrawal
bleed usually starts on day 2-3 after removal of the ring and may not
have finished before the next ring is inserted. In order to maintain
contraceptive effectiveness, the new ring must be inserted one week
after the previous one was removed even if menstrual bleeding has not
finished.<br/>When to Start
NuvaRing': IMPORTANT:
The possibility of ovulation and conception prior to the first
use of NuvaRing' should be considered.<br/>No hormonal contraceptive use
in the preceding cycle: Insert NuvaRing' on the first day of the woman's
natural cycle (i.e., the first day of her menstrual
bleeding). NuvaRing' may also be started on days 2-5 of
the woman's cycle, but in this case a barrier method,
such as male condoms or spermicide, is recommended for
the first seven days of NuvaRing' use in the first
cycle.<br/>Changing from a combined
hormonal contraceptive: The
woman may switch from her previous combined hormonal
contraceptive on any day, but at the latest on the day
following the usual hormone-free interval, if she has
been using her hormonal method consistently and
correctly, or if it is reasonably certain that she is
not pregnant.<br/>Changing from a
progestagen-only method (minipill, implant, or
injection) or from a progestagen-releasing intrauterine
system (IUS): The
woman may switch on any day from the minipill. She
should switch from an implant or the IUS on the day of
its removal and from an injectable on the day when the
next injection would be due. In all of these cases, the
woman should use an additional barrier method such as a
male condom or spermicide, for the first seven
days.<br/>Following complete first
trimester abortion: The
woman may start using NuvaRing' within the first five
days following a complete first trimester abortion and
does not need to use an additional method of
contraception. If use of NuvaRing' is not started within
five days following a first trimester abortion, the
woman should follow the instructions for���No hormonal
contraceptive use in the preceding cycle.���In the
meantime she should be advised to use a non-hormonal
contraceptive method.<br/>Following delivery or second
trimester abortion: The
use of NuvaRing' for contraception may be initiated four
weeks postpartum in women who elect not to breast-feed.
Women who are breast-feeding should be advised not to
use NuvaRing' but to use other forms of contraception
until the child is weaned. NuvaRing' use may be
initiated four weeks after a second trimester abortion.
When NuvaRing' is used postpartum or postabortion, the
increased risk of thromboembolic disease must be
considered. (See CONTRAINDICATIONS and WARNINGS concerning thromboembolic
disease. See PRECAUTIONS for���Nursing Mothers���.) If a
woman begins using NuvaRing' postpartum, she should be
instructed to use an additional method of contraception,
such as male condoms or spermicide, for the first seven
days. If she has not yet had a period, the possibility
of ovulation and conception occurring prior to
initiation of NuvaRing' should be
considered.<br/>Deviations from the
Recommended Regimen: To prevent
loss of contraceptive efficacy, women should not deviate from
the recommended regimen. NuvaRing' should be left in the vagina
for a continuous period of three weeks.<br/>Inadvertent removal,
expulsion, or prolonged ring-free interval: If
the ring is accidentally expelled and is left outside of
the vagina for less than three
hours contraceptive efficacy is not
reduced. NuvaRing' can be rinsed with cool to lukewarm
(not hot) water and reinserted
as soon as possible, but at the latest
within three hours. If NuvaRing' is lost, a new vaginal
ring shouldbe inserted and the regimen should be
continued without alteration. If NuvaRing' is out of the
vagina for more than three hours, the directions listed
under PRECAUTIONS, EXPULSION should be
followed. If
the ring-free interval has been extended beyond one
week, the possibility of pregnancy should be considered,
and an additional method of contraception, such as male
condoms or spermicide, MUST be used until NuvaRing' has been used
continuously for seven
days.<br/>Prolonged Use of
NuvaRing': If
NuvaRing' has been left in place for up to one extra
week (i.e., up to four weeks total), the woman will
remain protected. NuvaRing' should be removed and the
woman should insert a new ring after a one-week
ring-free interval. The mean serum etonogestrel
concentration during the fourth week of continuous use
of NuvaRing' was 1272��311 pg/mL compared to a mean
concentration range of 1578��408 to 1374��328 pg/mL
during weeks one to three. The mean serum ethinyl
estradiol concentration during the fourth week of
continuous use of NuvaRing' was 16.8��4.6 pg/mL
compared to a mean concentration range of 19.1��4.5 to
17.6��4.3 pg/mL during weeks one to three. If NuvaRing'
has been left in place for longer than four weeks,
pregnancy should be ruled out, and an additional method
of contraception, such as male condoms or spermicide,
MUST be used
until a new NuvaRing' has been used continuously for seven
days.<br/>In the event of a
missed menstrual period:
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| dailymed-instance:descripti... |
NuvaRing'
(etonogestrel/ethinyl estradiol vaginal ring) is a non-biodegradable,
flexible, transparent, colorless to almost colorless, combination
contraceptive vaginal ring containing two active components, a
progestin, etonogestrel
(13-ethyl-17-hydroxy-11-methylene-18,19-dinor-17��-pregn-4-en-20-yn-3-one)
and an estrogen, ethinyl estradiol
(19-nor-17��-pregna-1,3,5(10)-trien-20-yne-3, 17-diol). When placed in
the vagina, each ring releases on average 0.120 mg/day of etonogestrel
and 0.015 mg/day of ethinyl estradiol over a three-week period of use.
NuvaRing' is made of ethylene vinylacetate copolymers (28% and 9%
vinylacetate) and magnesium stearate and contains 11.7 mg etonogestrel
and 2.7 mg ethinyl estradiol. NuvaRing' is latex-free. NuvaRing' has an
outer diameter of 54 mm and a cross-sectional diameter of 4 mm. The
molecular weights for etonogestrel and ethinyl estradiol are 324.46 and
296.40, respectively. The structural
formulas are as follows:
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| dailymed-instance:clinicalP... |
Combination
hormonal contraceptives act by suppression of gonadotropins. Although
the primary effect of this action is inhibition of ovulation, other
alterations include changes in the cervical mucus (which increase the
difficulty of sperm entry into the uterus) and the endometrium (which
reduce the likelihood of implantation). Receptor binding
studies, as well as studies in animals, have shown that etonogestrel,
the biologically active metabolite of desogestrel, combines high
progestational activity with low intrinsic androgenicity. The relevance
of this latter finding in humans is unknown.<br/>Pharmacokinetics:<br/>Absorption: Etonogestrel:
Etonogestrel released by NuvaRing' is rapidly
absorbed. The bioavailability of etonogestrel after
vaginal administration is approximately 100%. The serum
etonogestrel and ethinyl estradiol concentrations
observed during three weeks of NuvaRing' use are
summarized in Table I. Ethinyl
estradiol: Ethinyl estradiol released by
NuvaRing' is rapidly absorbed. The bioavailability of
ethinyl estradiol after vaginal administration is
approximately 56%, which is comparable to that with oral
administration of ethinyl estradiol. The serum ethinyl
estradiol concentrations observed during three weeks of
NuvaRing' use are summarized in Table I. The
pharmacokinetic profile of etonogestrel and ethinyl
estradiol during use of NuvaRing' is shown in Figure 1. The
pharmacokinetic parameters of etonogestrel and ethinyl
estradiol were determined during one cycle of NuvaRing'
use in 16 healthy female subjects and are summarized in
Table II.<br/>Distribution: Etonogestrel:
Etonogestrel is approximately 32% bound to sex
hormone-binding globulin (SHBG) and approximately 66%
bound to albumin in blood. Ethinyl
estradiol: Ethinyl estradiol is highly but not
specifically bound to serum albumin (98.5%) and induces
an increase in the serum concentrations of
SHBG.<br/>Metabolism: In vitro data
shows that both etonogestrel and ethinyl estradiol are
metabolized in liver microsomes by the cytochrome P450
3A4 isoenzyme. Ethinyl estradiol is primarily
metabolized by aromatic hydroxylation, but a wide
variety of hydroxylated and methylated metabolites are
formed. These are present as free metabolites and as
sulfate and glucuronide conjugates. The hydroxylated
ethinyl estradiol metabolites have weak estrogenic
activity. The biological activity of etonogestrel
metabolites is unknown.<br/>Excretion: Etonogestrel and ethinyl estradiol are primarily
eliminated in urine, bile and feces.<br/>Special Populations:<br/>Race: No
formal studies were conducted to evaluate the effect of
race on the pharmacokinetics of NuvaRing'.<br/>Hepatic
Insufficiency: No
formal studies were conducted to evaluate the effect of
hepatic disease on the pharmacokinetics, safety, and
efficacy of NuvaRing'. However, steroid hormones may be
poorly metabolized in women with impaired liver function
.<br/>Renal Insufficiency: No
formal studies were conducted to evaluate the effect of
renal disease on the pharmacokinetics, safety, and
efficacy of NuvaRing'.<br/>Drug-Drug
Interactions: Interactions between contraceptive steroids and other
drugs have been reported in the literature (see
PRECAUTIONS). The drug interactions of
NuvaRing' were evaluated in several studies. A
single-dose vaginal administration of an oil-based 1200
mg miconazole nitrate capsule increased the serum
concentrations of etonogestrel and ethinyl estradiol by
approximately 17% and 16%, respectively. Following
multiple doses of 200 mg miconazole nitrate by vaginal
suppository or vaginal cream, the mean serum
concentrations of etonogestrel and ethinyl estradiol
increased by up to 40%. A
single-dose vaginal administration of 100 mg water-based
nonoxynol-9 spermicide gel did not affect the serum
concentrations of etonogestrel or ethinyl estradiol. The
serum concentrations of etonogestrel and ethinyl
estradiol were not affected by concomitant
administration of oral amoxicillin or doxycycline in
standard dosages during 10 days of antibiotic
treatment.<br/>Tampon Use: The
use of tampons had no effect on serum concentrations of
etonogestrel and ethinyl estradiol during use of
NuvaRing'.
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NuvaRing' should
not be used in women who currently have the following conditions:
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| dailymed-instance:supply |
Each NuvaRing'
(etonogestrel/ethinyl estradiol vaginal ring) is individually packaged
in a reclosable aluminum laminate sachet consisting of three layers,
from outside to inside: polyester, aluminum foil, and low-density
polyethylene. The ring should be replaced in this reclosable sachet
after use for convenient disposal. Box of 3
sachets NDC
0052-0273-03Box of 1
sachet NDC
0052-0273-01<br/>Storage: Prior to
dispensing to the user, store refrigerated 2���8��C (36���46��F).
After dispensing to the user, NuvaRing' can be stored for up to
four months at 25��C (77��F); excursions permitted to 15���30��C
(59���86��F) [see USP Controlled Room Temperature]. Avoid storing
NuvaRing' in direct sunlight or at temperatures above 30��C
(86��F). For the Dispenser: When NuvaRing' is dispensed to the
user, place an expiration date on the label. The date should not
exceed either four months from the date of dispensing or the
expiration date, whichever comes first. Rx only
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| dailymed-instance:precautio... |
1. SEXUALLY TRANSMITTED DISEASES Women should be counseled that this product
does not protect against HIV infection (AIDS) and other sexually
transmitted diseases.<br/>2. PHYSICAL
EXAMINATION AND FOLLOW-UP: It is
routine medical practice for women using NuvaRing', as for all
women, to have an annual medical evaluation including physical
examination and relevant laboratory tests. The physical
examination should include special reference to blood pressure,
breasts, abdomen, pelvic organs and vagina (including cervical
cytology). In case of undiagnosed, persistent or recurrent
abnormal vaginal bleeding, appropriate measures should be
conducted to rule out malignancy. Women with a family history of
breast cancer or who have breast nodules should be monitored
with particular care.<br/>3. LIPID DISORDERS: Women who
are being treated for hyperlipidemias should be followed closely
if they elect to use NuvaRing'. Some progestogens may elevate
LDL levels and may render the control of hyperlipidemias more
difficult. In women
with familial defects of lipoprotein metabolism receiving
estrogen-containing preparations, there have been case reports
of significant elevations of plasma triglycerides leading to
pancreatitis.<br/>4. LIVER FUNCTION: If jaundice
develops in any woman using NuvaRing', product use should be
discontinued. The hormones in NuvaRing' may be poorly
metabolized in women with impaired liver function.<br/>5. FLUID RETENTION: Steroid
hormones like those in NuvaRing', may cause some degree of fluid
retention. NuvaRing' should be prescribed with caution, and only
with careful monitoring, in women with conditions which might be
aggravated by fluid retention.<br/>6. EMOTIONAL
DISORDERS: Women
becoming significantly depressed while taking hormonal
contraceptives should stop the medication and use an alternate
method of contraception in an attempt to determine whether the
symptom is drug related. Women with a history of depression
should be carefully observed and the drug discontinued if
depression recurs to a serious degree.<br/>7. TAMPON USE: On rare
occasions, NuvaRing' may be expelled while removing a tampon
. Pharmacokinetic data show that the
use of tampons has no effect on the systemic absorption of the
hormones released by NuvaRing'.<br/>8. TOXIC SHOCK
SYNDROME (TSS): Cases of
toxic shock syndrome have been associated with tampons and
certain barrier contraceptives. Very rare cases of TSS have been
reported by NuvaRing' users; in some cases the women were also
using tampons. No causal relationship between the use of
NuvaRing' and TSS has been established. If a patient exhibits
signs or symptoms of TSS, the possibility of this diagnosis
should not be excluded and appropriate medical evaluation and
treatment initiated.<br/>9. CONTACT LENSES: Contact
lens wearers who develop visual changes or changes in lens
tolerance should be assessed by an ophthalmologist.<br/>10. DRUG
INTERACTIONS:<br/>Changes in contraceptive
effectiveness associated with co-administration of other
drugs:: a. Anti-infective agents and
anticonvulsants Contraceptive effectiveness may be reduced when
hormonal contraceptives are co-administered with some
antifungals, anticonvulsants, and other drugs that
increase metabolism of contraceptive steroids. This
could result in unintended pregnancy or breakthrough
bleeding. Examples include barbiturates, griseofulvin,rifampin, phenylbutazone, phenytoin, carbamazepine,
felbamate, oxcarbazepine, topiramate, and modafinil.
Women may need to use an additional contraceptive method
when taking such medications. b. Anti-HIV protease
inhibitors Several of the anti-HIV protease inhibitors have been
studied with co-administration of oral combination
hormonal contraceptives; significant changes (increases
and decreases) in the plasma levels of the estrogen and
progestin have been noted in some cases. The efficacy
and safety of hormonal contraceptive products may be
affected with co-administration of anti-HIV protease
inhibitors. Healthcare providers should refer to the
label of the individual anti-HIV protease inhibitors for
further drug-drug interaction information. c. Herbal products Herbal products containing St. John's Wort
(hypericum perforatum) may induce hepatic enzymes
(cytochrome P450) and p-glycoprotein transporter and may
reduce the effectiveness of contraceptive steroids. This
may also result in breakthrough bleeding.<br/>Increase in plasma hormone levels
associated with co-administered drugs:: Co-administration of atorvastatin and certain oral
contraceptives containing ethinyl estradiol increase AUC
values for ethinyl estradiol by approximately 20%.
Ascorbic acid and acetaminophen may increase plasma
ethinyl estradiol levels, possibly by inhibition of
conjugation. CYP 3A4 inhibitors such as itraconazole or
ketoconazole may increase plasma hormone levels.
Co-administration of vaginal miconazole nitrate and
NuvaRing' increases the serum concentrations of
etonogestrel and ethinyl estradiol by up to
40%.<br/>Changes in plasma levels of
co-administered drugs:: Combination hormonal contraceptives containing some
synthetic estrogens (e.g., ethinyl estradiol) may
inhibit the metabolism of other compounds. Increased
plasma concentrations of cyclosporine, prednisolone, and
theophylline have been reported with concomitant
administration of oral contraceptives. In addition, oral
contraceptives may induce the conjugation of other
compounds. Decreased plasma concentrations of
acetaminophen and increased clearance of temazepam,
salicylic acid, morphine and clofibric acid have been
noted when these drugs were administered with oral
contraceptives.<br/>11. INTERACTIONS
WITH LABORATORY TESTS: Certain
endocrine and liver function tests and blood components may be
affected by combined hormonal contraceptives:<br/>12. CARCINOGENESIS,
MUTAGENESIS, IMPAIRMENT OF FERTILITY: In a
24-month carcinogenicity study in rats with subdermal implants
releasing 10 and 20��g etonogestrel per day, (approximately 0.3
and 0.6 times the systemic steady-state exposure of women using
NuvaRing'), no drug-related carcinogenic potential was observed.
Etonogestrel was not genotoxic in the in vitro Ames/Salmonella
reverse mutation assay, the chromosomal aberration assay in
Chinese hamster ovary cells or in the in vivo mouse micronucleus
test. Fertility returned after withdrawal from treatment (see
WARNINGS).<br/>13. PREGNANCY: Pregnancy Category X
. Teratology studies have been performed in rats and
rabbits using the oral route of administration at doses up to
130 and 260 times, respectively, the human NuvaRing' dose (based
on body surface area) and have revealed no evidence of harm to
the fetus due to etonogestrel.<br/>14. NURSING MOTHERS: The effects
of NuvaRing' in nursing mothers have not been evaluated and are
unknown. Small amounts of contraceptive steroids have been
identified in the milk of nursing mothers and a few adverse
effects on the child have been reported, including jaundice and
breast enlargement. In addition, contraceptive steroids given in
the postpartum period may interfere with lactation by decreasing
the quantity and quality of breast milk. Long-term follow-up of
children whose mothers used combination hormonal contraceptives
while breast-feeding has shown no deleterious effects on
infants. However, women who are breast-feeding should be advised
not to use NuvaRing' but to use other forms of contraception
until the child is weaned.<br/>15. PEDIATRIC USE: Safety and
efficacy of NuvaRing' have been established in women of
reproductive age. Safety and efficacy are expected to be the
same for postpubertal adolescents under the age of 16 and for
users 16 years and older. Use of this product before menarche is
not indicated.<br/>16. GERIATRIC USE: This
product has not been studied in women over 65 years of age and
is not indicated in this population.<br/>17. VAGINAL USE: NuvaRing'
may not be suitable for women with conditions that make the
vagina more susceptible to vaginal irritation or ulceration.
Vaginal/cervical erosion or ulceration in women using NuvaRing'
has been rarely reported. In some cases, the ring adhered to
vaginal tissue, necessitating removal by a healthcare provider. Some women
are aware of the ring at random times during the 21 days of use
or during intercourse. During intercourse some sexual partners
may feel NuvaRing' in the vagina. However, clinical studies
revealed that 90% of couples did not find this to be a problem. NuvaRing'
may interfere with the correct placement and position of a
diaphragm. A diaphragm is therefore not recommended as a back-up
method with NuvaRing' use.<br/>18. URINARY BLADDER
INSERTION: There have
been rare reports of inadvertent insertions of NuvaRing' into
the urinary bladder, which required cystoscopic removal.
Healthcare providers should assess for ring insertion into the
urinary bladder in NuvaRing' users who present with persistent
urinary symptoms and are unable to locate the ring.<br/>19. EXPULSION: NuvaRing'
can be accidentally expelled, for example, while removing a
tampon, during intercourse, or with straining during a bowel
movement. NuvaRing' should be left in the vagina for a
continuous period of three weeks. If the ring is accidentally
expelled and is left outside of the vagina for less than three hours
contraceptive efficacy is not reduced. NuvaRing' can be rinsed
with cool to lukewarm (not hot) water and reinserted as soon as
possible, but at the latest within three hours. If NuvaRing' is
lost, a new vaginal ring should be inserted and the regimen
should be continued without alteration. If NuvaRing' is out of the vagina for
more than three continuous hours: During Weeks 1 and 2: If
NuvaRing' has been out of the vagina for more than three
continuous hours during the 1st or 2nd week of use,
contraceptive efficacy may be reduced. The woman should reinsert
the ring as soon as she remembers. A barrier method such as
condoms or spermicides must be used until the ring has been used
continuously for seven days. During Week 3: If NuvaRing'
has been out of the vagina for more than three continuous hours
during the 3rd week of the three-week use period, the woman
should discard that ring. One of the following two options
should be chosen: A barrier
method such as condoms or spermicides must be used until the new
ring has been used continuously for seven days.<br/>20. DISCONNECTED
RING: There have
been reported cases of NuvaRing' disconnecting at the weld
joint. This is not expected to affect the contraceptive
effectiveness of NuvaRing'. In the event of a disconnected ring,
vaginal discomfort or expulsion (slipping out) is more likely to
occur . If a woman discovers that her NuvaRing'
has disconnected, she should discard the ring and replace it
with a new ring.
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| dailymed-instance:overdosag... |
Overdosage of
combination hormonal contraceptives may cause nausea, vomiting, vaginal
bleeding, or other menstrual irregularities. Given the nature and design
of NuvaRing' it is unlikely that overdosage will occur. If NuvaRing' is
broken, it does not release a higher dose of hormones. Serious ill
effects have not been reported following acute ingestion of large doses
of oral contraceptives by young children. There are no antidotes and
further treatment should be symptomatic.
|
| dailymed-instance:genericMe... |
etonogestrel and ethinyl estradiol
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| dailymed-instance:fullName |
NuvaRing (Insert, Extended Release)
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| dailymed-instance:adverseRe... |
The most common
adverse events reported by five to 14% of women using NuvaRing' in
clinical trials (n=2501) were the following: vaginitis, headache, upper
respiratory tract infection, vaginal secretion, sinusitis, weight gain,
and nausea. The most frequent
system-organ class adverse events leading to discontinuation in one to
2.5% of women using NuvaRing' in the trials included the following:
device-related events (foreign body sensation, coital problems, device
expulsion), vaginal symptoms (discomfort/vaginitis/vaginal secretion),
headache, emotional lability, and weight gain. Listed below are
adverse reactions that have been associated with the use of combination
hormonal contraceptives. These are also likely to apply to combination
vaginal hormonal contraceptives, such as NuvaRing'. An increased risk
of the following serious adverse reactions has been associated with the
use of combination hormonal contraceptives : There is evidence
of an association between the following conditions and the use of
combination hormonal contraceptives: The following
additional adverse reactions have been reported in users of combination
hormonal contraceptives and are believed to be drug-related: The following
additional adverse reactions have been reported in users of combination
hormonal contraceptives and a causal association has been neither
confirmed nor refuted:
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| dailymed-instance:warning |
Cigarette smoking increases the risk
of serious cardiovascular side effects from combination oral
contraceptive use. This risk increases with age and with
heavy smoking (15 or more cigarettes per day) and is quite
marked in women over 35 years of age. Women who use
combination hormonal contraceptives, including NuvaRing',
should be strongly advised not to smoke. NuvaRing'
and other contraceptives that contain both an estrogen and a
progestin are called combination hormonal contraceptives. There
is no epidemiologic data available to determine whether safety
and efficacy with the vaginal route of administration of
combination hormonal contraceptives would be different than the
oral route. The use of
oral contraceptives is associated with increased risks of
several serious conditions including venous and arterial
thrombotic and thromboembolic events (such as myocardial
infarction, thromboembolism, and stroke), hepatic neoplasia,
gallbladder disease, and hypertension, although the risk of
serious morbidity or mortality is very small in healthy women
without underlying risk factors. The risk of morbidity and
mortality increases significantly in the presence of other
underlying risk factors such as certain inherited
thrombophilias, hypertension, hyperlipidemias, obesity, and
diabetes. The
information contained in this package insert is principally
based on studies carried out in women who used oral
contraceptives with formulations of higher doses of estrogens
and progestogens than those in common use today. The effect of
long-term use of oral contraceptives with lower doses of both
estrogens and progestogens remains to be determined. Throughout
this labeling, epidemiologic studies reported are of two types:
retrospective or case control studies and prospective or cohort
studies. Case control studies provide a measure of the relative
risk of a disease, namely, a
ratio of the incidence of a disease among oral
contraceptive users to that among non-users. The relative risk
does not provide information on the actual clinical occurrence
of a disease. Cohort studies provide a measure of attributable
risk, which is the difference in the incidence of disease between oral
contraceptive users and non-users. The attributable risk does
provide information about the actual occurrence of a disease in
the population. For further information, the reader is referred
to a text on epidemiologic methods.<br/>1. THROMBOEMBOLIC
DISORDERS AND OTHER VASCULAR PROBLEMS:<br/>a.
Thromboembolism: An
increased risk of thromboembolic and thrombotic disease
associated with the use of oral contraceptives is well
established. Case control studies have found the
relative risk of users compared to non-users to be three
for the first episode of superficial venous thrombosis,
four to 11 for deep vein thrombosis or pulmonary
embolism, and 1.5 to six for women with predisposing
conditions for venous thromboembolic disease. Cohort
studies have shown the relative risk to be somewhat
lower, about three for new cases and about 4.5 for new
cases requiring hospitalization. The risk of
thromboembolic disease associated with oral
contraceptives is not related to length of use and
disappears afterpill use is stopped. Several epidemiology studies indicate that third
generation oral contraceptives, including those
containing desogestrel (etonogestrel, the progestin in
NuvaRing', is the biologically active metabolite of
desogestrel), are associated with a higher risk of
venous thromboembolism than certain second generation
oral contraceptives. In general, these studies indicate
an approximate two-fold increased risk, which
correspondsto an additional one to two cases of venous
thromboembolism per 10,000 women-years of use. However,
data from additional studies have not shown this
two-fold increase in risk. It is unknown if NuvaRing'
has a different risk of venous thromboembolism than
second generation oral contraceptives. A
two- to four-fold increase in relative risk of
post-operative thromboembolic complications has been
reported with the use of oral contraceptives. The
relative risk of venous thrombosis in women who have
predisposing conditions is twice that of women without
such medical conditions. If feasible, combination
hormonal contraceptives, including NuvaRing', should be
discontinued at least four weeks prior to and for two
weeks after elective surgery of a type associated with
an increase in risk of thromboembolism and during and
following prolonged immobilization. Since the immediate
postpartum period is also associated with an increased
risk of thromboembolism, combination hormonal
contraceptives, such as NuvaRing', should be started no
earlier than four to six weeks after delivery in women
who elect not to breast-feed. The
clinician should be alert to the earliest manifestations
of thrombotic disorders (thrombophlebitis, pulmonary
embolism, cerebrovascular disorders, and retinal
thrombosis). Should any of these occur or be suspected,
NuvaRing' should be discontinued
immediately.<br/>b.
Myocardial Infarction: An
increased risk of myocardial infarction has been
attributed to oral contraceptive use. This risk is
primarily in smokers or women with other underlying risk factors for coronary artery disease such as
hypertension, hypercholesterolemia, morbid obesity, and
diabetes. The relative risk of heart attack for current
combination oral contraceptive users has been estimated
to be two to six. The risk is very low in women under
the age of 30. Smoking in combination with oral contraceptive use has
been shown to contribute substantially to the incidence
of myocardial infarction in women in their mid-thirties
or older with smoking accounting for the majority of
excess cases. Mortality rates associated with
circulatory disease have been shown to increase
substantially in smokers, over the age of 35 and
non-smokers over the age of 40 among women who use oral
contraceptives (see Table IV). Oral contraceptives may compound the effects of
well-known risk factors, such as hypertension, diabetes,
hyperlipidemias, age, and obesity. In particular, some
progestogens are known to decrease HDL cholesterol and
cause glucose intolerance, while estrogens may create a
state of hyperinsulinism. Oral contraceptives have been
shown to increase blood pressure among users (see
WARNINGS). Similar effects on risk
factors have been associated with an increased risk of
heart disease. NuvaRing' must be used with caution in
women with cardiovascular disease risk
factors.<br/>c.
Cerebrovascular Diseases: Oral contraceptives have been shown to increase both
the relative and attributable risks of cerebrovascular
events (thrombotic and hemorrhagic strokes), although,
in general, the risk is greatest among older (>35
years), hypertensive women who also smoke. Hypertension
was found to be a risk factor for both users and
non-users, for both types of strokes, while smoking
interacted to increase the risk for hemorrhagic strokes. In
a large study, the relative risk of thrombotic strokes
has been shown to range from three for normotensive
users to 14 for users with severe hypertension. The
relative risk of hemorrhagic stroke is reported to be
1.2 for non-smokers who used oral contraceptives, 2.6
for smokers who did not use oral contraceptives, 7.6 for
smokers who used oral contraceptives, 1.8 for
normotensive users and 25.7 for users with severe
hypertension. The attributable risk is also greater in
older women. Oral contraceptives also increase the risk
for stroke in women with other underlying risk factors
such as certain inherited or acquired thrombophilias,
hyperlipidemias, and obesity. Women with migraine
(particularly migraine with aura) who take combination
oral contraceptives may be at an increasedrisk of
stroke.<br/>d.
Dose-related risk of vascular disease from oral
contraceptives: A
positive association has been observed between the
amount of estrogen and progestogen in oral
contraceptives and the risk of vascular disease. A
decline in serum high-density lipoproteins (HDL) has
been reported with many progestational agents. A decline
in serum high-density lipoproteins has been associated
with an increased incidence of ischemic heart disease.
Because estrogens increase HDL cholesterol, the net
effect of an oral contraceptive depends on a balance
achieved between doses of estrogen and progestogen and
the nature and absolute amount of progestogensused in
the contraceptives. The activity and amount of both
hormones should be considered in the choice of a
hormonal contraceptive. Minimizing exposure to estrogen and progestogen is in
keeping with good principles of therapeutics. For any
particular estrogen/progestogen combination, the dosage
regimen prescribed should be one which contains the
least amount of estrogen and progestogen that is
compatible with a low failure rate and the needs of the
individual patient. New acceptors of hormonal
contraceptive agents should be started on a product
containing the lowest hormone content that provides
satisfactory results in the individual.<br/>e.
Persistence of risk of vascular disease: There are two studies that have shown persistence of
risk of vascular disease for ever-users of oral
contraceptives. In a study in the United States, the
risk of developing myocardial infarction after
discontinuing oral contraceptives persists for at least
nine years for women 40-49 years old who had used oral
contraceptives for five or more years, but this
increased risk was not demonstrated in other age groups.
In another study in Great Britain, the risk of
developing cerebrovascular disease persisted for at
least six years after discontinuation of oral
contraceptives, although excess risk was very small.
However, both studies were performed with oral
contraceptive formulations containing 50 micrograms or
more of estrogen. It
is unknown whether NuvaRing' is distinct from
combination oral contraceptives with regard to the
occurrence of venous or arterial thrombosis.<br/>2. ESTIMATES OF
MORTALITY FROM CONTRACEPTIVE USE: One study
gathered data from a variety of sources that have estimated the
mortality rate associated with different methods of
contraception at different ages (Table V). These estimates
include the combined risk of death associated with contraceptive
methods plus the risk attributable to pregnancy in the event of
method failure. Each method of contraception has its specific
benefits and risks. The study concluded that with the exception
of oral contraceptive users age 35 and older who smoke and age
40 and older who do not smoke, mortality associated with all
methods of birth control is low and below that associated with
childbirth. The
observation of a possible increase in risk of mortality with age
for oral contraceptive users is based on data gathered in the
1970's, but not reported until 1983. However, current clinical
practice involves the use of lower estrogen-dose formulations
combined with careful restriction of hormonal contraceptive use
to women who do not have the various risk factors listed in this
labeling. Because of
these changes in practice and, also, because of some limited new
data which suggest that the risk of cardiovascular disease with
the use of oral contraceptives may now be less than previously
observed, the Fertility and Maternal Health Drugs Advisory
Committee was asked to review the topic in 1989. The Committee
concluded that although cardiovascular disease risks may be
increased with oral contraceptive use after age 40 in healthy
non-smoking women (even with the newer low-dose formulations),
there are also greater potential health risks associated with
pregnancy in older women and with the alternative surgical and
medical procedures which may be necessary if such women do not
have access to effective and acceptable means of contraception.
Therefore, the Committee recommended that the benefits of
low-dose hormonal oral contraceptive use by healthy non-smoking
women over 40 may outweigh the possible risks. Older women, as
all women who take hormonal contraceptives, should take the
lowest possible dose formulation that is effective and meets the
individual patient needs.<br/>3. CARCINOMA OF THE
REPRODUCTIVE ORGANONS AND BREASTS: Numerous
epidemiologic studies have been performed on the incidence of
breast, endometrial, ovarian, and cervical cancer in women using
combination oral contraceptives. Although the risk of breast
cancer may be slightly increased among current users of oral
contraceptives (RR = 1.24), this excess risk decreases over time
after oral contraceptive discontinuation and by 10 years after
cessation the increased risk disappears. The risk does not
increase with duration of use, and no relationships have been
found with dose or type of steroid. The patterns of risk are
also similar regardless of a woman's reproductive history or her
family breast cancer history. The subgroup for whom risk has
been found to be significantly elevated is women who first used
oral contraceptives before age 20, but because breast cancer is
so rare at these young ages, the number of cases attributable to
this early oral contraceptive use is extremely small. Breast
cancers diagnosed in current or previous oral contraceptive
users tend to be less advanced clinically than in never-users.
Women who currently have or have had breast cancer should not
use hormonal contraceptives because breast cancer is a
hormone-sensitive tumor. Some
studies suggest that combination oral contraceptive use has been
associated with an increase in the risk of cervical
intraepithelial neoplasia in some populations of women. However,
there continues to be controversy about the extent to which such
findings may be due to differences in sexual behavior and other
factors. In spite of
many studies of the relationship between oral contraceptive use
and breast and cervical cancers, a cause-and-effect relationship
has not been established. It is
unknown whether NuvaRing' is distinct from oral contraceptives
with regard to the above statements.<br/>4. HEPATIC
NEOPLASIA: Benign
hepatic adenomas are associated with oral contraceptive use,
although the incidence of benign tumors is rare in the United
States. Indirect calculations have estimated the attributable
risk to be in the range of 3.3 cases per 100,000 for users, a
risk that increases after four or more years of use. Rupture of
rare, benign, hepatic adenomas may cause death through
intra-abdominal hemorrhage. Studies
from Britain have shown an increased risk of developing
hepatocellular carcinoma in long term (>8 years) oral
contraceptive users. However, these cancers are extremely rare
in the US and the attributable risk (the excess incidence) of
liver cancers in oral contraceptive users approaches less than
one per million users. It is unknown whether NuvaRing' is
distinct from oral contraceptives in this regard.<br/>5. OCULAR LESIONS: There have
been clinical case reports of retinal thrombosis associated with
the use of oral contraceptives. NuvaRing' should be discontinued
if there is unexplained partial or complete loss of vision,
onset of proptosis or diplopia, papilledema, or retinal vascular
lesions. Appropriate diagnostic and therapeutic measures should
be undertaken immediately.<br/>6. HORMONAL
CONTRACEPTIVE USE BEFORE OR DURING EARLY PREGNANCY: Hormonal
contraceptives should not be used during pregnancy. Extensive
epidemiologic studies have revealed no increased risk of birth
defects in women who have used oral contraceptives prior to
pregnancy. Studies also do not suggest a teratogenic effect,
particularly in so far as cardiac anomalies and limb reduction
defects are concerned, when oral contraceptives are taken
inadvertently during early pregnancy. Combination
hormonal contraceptives, such as NuvaRing', should not be used
to induce withdrawal bleeding as a test for pregnancy. NuvaRing'
should not be used during pregnancy to treat threatened or
habitual abortion. It is recommended that for any woman who has
not adhered to the prescribed regimen for use of NuvaRing' and
has missed a menstrual period or who has missed two consecutive
periods, pregnancy should be ruled out.<br/>7. GALLBLADDER
DISEASE: Combination
hormonal contraceptives, such as NuvaRing', may worsen existing
gallbladder disease and may accelerate the development of this
disease in previously asymptomatic women. Women with a history
of combination hormonal contraceptive-related cholestasis are
more likely to have the condition recur with subsequent
combination hormonal contraceptive use.<br/>8. CARBOHYDRATE AND
LIPID METABOLIC EFFECTS: Hormonal
contraceptives have been shown to cause a decrease in glucose
tolerance in some users. However, in the non-diabetic woman,
combination hormonal contraceptives appear to have no effect on
fasting blood glucose. Prediabetic and diabetic women should be
carefully observed while taking combination hormonal
contraceptives, such as NuvaRing'. In a clinical study involving
37 NuvaRing'-treated subjects, glucose tolerance tests showed no
clinically significant changes in serum glucose levels from
baseline to cycle six. A small
proportion of women will have persistent hypertriglyceridemia
while using oral contraceptives. Changes in serum triglycerides
and lipoprotein levels have been reported in combination
hormonal contraceptive users.<br/>9. ELEVATED BLOOD
PRESSURE: Women with
severe hypertension should not be started on hormonal
contraceptives. An increase in blood pressure has been reported
in women taking oral contraceptives and this increase is more
likely in older oral contraceptive users and with continued use.
Data from the Royal College of General Practitioners and
subsequent randomized trials have shown that the incidence of
hypertension increases with increasing concentrations of
progestogens. Women with
a history of hypertension or hypertension-related diseases, or
renal disease should be encouraged to use another method of
contraception. If these women elect to use NuvaRing', they
should be monitored closely and if significant elevation of
blood pressure occurs, NuvaRing' should be discontinued. For
most women, elevated blood pressure will return to normal after
stopping hormonal contraceptives, and there is no difference in
the occurrence of hypertension between former and
never-users.<br/>10. HEADACHE: The onset
or exacerbation of migraine or development of headache with a
new pattern which is recurrent, persistent, or severe requires
discontinuation of NuvaRing' and evaluation of the
cause.<br/>11. BLEEDING
IRREGULARITIES:<br/>Bleeding Patterns: Breakthrough bleeding and spotting are sometimes
encountered in women using NuvaRing'. If abnormal
bleeding while using NuvaRing' persists or is severe,
appropriate investigation should be instituted to rule
out the possibility of organic pathology or pregnancy,
and appropriate treatment should be instituted when
necessary. In the event of amenorrhea, pregnancy should
be ruled out. Bleeding patterns were evaluated in three large
clinical studies. In the US-Canadian study (n=1177), the
percentages of subjects with breakthrough
bleeding/spotting ranged from 7.2 to 11.7% during cycles
1-13. In the two non-US studies, the percentages of
subjects with breakthrough bleeding/spotting ranged from
2.6 to 6.4% (Study 1, n=1145 European and Israeli
subjects) and from 2.0 to 8.7% (Study 2, n=512 European
and South American subjects). In these three studies,
the percentages of women who did not have withdrawal
bleeding in a given cycle ranged from 0.3 to 3.8%. Some women may encounter amenorrhea or oligomenorrhea
after discontinuing use of NuvaRing', especially when
such a condition was pre-existent.<br/>12. ECTOPIC
PREGNANCY: Ectopic as
well as intrauterine pregnancy may occur in contraceptive
failures.
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NuvaRing' is
indicated for the prevention of pregnancy in women who elect to use this
product as a method of contraception. Like oral contraceptives,
NuvaRing' is highly effective if used as recommended in this label. In three large
clinical trials of 13 cycles of NuvaRing' use, pregnancy rates were
between one and two per 100 women-years of use. Table III lists the
pregnancy rates for users of various contraceptive methods.
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| dailymed-instance:name |
NuvaRing
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