Included as part of the PRECAUTIONS section.
Thromboembolic Disorders And Other Vascular Problems
Stop NuvaRing use if an arterial thrombotic or venous
thromboembolic event (VTE) occurs. Stop NuvaRing use if there is unexplained
loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions.
Evaluate for retinal vein thrombosis immediately. [See ADVERSE REACTIONS]
If feasible, stop NuvaRing at least four weeks before and
through two weeks after major surgery or other surgeries known to have an
elevated risk of thromboembolism, and during and following prolonged
Start NuvaRing no earlier than 4 weeks after delivery, in
women who are not breastfeeding. The risk of postpartum thromboembolism
decreases after the third postpartum week, whereas the risk of ovulation
increases after the third postpartum week.
The use of CHCs increases the risk of VTE. Known risk
factors for VTE include smoking, obesity, and family history of VTE, in
addition to other factors that contraindicate use of CHCs [see CONTRAINDICATIONS].
Two epidemiologic studies1, 2, 3 that assessed
the risk of VTE associated with the use of NuvaRing are described below.
In these studies, which were required or sponsored by
regulatory agencies, NuvaRing users had a risk of VTE similar to COC users (see
Table 1 for adjusted hazard ratios). A large prospective, observational study,
the Transatlantic Active Surveillance on Cardiovascular Safety of NuvaRing
(TASC), investigated the risk of VTE for new users, and women who were
switching to or restarting NuvaRing or COCs in a population that is
representative of routine clinical users. The women were followed for 24 to 48
months. The results showed a similar risk of VTE among NuvaRing users (VTE incidence
8.3 per 10,000 WY) and women using COCs (VTE incidence 9.2 per 10,000 WY). For
women using COCs that did not contain the progestins desogestrel (DSG) or
gestodene (GSD), VTE incidence was 8.9 per 10,000 WY.
A retrospective cohort study using data from 4 health
plans in the US (FDA-funded Study in Kaiser Permanente and Medicaid databases)
showed the VTE incidence for new users of NuvaRing to be 11.4 events per 10,000
WY, for new users of a levonorgestrel (LNG)-containing COC 9.2 events per
10,000 WY, and for users of other COCs available during the course of the
study* 8.2 events per 10,000 WY.
* Includes low-dose COCs containing the following
progestins: norgestimate, norethindrone, or levonorgestrel.
Table 1: Estimates (Hazard Ratios) of Venous
Thromboembolism Risk in Users of NuvaRing Compared to Users of Combined Oral
|Epidemiologic Study (Author, Year of Publication) Population Studied
||Hazard Ratios (HR) (95% CI)
|Initiators, including new users, switchers and restarters
||All COCs available during the course of the study *
||HR†: 0.8 (0.5-1.5)
|COCs available excluding DSG- or GSD -containing OCs
||HR†: 0.8 (0.4-1.7)
|FDA-funded Study in Kaiser Permanente and Medicaid databases (Sidney, 2011)
|First use of a combined hormonal contraceptive (CHC) during the study period
||COCs available during the course of the study‡
||HR§: 1.1 (0.6-2.2)
|LNG/0.03 mg ethinyl estradiol
||HR§: 1.0 (0.5-2.0)
|* Includes low-dose COCs containing the following
progestins: chlormadinone acetate, cyproterone acetate, desogestrel, dienogest,
drospirenone, ethynodiol diacetate, gestodene, levonorgestrel, norethindrone,
norgestimate, or norgestrel
† Adjusted for age, BMI, duration of use, VTE history
‡Includes low-dose COCs containing the following progestins: norgestimate,
norethindrone, or levonorgestrel
§Adjusted for age, site, year of entry into study
An increased risk of thromboembolic and thrombotic
disease associated with the use of CHCs is well-established. Although the
absolute VTE rates are increased for users of CHCs compared to nonusers, the
rates associated with pregnancy are even greater, especially during the
post-partum period (see Figure 1).
The frequency of VTE in women
using CHCs has been estimated to be 3 to 12 cases per 10,000 women-years.
The risk of VTE is highest
during the first year of CHC use and after restarting a CHC following a break
of at least four weeks. The risk of VTE due to CHCs gradually disappears after
use is discontinued.
Figure 1 shows the risk of
developing a VTE for women who are not pregnant and do not use CHCs, for women
who use CHCs, for pregnant women, and for women in the postpartum period. To
put the risk of developing a VTE into perspective: If 10,000 women who are not
pregnant and do not use CHCs are followed for one year, between 1 and 5 of
these women will develop a VTE.
Figure 1: Likelihood of Developing a VTE
contraception **Pregnancy data based on actual duration of pregnancy in the
reference studies. Based on a model assumption that pregnancy duration is nine
months, the rate is 7 to 27 per 10,000 WY.
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), may be associated with a higher risk of VTE
than oral contraceptives containing other progestins. Some of these studies
indicate an approximate two-fold increased risk. However, data from other
studies have not shown this two-fold increase in risk.
Use of CHCs also increases the
risk of arterial thromboses such as strokes and myocardial infarctions,
especially in women with other risk factors for these events. CHCs have been
shown to increase both the relative and attributable risks of cerebrovascular
events (thrombotic and hemorrhagic strokes). In general, the risk is greatest
among older (>35 years of age), hypertensive women who also smoke.
Use NuvaRing with caution in
women with cardiovascular disease risk factors.
Toxic Shock Syndrome (TSS)
Cases of TSS have been reported
by NuvaRing users. TSS has been associated with tampons and certain barrier
contraceptives, and, in some cases the NuvaRing users were also using tampons.
A causal relationship between the use of NuvaRing and TSS has not been
established. If a patient exhibits signs or symptoms of TSS, consider the
possibility of this diagnosis and initiate appropriate medical evaluation and
Impaired Liver Function
Do not use NuvaRing in women
with liver disease such as acute viral hepatitis or severe (decompensated)
cirrhosis of the liver [see CONTRAINDICATIONS]. Acute or chronic
disturbances of liver function may necessitate the discontinuation of CHC use
until markers of liver function return to normal and CHC causation has been
excluded [see Use In Specific Populations]. Discontinue NuvaRing use if
NuvaRing is contraindicated in women with benign and
malignant liver tumors [see CONTRAINDICATIONS]. Hepatic adenomas are
associated with CHC use. An estimate of the attributable risk is 3.3 cases per
100,000 CHC users. Rupture of hepatic adenomas may cause death through
Studies have shown an increased risk of developing
hepatocellular carcinoma in long term (>8 years) CHC users. However, the
attributable risk of liver cancers in CHC users is less than one case per
Risk Of Liver Enzyme Elevations With Concomitant
Hepatitis C Treatment
During clinical trials with the Hepatitis C combination
drug regimen that contains ombitasvir/paritaprevir/ritonavir, with and without
dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN),
including some cases greater than 20 times the ULN, were significantly more
frequent in women using ethinyl estradiol-containing medications, such as CHCs.
Discontinue NuvaRing prior to starting therapy with the combination drug
regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see CONTRAINDICATIONS].
NuvaRing can be restarted approximately 2 weeks following completion of
treatment with the Hepatitis C combination drug regimen.
High Blood Pressure
NuvaRing is contraindicated in women with uncontrolled
hypertension or hypertension with vascular disease [see CONTRAINDICATIONS].
For women with well-controlled hypertension, monitor blood pressure and stop
NuvaRing use if blood pressure rises significantly.
An increase in blood pressure has been reported in women
using CHCs and this increase is more likely in older women and with extended
duration of use. The incidence of hypertension increases with increasing
concentrations of progestin.
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
reported. In some cases, the ring adhered to vaginal tissue, necessitating
removal by a healthcare provider.
Some women are aware of the ring on occasion during the
21 days of use or during intercourse, and sexual partners may feel NuvaRing in
Studies suggest a small increased relative risk of
developing gallbladder disease among CHC users. Use of CHCs may also worsen existing
A past history of CHC-related cholestasis predicts an
increased risk with subsequent CHC use. Women with a history of
pregnancy-related cholestasis may be at an increased risk for CHC-related
Carbohydrate And Lipid Metabolic Effects
Carefully monitor prediabetic and diabetic women who are
using NuvaRing. CHCs may decrease glucose tolerance.
Consider alternative contraception for women with
uncontrolled dyslipidemia. Some women will have adverse lipid changes while on
Women with hypertriglyceridemia, or a family history
thereof, may be at an increased risk of pancreatitis when using CHCs.
If a woman using NuvaRing develops new headaches that are
recurrent, persistent, or severe, evaluate the cause and discontinue NuvaRing
Consider discontinuation of NuvaRing in the case of an
increased frequency or severity of migraine during CHC use (which may be
prodromal of a cerebrovascular event) [see CONTRAINDICATIONS].
Bleeding Irregularities And Amenorrhea
Unscheduled Bleeding And Spotting
Unscheduled bleeding (breakthrough or intracyclic)
bleeding and spotting sometimes occur in women using CHCs, especially during
the first three months of use. If bleeding persists or occurs after previously
regular cycles, check for causes such as pregnancy or malignancy. If pathology
and pregnancy are excluded, bleeding irregularities may resolve over time or
with a change to a different CHC.
Bleeding patterns were evaluated in three large clinical
studies. In the North American study (US and Canada, N=1,177), 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% (Europe, N=1,145) and
from 2.0% to 8.7% (Europe, Brazil, Chile, N=512).
Amenorrhea And Oligomenorrhea
If scheduled (withdrawal) bleeding does not occur,
consider the possibility of pregnancy. If the patient has not adhered to the
prescribed dosing schedule, consider the possibility of pregnancy at the time
of the first missed period and take appropriate diagnostic measures.
Occasional missed periods may occur with the appropriate
use of NuvaRing. In the clinical studies, the percent of women who did not have
withdrawal bleeding in a given cycle ranged from 0.3% to 3.8%.
If the patient has adhered to the prescribed regimen and
misses two consecutive periods, rule out pregnancy.
Some women may experience amenorrhea or oligomenorrhea
after discontinuing CHC use, especially when such a condition was pre-existent.
Inadvertent Urinary Bladder Insertion
There have been reports of inadvertent insertions of
NuvaRing into the urinary bladder, which required cystoscopic removal. Assess
for ring insertion into the urinary bladder in NuvaRing users who present with
persistent urinary symptoms and are unable to locate the ring.
Carefully observe women with a history of depression and
discontinue NuvaRing use if depression recurs to a serious degree.
Carcinoma Of The Breasts And Cervix
NuvaRing is contraindicated in women who currently have
or have had breast cancer because breast cancer is a hormonally-sensitive tumor
There is substantial evidence that CHCs do not increase
the incidence of breast cancer. Although some past studies have suggested that
CHCs might increase the incidence of breast cancer, more recent studies have
not confirmed such findings.
Some studies suggest that CHCs are associated with an
increase in the risk of cervical cancer or intraepithelial neoplasia. However,
there is controversy about the extent to which these findings may be due to
differences in sexual behavior and other factors.
Effect On Binding Globulins
The estrogen component of CHCs may raise the serum
concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and
cortisol-binding globulin. The dose of replacement thyroid hormones or cortisol
therapy may need to be increased.
A woman who is using NuvaRing should have a yearly visit
with her healthcare provider for a blood pressure check and for other indicated
In women with hereditary angioedema, exogenous estrogens
may induce or exacerbate symptoms of angioedema.
Chloasma may occasionally occur, especially in women with
a history of chloasma gravidarum. Women with a tendency to chloasma should
avoid exposure to the sun or ultraviolet radiation while using NuvaRing.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (PATIENT INFORMATION and Instructions for Use).
Counsel patients regarding the following:
Increased Risk Of Cardiovascular Events
- Advise patients that cigarette smoking increases the risk
of serious cardiovascular events from use of NuvaRing, and women who are over
35 years old and smoke should not use NuvaRing [see BOXED WARNING].
- Inform patients that the increased risk of VTE compared
to non-users of CHCs is greatest after initially starting a CHC or restarting
(following a 4-week or greater CHC-free interval) the same or a different CHC [see WARNINGS AND PRECAUTIONS].
Use And Administration
- Inform patients that NuvaRing does not protect against
HIV infection (AIDS) and other sexually transmitted infections.
- Advise patients on the proper usage of NuvaRing and what
to do if she does not comply with the labeled timing of insertion and removal [see DOSAGE AND ADMINISTRATION].
- Advise patients to regularly check for the presence of
NuvaRing in the vagina (for example, before and after intercourse) [see DOSAGE
- Inform patients that NuvaRing is not to be used during
pregnancy. If pregnancy is planned or occurs during treatment with NuvaRing,
instruct the patient to discontinue NuvaRing use [see Use In Specific Populations].
Use Of Additional Contraception
- Inform patients that they need to use a barrier method of
contraception when the ring is out for more than three continuous hours until
NuvaRing has been used continuously for at least seven days [see DOSAGE AND
- Advise patients to use a back-up or alternative method of
contraception when enzyme inducers are used with NuvaRing [see DRUG
- Inform patients who start NuvaRing postpartum and have
not yet had a normal period that they should use an additional non-hormonal
method of contraception for the first seven days [see DOSAGE AND
- Inform patients that CHCs may reduce breast milk
production. This is less likely to occur if breastfeeding is well established [see
Use In Specific Populations].
- Inform patients that amenorrhea may occur. Rule out
pregnancy in the event of amenorrhea if NuvaRing has been out of the vagina for
more than three consecutive hours, if the ring-free interval was extended
beyond one week, if the woman has missed a period for two or more consecutive
cycles, and if the ring has been retained for longer than four weeks [see WARNINGS
- Advise patients on the proper disposal of a used NuvaRing
[see HOW SUPPLIED/Storage And Handling].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a 24-month carcinogenicity study in rats with
subdermal implants releasing 10 and 20 mcg 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.
Impairment Of Fertility
A fertility study was conducted with etonogestrel in rats
at approximately 600 times the anticipated daily vaginal human dose (~0.002
mg/kg/day). Treatment did not have any adverse effect on resulting litter
parameters after cessation of treatment supporting the return to fertility
after suppression with etonogestrel.
Use In Specific Populations
NuvaRing is contraindicated during pregnancy because
there is no need for pregnancy prevention in a woman who is already pregnant.
Epidemiologic studies and meta-analyses have not shown an increased risk of
genital or non-genital birth defects (including cardiac anomalies and
limb-reduction defects) following maternal exposure to low dose CHCs prior to
conception or during early pregnancy. No adverse developmental outcomes were
observed in pregnant rats and rabbits with the administration of etonogestrel
during organogenesis at doses approximately 300 times the anticipated daily
vaginal human dose (~0.002 mg/kg/day).
No adverse developmental outcomes were observed in
pregnant rats and rabbits with the co-administration of the combination
desogestrel/ethinyl estradiol during organogenesis at desogestrel/ethinyl
estradiol doses at least 2/5 times, respectively, the anticipated daily vaginal
human dose (~0.002 desogestrel/0.00025 ethinyl estradiol mg/kg/day).
Discontinue NuvaRing use if pregnancy is confirmed.
In rats and rabbits at dosages up to 300 times the
anticipated dose, etonogestrel is neither embryotoxic nor teratogenic.
Co-administration of a maternally toxic dose of desogestrel/ethinyl estradiol
to pregnant rats was associated with embryolethality and wavy ribs at a
desogestrel/ethinyl estradiol dose that was 40/130 times, respectively, the
anticipated vaginal human dose (0.002 desogestrel/0.00025 ethinyl estradiol
mg/kg/day). No adverse embryofetal effects were observed when the combination
was administered to pregnant rats at a desogestrel/ethinyl estradiol dose that
was 4/13 times, respectively, the anticipated vaginal human dose. When
desogestrel/ethinyl estradiol was given to pregnant rabbits, preimplantation
loss was observed at a desogestrel/ethinyl estradiol dose that was 3/10 times,
respectively, the anticipated vaginal human dose. No adverse embryofetal
effects were observed when the combination was administered to pregnant rabbits
at a desogestrel/ethinyl estradiol dose that was 2/5 times the anticipated
vaginal human dose.
Small amounts of contraceptive steroids and/or
metabolites, including etonogestrel and ethinyl estradiol are transferred to
human milk. Harmful effects have not been observed in breastfed infants exposed
to CHCs through breast milk. CHCs can reduce milk production in breastfeeding
mothers. This is less likely to occur once breastfeeding is well-established;
however, it can occur at any time in some women.
When possible, advise the nursing mother to use
non-estrogen-containing contraception until she has completely weaned her
child. The developmental and health benefits of breastfeeding should be
considered along with the mother's clinical need for NuvaRing and any potential
adverse effects on the breastfed child from NuvaRing or from the underlying
Safety and efficacy of NuvaRing have been established in
women of reproductive age. Efficacy is expected to be the same for postpubertal
adolescents under the age of 18 and for users 18 years and older. Use of this
product before menarche is not indicated.
NuvaRing has not been studied in postmenopausal women and
is not indicated in this population.
The effect of hepatic impairment on the pharmacokinetics
of NuvaRing has not been studied. Steroid hormones may be poorly metabolized in
patients with impaired liver function. Acute or chronic disturbances of liver function
may necessitate the discontinuation of CHC use until markers of liver function
return to normal. [See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
The effect of renal impairment on the pharmacokinetics of
NuvaRing has not been studied.
1. Dinger, J et. al., Cardiovascular risk associated with
the use of an etonogestrel-containing vaginal ring. Obstetrics & Gynecology
2013; 122(4): 800-808.
2. Sidney, S. et. al., Recent combined hormonal
contraceptives (CHCs) and the risk of thromboembolism and other cardiovascular
events in new users. Contraception 2013; 87: 93– Â 100.
3. Combined hormonal contraceptives (CHCs) and the risk
of cardiovascular endpoints. Sidney, S. (primary author)