"The U.S. Food and Drug Administration on Wednesday approved a request by Danco Laboratories to expand authorized use of its abortion pill Mifeprex (mifepristone), formerly known as RU-486, to 70 days of gestation from 49 days.
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 immobilization.
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 study1 8.2 events per 10,000 WY.
Table 1: Estimates (Hazard Ratios) of Venous
Thromboembolism Risk in Users of NuvaRing Compared to Users of Combined Oral Contraceptives
|Epidemiologic Study (Author, Year of Publication) Population Studied||Comparator Product(s)||Hazard Ratios (HR) (95% CI)|
|TASC (Dinger, 2012) Initiators, including new||All COCs available during the course of the study *||HR†; 0.8 (0.5-1.5)|
|users, switchers and restarters||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 wellestablished. Although the absolute VTE rates are increased for users of CHCs compared to non-users, 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
*CHC=combination hormonal 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.
1 Includes low-dose COCs containing the following progestins: norgestimate, norethindrone, or levonorgestrel.
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 treatment.
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 jaundice develops.
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 intra-abdominal hemorrhage.
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 million users.
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 the vagina.
Studies suggest a small increased relative risk of developing gallbladder disease among CHC users. Use of CHCs may also worsen existing gallbladder disease.
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 cholestasis.
Carbohydrate And Lipid Metabolic Effects
Carefully monitor prediabetic and diabetic women who are using NuvaRing. CHCs may decrease glucose tolerance.
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 if indicated.
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.
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.
CHC Use Before Or During Early Pregnancy
Extensive epidemiological 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 taken inadvertently during early pregnancy. Discontinue NuvaRing if pregnancy is confirmed.
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
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 healthcare.
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
See FDA-approved patient labeling (Patient Information and Instructions for Use).
Counsel patients regarding the following:
- 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.
- 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.
- NuvaRing does not protect against HIV infection (AIDS) and other sexually transmitted infections.
- The WARNINGS AND PRECAUTIONS associated with NuvaRing.
- 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.
- The proper usage of NuvaRing and what to do if she does not comply with the labeled timing of insertion and removal.
- The 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.
- The proper disposal of a used NuvaRing.
- Use a back-up or alternative method of contraception when enzyme inducers are used with NuvaRing.
- CHCs may reduce breast milk production. This is less likely to occur if breastfeeding is well established.
- Women who start NuvaRing postpartum and have not yet had a normal period should use an additional non-hormonal method of contraception for the first seven days.
- 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.
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. Fertility returned in rats after withdrawal from treatment.
Use In Specific Populations
There is little or no increased risk of birth defects in women who inadvertently use CHCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to low dose CHCs prior to conception or during early pregnancy.
The administration of CHCs to induce withdrawal bleeding should not be used as a test for pregnancy. CHCs should not be used during pregnancy to treat threatened or habitual abortion.
The effects of NuvaRing in nursing mothers have not been evaluated and are unknown. When possible, advise the nursing mother to use other forms of contraception until she has completely weaned her child. 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. Small amounts of contraceptive steroids and/or metabolites are present in breast milk.
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.
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: 93–100.
3. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular endpoints. Sidney, S. (primary author) http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf, accessed 23- Aug-2013.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 5/17/2016
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