Pharmacokinetics

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.

TABLE I: MEAN (SD) SERUM ETONOGESTREL AND ETHINYL ESTRADIOL CONCENTRATIONS (n=16).

	1 week	2 weeks	3 weeks
etonogestrel (pg/mL)	1578 (408)	1476 (362)	1374 (328)
ethinyl estradiol (pg/mL)	19.1 (4.5)	18.3 (4.3)	17.6 (4.3)

The pharmacokinetic profile of etonogestrel and ethinyl estradiol during use of NuvaRing® is shown in Figure 1.

Figure 1. Mean serum concentration-time profile of etonogestrel and ethinyl estradiol during three weeks of NuvaRing® use.

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.

TABLE II: MEAN (SD) PHARMACOKINETIC PARAMETERS OF NuvaRing® (n=16).

Hormone	Cmax pg/mL	Tmax hr	t1/2 hr	CL L/hr
Cmax- maximum serum drug concentration Tmax- time at which maximum serum drug concentration occurs t1/2 - elimination half-life, calculated by 0.693/Kelim CL - apparent clearance
etonogestrel	1716 (445)	200.3 (69.6)	29.3 (6.1)	3.4 (0.8)
ethinyl estradiol	34.7 (17.5)	59.3 (67.5)	44.7 (28.8)	34.8 (11.6)

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.

1. THROMBOEMBOLIC DISORDERS AND OTHER VASCULAR PROBLEMS

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.

3. CARCINOMA OF THE REPRODUCTIVE ORGANS 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.

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.

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.

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.

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.

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.

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.

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.

11. BLEEDING IRREGULARITIES

12. ECTOPIC PREGNANCY

Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.

1. SEXUALLY TRANSMITTED DISEASES

Women should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.

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.

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.

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.

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.

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.

7. TAMPON USE

On rare occasions, NuvaRing® may be expelled while removing a tampon (see EXPULSION). Pharmacokinetic data show that the use of tampons has no effect on the systemic absorption of the hormones released by NuvaRing®.

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.

9. CONTACT LENSES

Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.

10. DRUG INTERACTIONS

Changes in contraceptive effectiveness associated with co-administration of other drugs:

11. INTERACTIONS WITH LABORATORY TESTS

Certain endocrine and liver function tests and blood components may be affected by combined hormonal contraceptives:

1. Increased prothrombin and factors VII, VIII, IX and X; decreased antithrombin 3, increased norepinephrine-induced platelet aggregability.
2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.
3. Other binding proteins may be elevated in serum.
4. Sex hormone-binding globulins are increased and result in elevated levels of total circulating sex steroids; however, free or biologically active levels either decrease or remain unchanged.
5. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.
6. Glucose tolerance may be decreased.
7. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing NuvaRing®.

12. 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 after withdrawal from treatment (see WARNINGS).

13. PREGNANCY

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.

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.

16. GERIATRIC USE

This product has not been studied in women over 65 years of age and is not indicated in this population.

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.

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.

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.

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 (see EXPULSION). If a woman discovers that her NuvaRing® has disconnected, she should discard the ring and replace it with a new ring.

INFORMATION FOR THE PATIENT

The woman should be instructed regarding the proper use of NuvaRing® (see PATIENT INFORMATION printed below).

When to Start NuvaRing®

IMPORTANT: The possibility of ovulation and conception prior to the first use of NuvaRing® should be considered.

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.

In the event of a missed menstrual period

1. If the woman has not adhered to the prescribed regimen (NuvaRing® has been out of the vagina for more than three hours or the preceding ring-free interval was extended beyond one week) the possibility of pregnancy should be considered at the time of the first missed period and NuvaRing® use should be discontinued if pregnancy is confirmed.
2. If the woman has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out.
3. If the woman has retained one NuvaRing® for longer than four weeks, pregnancy should be ruled out.

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 4 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 4 months from the date of dispensing or the expiration date, whichever comes first.

Additional barcode labeling by:
Physicians Total Care, Inc.
Tulsa, Oklahoma      74146

Do not use NuvaRing® if you have any of the following conditions:

• a history of heart attack or stroke
• a history of blood clots in your legs (thrombophlebitis), lungs (pulmonary embolism), or eyes
• a history of blood clots in the deep veins of your legs
• chest pain (angina pectoris)
• severe high blood pressure
• diabetes with complications of the kidneys, eyes, nerves, or blood vessels
• headaches with neurological symptoms
• known or suspected breast cancer or cancer of the lining of the uterus, cervix, or vagina (now or in the past)
• unexplained vaginal bleeding (until a diagnosis is reached by your healthcare provider)
• yellowing of the whites of the eyes or of the skin (jaundice) during pregnancy or during previous use of hormonal birth control of any kind (the pill, patch, vaginal ring, injection, or implant)
• liver tumor (benign or cancerous)
• heart valve or heart rhythm disorders that may be associated with formation of blood clots
• need for a long period of bed rest following major surgery
• known or suspected pregnancy
• active liver disease with abnormal liver function tests
• an allergy or hypersensitivity to any of the components of NuvaRing®

Tell your healthcare provider if you have ever had any of the conditions just listed. Your healthcare provider can suggest another method of birth control.

Talk with your healthcare provider about using NuvaRing® if you:

• smoke
• recently had a baby
• recently had a miscarriage or abortion
• are breast-feeding
• are taking other medications

In addition, talk to your healthcare provider about using NuvaRing® if you have any of the following conditions. Women with any of these conditions should be checked often by their doctor or healthcare provider if they choose to use NuvaRing®.

• a family history of breast cancer
• breast nodules, fibrocystic disease, an abnormal breast x-ray, or abnormal mammogram
• diabetes
• elevated cholesterol or triglycerides
• high blood pressure
• migraine or other headaches or epilepsy
• depression
• gallbladder, liver, heart, or kidney disease
• scanty or irregular menstrual periods
• plan to have major surgery (You may need to stop using NuvaRing® for a while to reduce your chance of getting blood clots.)
• any condition that makes the vagina get irritated easily
• prolapsed (dropped) uterus, dropped bladder (cystocele), or rectal prolapse (rectocele)
• severe constipation
• history of toxic shock syndrome

How should I use NuvaRing®?

For the best protection from pregnancy, use NuvaRing® exactly as directed. Insert one NuvaRing® in the vagina and keep it in place for three weeks in a row. Remove it for a one-week break and then insert a new ring. During the one-week break, you will usually have your menstrual period. Your healthcare provider should examine you at least once a year to see if there are any signs of side effects of NuvaRing® use.

When should I start NuvaRing®?

Follow the instructions in one of the sections below to find out when to start using NuvaRing®:

If you did not use a hormonal contraceptive in the preceding cycle

 

Insert NuvaRing® on the first day of your cycle, (i.e., the first day of menstrual bleeding). NuvaRing® will work immediately, it is not necessary to use an additional contraceptive method. You may also start on days 2–5 of your cycle, but in this case make sure you also use an extra method of birth control (barrier method), such as male condoms or spermicide for the first seven days of NuvaRing® use in the first cycle.

If you are changing from a combined hormonal contraceptive pill or patch (containing both progestin and estrogen)

 

Switch from your previous combined hormonal contraceptive on any day, but at the latest on the day following the usual hormone-free interval by inserting NuvaRing®. If you have been using your hormonal contraceptive method consistently and correctly, no extra birth control method should be needed.

If you are changing from a progestagen-only method (minipill, implant or injection) or from a progestagen-releasing intrauterine system (IUS)

 

You may switch on any day from a minipill. You 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, you should use an extra method of birth control, such as a male condom or spermicide, for the first seven days of ring use.

Following first trimester abortion or miscarriage

 

If you start using NuvaRing® within five days after a complete first trimester abortion or miscarriage, you do not need to use an extra method of contraception.

 

If NuvaRing® is not started within five days after a first trimester abortion or miscarriage, begin NuvaRing® at the time of your next menstrual period. Counting the first day of your menstrual period as "Day 1", insert NuvaRing® on or before Day 5 of the cycle, even if you have not finished bleeding. During this first cycle, use an extra method of birth control, such as male condoms or spermicide, for the first seven days of ring use.

How do I insert NuvaRing®?

1.

Each NuvaRing® comes in a reclosable foil pouch. After washing and drying your hands, remove NuvaRing® from its foil pouch. Keep the foil pouch for proper disposal of the ring after use. Choose the position that is most comfortable for you. For example, lying down, squatting, or standing with one leg up (Figures 1a, 1b, and 1c, respectively).

Figures 1a, 1b, and 1c. Positions for NuvaRing® insertion.

2.

Hold NuvaRing® between your thumb and index finger (Figure 2a) and press the opposite sides of the ring together (Figure 2b).

Figures 2a and 2b. Holding NuvaRing® and pressing the sides together.

3.

Gently push the folded ring into your vagina (Figures 3a and 3b). The exact position of NuvaRing® in the vagina is not important for it to work (Figures 3c and 3d).

Figures 3a, 3b, 3c, and 3d. Inserting and positioning of NuvaRing®.

Although some women may be aware of NuvaRing® in the vagina, most women do not feel it once it is in place. If you feel discomfort, NuvaRing® is probably not inserted back far enough in the vagina. Use your finger to gently push the NuvaRing® farther into your vagina. There is no danger of NuvaRing® being pushed too far up in the vagina or getting lost. NuvaRing® can be inserted only as far as the end of the vagina, where the cervix (the narrow, lower end of the uterus) will block NuvaRing® from going any farther.

4.

Once inserted, keep NuvaRing® in place for three weeks in a row.

How do I remove NuvaRing®?

Figure 4. Removing NuvaRing®.

1.

Remove the ring three weeks after insertion on the same day of the week as it was inserted, at about the same time of day.

 

You can remove NuvaRing® by hooking the index finger under the forward rim or by holding the rim between the index and middle finger and pulling it out (Figure 4).

2.

Place the used ring in the foil pouch and properly dispose of it in a waste receptacle out of the reach of children and pets. Do not throw it in the toilet.

 

Your menstrual period will usually start two to three days after the ring is removed and may not have finished before the next ring is inserted. To continue to have pregnancy protection, you must insert the new ring one week after the last one was removed, even if your menstrual period has not stopped.

If you locate the ring in your vagina, but are unable to remove it, please contact your healthcare provider.

When do I insert a new ring?

After no more than a one-week ring-free break, insert a new ring on the same day of the week as it was removed in the last cycle. If the ring-free interval has been extended beyond one week, the possibility of pregnancy should be considered, and an extra method of birth control, such as male condoms or spermicide, MUST be used until NuvaRing® has been used continuously for seven days.

If NuvaRing® slips out:

NuvaRing® can accidentally slip out of the vagina while removing a tampon, during intercourse, or straining during a bowel movement. If NuvaRing® slips out of the vagina and it has been out for less than three hours, you should still be protected from pregnancy. NuvaRing® can be rinsed with cool to lukewarm (not hot) water and reinserted as soon as possible, and at the latest within three hours of removal or expulsion (slipping out).

If NuvaRing® is out of the vagina for more than three continuous hours:

During Weeks 1 and 2: If the ring has been out of the vagina for more than three continuous hours during the 1st or 2nd week of use, contraceptive effectiveness may be reduced. Reinsert ring as soon as you remember and use an extra method of birth control, such as male condoms or spermicide, until the ring has been used continuously for seven days.

During Week 3: If NuvaRing® slips out of the vagina for more than three continuous hours during the 3rd week of the three-week use period, throw the ring away and choose one of the following two options.

1. Insert a new ring immediately. Inserting a new ring will start the next three-week use period. You may not experience a period from your previous cycle. However, breakthrough spotting or bleeding may occur.
2. Have your period and insert a new ring no later than seven days (7×24 hours) from the time the previous ring was removed or expelled. This option should only be chosen if the ring was used continuously for the preceding seven days.

In addition, a barrier method such as condoms or spermicides must be used until the ring has been used continuously for seven days.

Women with conditions affecting the vagina, such as a prolapsed (dropped) uterus, may be more likely to have NuvaRing® slip out of the vagina. If NuvaRing® slips out repeatedly, you should consult with your healthcare provider.

If NuvaRing® is in your vagina too long:

If NuvaRing® has been left in your vagina for an extra week or less (four weeks total or less), you will remain protected. Remove NuvaRing® and insert a new ring after a one-week ring-free break.

If NuvaRing® has been left in place for more than four weeks, you may not be adequately protected from pregnancy and you must check to be sure you are not pregnant. You MUST use an extra method of birth control, such as male condoms or spermicide, until the new NuvaRing® has been in place for seven days in a row.

If you miss a menstrual period:

You must check to be sure that you are not pregnant if:

1. you miss a period and NuvaRing® was out of the vagina for more than three hours during the three weeks of ring use
2. you miss a period and waited longer than one week to insert a new ring
3. you have followed the instructions and you miss two periods in a row
4. you have left NuvaRing® in place for longer than four weeks

Can I use tampons when using NuvaRing®?

Use of tampons will not reduce the contraceptive efficacy of NuvaRing®. Insert NuvaRing® before inserting a tampon. You should pay particular attention when removing a tampon to be sure that the ring is not accidentally pulled out. If this should occur, simply rinse the ring in cool to lukewarm (not hot) water and immediately reinsert it.

Can I use vaginal medications?

Use of spermicides or vaginal yeast products will not reduce the contraceptive efficacy of NuvaRing®.

What should I do if my NuvaRing® disconnects?

There have been reported cases of NuvaRing® disconnecting at the weld joint causing the ring to change shape and straighten out. This is not expected to affect the contraceptive effectiveness of NuvaRing®. If NuvaRing® disconnects, expulsion (slipping out) is more likely to occur (see "If NuvaRing® slips out"). If you discover the ring has disconnected, you should discard the ring and replace it with a new ring.

Overdose

NuvaRing® is unlikely to cause an overdose because the ring holding the medicine releases a steady amount of contraceptive hormones. Do not use more than one ring at a time. Overdose of combination hormonal contraceptives may cause nausea, vomiting, or vaginal bleeding.

What should I avoid while using NuvaRing®?

Cigarette smoking increases the risk of serious cardiovascular side effects when you use combination oral contraceptives, including NuvaRing®. This risk increases even more if you are over age 35 and if you smoke 15 or more cigarettes a day. Women who use combination hormonal contraceptives, like NuvaRing®, are strongly advised not to smoke.

Do not breast-feed while using NuvaRing®. Some of the medicine may pass through the milk to the baby and could cause yellowing of the skin (jaundice) and breast enlargement in your baby. NuvaRing® could also decrease the amount and quality of your breast milk.

The hormones in NuvaRing® can interact with many other medicines and herbal supplements. Tell your healthcare provider about any medicines you are taking, including prescription medicines, over-the-counter medicines, herbal remedies, and vitamins.

The blood levels of the hormones released by NuvaRing® were increased when women used a vaginal medication (miconazole nitrate) for a yeast infection while NuvaRing® was in place. The pregnancy protection of NuvaRing® is not likely to be changed by use of these products. The blood levels of these hormones were not changed when women used vaginal, water-based spermicides (nonoxynol or N-9 products) along with NuvaRing®.

Certain drugs and herbal supplements may interact with combined hormonal contraceptives to make them less effective in preventing pregnancy or cause an increase in breakthrough bleeding. Such drugs include rifampin, drugs used for epilepsy such as barbiturates (for example, phenobarbital), carbamazepine, and phenytoin, primidone, topiramate, phenylbutazone, modafinil, and some drugs used for HIV such as ritonavir. Pregnancies and breakthrough bleeding have been reported by users of combined hormonal contraceptives who also used the herbal supplement St. John's Wort. You may need to use a non-hormonal method of contraception during any cycle in which you take drugs that can make oral contraceptives less effective. Be sure to tell your healthcare provider if you are taking or start taking any other medications, including non-prescription products or herbal products while using NuvaRing®.

While using NuvaRing®, you should not rely upon a diaphragm when you need a back-up method of birth control because NuvaRing® may interfere with the correct placement and position of a diaphragm.

If you are scheduled for any laboratory tests, tell your doctor or healthcare provider you are using NuvaRing®. Contraceptive hormones may change certain blood tests results.

What are the possible risks and side effects of NuvaRing®?

• Blood clots
  The hormones in NuvaRing® may cause changes in your blood clotting system which may allow your blood to clot more easily. If blood clots form in your legs, they can travel to the lungs and cause a sudden blockage of a vessel carrying blood to the lungs. Rarely, clots occur in the blood vessels of the eye and may cause blindness, double vision, or other vision problems. The risk of getting blood clots may be greater with the type of progestin in NuvaRing® than with some other progestins in certain low-dose birth control pills. It is unknown if the risk of blood clots is different with NuvaRing® use than with the use of certain birth control pills.
   
  If you take hormonal contraceptives and need elective surgery, need to stay in bed for a prolonged illness or have recently delivered a baby, you may be at risk of developing blood clots. You should consult your doctor or healthcare provider about stopping hormonal contraceptives three to four weeks before surgery and not taking hormonal contraceptives for two weeks after surgery or during bed rest. You should also not take hormonal contraceptives soon after delivery of a baby. It is advisable to wait for at least four weeks after delivery if you are not breast-feeding. If you are breast-feeding, you should wait until you have weaned your child before using the pill (see PRECAUTIONS, NURSING MOTHERS).
• Strokes and heart attacks
  Hormonal contraceptives may increase your risk of strokes (blockage of blood flow to the brain) or heart attacks (blockage of blood flow to the heart). Any of these conditions can cause death or serious disability. Smoking greatly increases the risk of having strokes and heart attacks. Furthermore, smoking and the use of combination hormonal contraceptives, like NuvaRing®, greatly increases the chances of developing and dying of heart disease. If you use combination hormonal contraceptives, including NuvaRing®, you should not smoke.
• High blood pressure and heart disease
  Combination hormonal contraceptives, including NuvaRing®, can worsen conditions like high blood pressure, diabetes, and problems with cholesterol and triglycerides.
• Cancer of the reproductive organs and breast
  Breast cancer has been diagnosed slightly more often in women who use the pill than in women of the same age who do not use the pill. This small increase in the number of breast cancer diagnoses gradually disappears during the 10 years after stopping use of the pill. It is not known whether the difference is caused by the pill. It may be that women taking the pill are examined more often, so that breast cancer is more likely to be detected. You should have regular breast examinations by a healthcare provider and examine your own breasts monthly. Tell your healthcare provider if you have a family history of breast cancer or if you have had breast nodules or an abnormal mammogram.
   
  Women who currently have or have had breast cancer should not use hormonal contraceptives, including NuvaRing®, because breast cancer is usually a hormone-sensitive tumor.
   
  Some studies have found an increase in the incidence of cancer of the cervix in women who use oral contraceptives. However, this finding may be related to factors other than the use of oral contraceptives. There is insufficient evidence to rule out the possibility that pills may cause such cancers.
• Gallbladder disease
  Combination hormonal contraceptive users may have a higher chance of having gallbladder disease.
• Liver tumors
  In rare cases, combination hormonal contraceptives, like NuvaRing®, can cause non-cancerous (benign) but dangerous liver tumors. These benign liver tumors can break and cause fatal internal bleeding. In addition, it is possible that women who use combination hormonal contraceptives, like NuvaRing®, have a higher chance of getting liver cancer. However, liver cancers are extremely rare.
• Lipid metabolism and inflammation of the pancreas
  In women with inherited defects of lipid metabolism, there have been reports of significant elevations of plasma triglycerides during estrogen therapy. This has led to pancreatitis in some cases.

The common side effects reported by NuvaRing® users are:

• vaginal infections and irritation
• vaginal secretion
• headache
• weight gain
• nausea

In addition to the risks and side effects listed above, users of combination hormonal contraceptives have reported the following side effects:

• vomiting
• change in appetite
• abdominal cramps and bloating
• breast tenderness or enlargement
• irregular vaginal bleeding or spotting
• changes in menstrual cycle
• temporary infertility after treatment
• fluid retention (edema)
• spotty darkening of the skin, particularly on the face
• rash
• weight changes
• depression
• intolerance to contact lenses
• nervousness
• dizziness
• loss of scalp hair

Call your healthcare provider right away if you get any of the symptoms listed below. They may be signs of a serious problem:

• sharp chest pain, coughing blood, or sudden shortness of breath (possible clot in the lung)
• pain in the calf (back of lower leg; possible clot in the leg)
• crushing chest pain or heaviness in the chest (possible heart attack)
• sudden severe headache or vomiting, dizziness or fainting, problems with vision or speech, weakness, or numbness in an arm or leg (possible stroke)
• sudden partial or complete loss of vision (possible clot in the eye)
• yellowing of the skin or whites of the eyes (jaundice), especially with fever, tiredness, loss of appetite, dark colored urine, or light colored bowel movements (possible liver problems)
• severe pain, swelling, or tenderness in the abdomen (gallbladder or liver problems)
• sudden fever (usually 102°F or more), vomiting, diarrhea, dizziness, fainting, or a sunburn-like rash on the face or body (very rarely, toxic shock syndrome)
• breast lumps (possible breast cancer or benign breast disease)
• irregular vaginal bleeding or spotting that happens in more than one menstrual cycle or lasts for more than a few days
• urgent, frequent, burning and/or painful urination, and cannot locate the ring in the vagina (rarely, accidental placement of NuvaRing® into the urinary bladder)
• swelling (edema) of your fingers or ankles
• difficulty in sleeping, weakness, lack of energy, fatigue, or a change in mood (possible severe depression)

How effective is NuvaRing®?

If NuvaRing® is used according to the directions, your chance of getting pregnant is about 1 to 2% a year. This means that, for every 100 women who use NuvaRing® for a year, one or two will become pregnant. Your chance of getting pregnant increases if NuvaRing® is not used exactly according to the directions.

By comparison, the chances of getting pregnant in the first year of typical use (not always following directions exactly) of other methods of birth control are as follows:

Other Information

• Store NuvaRing® at room temperature, 25°C (77°F). Temperatures can be from 15°-30°C (59°-86°F). Avoid direct sunlight or storing above 30°C (86°F).
• Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use NuvaRing® for a condition for which it was not prescribed. Do not give NuvaRing® to anyone else who may want to use it.
• Place the used ring in the reclosable foil pouch and properly dispose of it in a waste receptacle out of the reach of children and pets.

This leaflet summarizes the most important information about NuvaRing®. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NuvaRing® that is written for health professionals.

1-877-NUVARING

U.S. Patent No. 5,989,581.

Copyright © 2001, 2010 N.V. Organon, a subsidiary of Merck & Co., Inc. All rights reserved.

34823804T
Rev. 11/10