Nuvaring 11.4mg/2.6mg

Interactions with food have not been established.

Results of laboratory tests should be interpreted in the light that the patient is on combination hormonal contraceptives (including NuvaRing). The following laboratory tests are modified.

1. Liver function tests: Aspartate serum transaminase (AST)—variously reported elevations. Alkaline phosphatase and gamma glutamine transaminase (GGT)—slightly elevated.

   
   

2. Coagulation tests: Minimal elevation of test values reported for such parameters as prothrombin and Factors VII, VIII, IX and X.

   
   

3. Thyroid function tests: Protein binding of thyroxine is increased as indicated by increased total serum thyroxine concentrations and decreased T₃ resin uptake.

   
   

4. Lipoproteins: Small changes of unproven clinical significance may occur in lipoprotein cholesterol fractions.

   
   

5. Gonadotropins: LH and FSH levels are suppressed by the use of oral contraceptives. Wait two weeks after discontinuing the use of oral contraceptives before measurements are made.

NuvaRing can be accidentally expelled, for example, when it has not been inserted properly, or while removing a tampon, during intercourse, or with straining during a bowel movement.

Clinical trial data indicate that expulsion of NuvaRing is most common in the first few cycles of use when women are becoming accustomed to this method of contraception. In a retrospective analysis of four one-year NuvaRing trials it was found that expulsion occurred in 0.5% of cycles (N=33 462) and this percentage decreased to zero with duration of use (1.1% at cycle 1; N=3228 and 0% at cycle 13; N=2071). Overall, 2.3% of subjects (N=3333) experienced expulsion over 13 cycles of use.

If the ring is accidentally expelled and is left outside of the vagina for less than 3 hours, contraceptive efficacy is not reduced. The vaginal ring can be rinsed with cool to lukewarm (not hot) water and re-inserted as soon as possible, but at the latest within 3 hours (see Dosage and Administration, Missed Dose and Information for the Patient, Missed Dose). If NuvaRing is lost, a new vaginal ring should be inserted and the regimen should be continued without alteration.

If the ring has been out of the vagina for more than three hours during the 1^st or 2^nd week, contraceptive effectiveness may be reduced. The woman should reinsert the ring as soon as she remembers and an additional barrier method of contraception, such as condoms and/or spermicide, must be used until the ring has been used continuously for seven days. The longer the time NuvaRing has been out of the vagina and the closer this is to the ring free interval, the higher the risk of a pregnancy.

If NuvaRing has been out of the vagina for more than 3 hours during the 3rd week of the three-week use period contraceptive efficacy may be reduced. The woman should discard that ring, and one of the following two options should be chosen:

1. Insert a new ring immediately. Note: Inserting a new ring will start the next three-week use period. The woman may not experience a withdrawal bleed from her previous cycle. However, breakthrough spotting or bleeding may occur.

   
   

2. Have a withdrawal bleeding and insert a new ring no later than 7 days (7×24 hours) from the time the previous ring was removed or expelled. Note: This option should only be chosen if the ring was used continuously for the preceding 7 days.

   
   

Women with conditions affecting the vagina, such as a prolapsed uterus, may be more likely to have NuvaRing slip out of the vagina.

Several health advantages other than contraception have been reported.

1. Combination hormonal contraceptives (including NuvaRing) reduce the incidence of cancer of the endometrium and ovaries.

   
   

2. Combination hormonal contraceptives (including NuvaRing) reduce the likelihood of developing benign breast disease and as a result decrease the incidence of breast biopsies.

   
   

3. Combination hormonal contraceptives (including NuvaRing) reduce the likelihood of development of functional ovarian cysts.

   
   

4. Combination hormonal contraceptive (including NuvaRing) users have less menstrual blood loss and have more regular cycles, thereby reducing the chance of developing iron-deficiency anemia.

   
   

5. The use of combination hormonal contraceptives (including NuvaRing) may decrease the severity of dysmenorrhea and premenstrual syndrome and may improve acne vulgaris, hirsutism and other androgen-mediated disorders.

   
   

6. Combination hormonal contraceptives (including NuvaRing) decrease the incidence of acute pelvic inflammatory disease and thereby reduce as well the incidence of ectopic pregnancy.

   
   

7. Combination hormonal contraceptives (including NuvaRing) have potential beneficial effects on endometriosis.

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. Physicians and other health care providers should be made aware of the non-prescription products concomitantly used by the patient, including herbal and natural products.

The pharmacokinetics of NuvaRing was evaluated in one cycle in 10 healthy female subjects randomized to tampon use (Kotex, regular strength) on Day 8, 9, 10 of the NuvaRing cycle. The use of tampons had no effect on serum concentrations of etonogestrel and ethinyl estradiol during use of NuvaRing. It is unknown how this affects the safety and efficacy of NuvaRing.

NuvaRing is designed to be a once-a-month contraceptive regimen, therefore NuvaRing should be left in the vagina for a continuous period of 3 weeks. 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 should not be removed during intercourse.

NuvaRing may interfere with the correct placement and position of a diaphragm or cervical cap. A diaphragm or cervical cap is therefore not recommended as a back-up method with NuvaRing use.

Interactions between contraceptive steroids and other drugs have been reported in the literature (see Overview).

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.

The pharmacokinetics of NuvaRing were evaluated in one cycle in 24 healthy female subjects randomized to a single-dose vaginal administration on Day 8 of 100 mg of a nonoxynol-9 spermicide gel or a 1200 mg miconazole nitrate antimycotic capsule.

The single dose of 100 mg vaginally administered, water-based nonoxyl-9 gel did not affect the serum concentrations of etonogestrel or ethinyl estradiol.

The single dose of 1200 mg vaginally-administered, oil-based miconazole nitrate capsule increased the serum concentrations of etonogestrel and ethinyl estradiol by approximately 17% and 16% respectively. The clinical significance of these findings is unknown; however the contraceptive effectiveness of NuvaRing is not expected to change.

In a separate trial, the pharmacokinetics of NuvaRing were evaluated in one cycle in 12 healthy female subjects randomized to 3 doses of an oil-based 200 mg miconazole nitrate antimycotic suppository or a water-based 200 mg miconazole nitrate antimycotic vaginal cream on Days 8, 9, and 10 of the NuvaRing cycle. Following multiple doses, the mean serum concentrations of etonogestrel and ethinyl estradiol remained elevated compared to the concentrations on the first day of interaction treatment, and were elevated by up to 40%. This effect was more pronounced with the oil-based suppository treatment than in the water-based cream treatment.

The effects of chronic administration of these products with NuvaRing are unknown.

Several of the anti-HIV protease inhibitors have been studied with coadministration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the mean AUC of the estrogen and progestin have been noted in some cases. The efficacy and safety of oral contraceptive products may be affected; it is unknown whether this applies to NuvaRing. Healthcare providers should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information.

Pathologists should be advised of combination hormonal contraceptives (including NuvaRing) therapy when specimens obtained from surgical procedures and Pap smears are submitted for examination.

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 patient 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.

If the patient 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.

To achieve maximum contraceptive effectiveness, NuvaRing (etonogestrel/ethinyl estradiol slow release vaginal ring) must be used as directed (see When to Start NuvaRing). One NuvaRing is inserted in the vagina by the woman herself. As NuvaRing is designed to be a once-a-month contraceptive regimen the ring is to remain in place continuously for three weeks. It is a good habit for the woman to regularly verify the presence of NuvaRing. It is removed for a one-week break, during which a withdrawal bleed usually occurs. A new ring is inserted no more than one week after removal of the last ring.

To prevent loss of contraceptive efficacy patients should not deviate from the recommended regimen.

There are several types of progestin-only methods. Women should insert the first NuvaRing as follows:

• Any day of the month when switching from a progestin-only pill; do not skip any days between the last pill and the first day of NuvaRing use.

  
  

• On the same day as contraceptive implant removal.

  
  

• On the same day as removal of a progestin-containing IUD, or

  
  

• On the day when the next contraceptive injection would be due.

  
  

In all of these cases, the patient should be advised to use an additional method of contraception, such as condoms and/or spermicide, for the first seven days after insertion of the ring.

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, contraceptive efficacy may be reduced. Pregnancy should be ruled out before inserting a new NuvaRing, and an additional method of contraception, such as condoms and/or spermicide, must be used until a new NuvaRing has been used continuously for seven days.

If the woman wishes to change the day on which she starts a new NuvaRing cycle, she should complete the current cycle, removing NuvaRing on the same day of the week as the one on which she started. During the ring-free period, a new start day may be selected by inserting the new NuvaRing on the first occurrence of the desired day. In no case should there be more than 7 consecutive ring-free days. The shorter the ring-free interval, the higher the risk that she does not have a withdrawal bleed and may experience breakthrough bleeding and spotting during the use of the next ring. This practice is for a one-time only change and should not to be used as a standard dosing regimen, as there are no long-term safety data available on the continuous use of NuvaRing.

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 until it feels comfortable. The exact position of NuvaRing inside the vagina is not critical for the contraceptive effect of the ring. 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). The withdrawal bleeding usually starts 2-3 days 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. For example, if NuvaRing is inserted on Wednesday at 22:00 h the ring should be removed again on the Wednesday 3 weeks later at about 22:00 h. The following Wednesday a new ring should be inserted.

The use of NuvaRing for contraception may be initiated four weeks after a second trimester abortion or four weeks postpartum in women who elect not to breastfeed. When NuvaRing is used postpartum or postabortion, the increased risk of thromboembolic disease must be considered (See Contraindications and Warnings and Precautions, Hematologic concerning thromboembolic disease. Also see Warnings and Precautions for Special Populations: Nursing Women regarding breast-feeding.) 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.

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

The woman may switch from her previous combined hormonal contraceptive on any day of the cycle, if she has been using this method consistently and correctly, and if it is reasonably certain that she is not pregnant. Otherwise, the woman should insert NuvaRing at the latest on the day following the usual tablet-free, patch-free or placebo tablet interval of her previous combined hormonal contraceptive. The hormone-free interval of the previous method should never be extended beyond its recommended length.

The woman may start using NuvaRing within the first five days of her natural cycle. (i.e. Day 1-5 of her menstrual bleeding). During the first seven days of NuvaRing use in the first cycle, an additional barrier method, such as male condoms or spermicide, is recommended.

NuvaRing should be left in the vagina for a continuous period of 3 weeks. If the ring is accidentally expelled and is left outside of the vagina for less than 3 hours contraceptive efficacy is not reduced i.e. the woman should still be protected from pregnancy. NuvaRing should be rinsed with cool to lukewarm (not hot) water and re-inserted as soon as possible, but at the latest within 3 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 3 continuous hours: During Weeks 1 and 2: If NuvaRing has been out of the vagina for more than 3 continuous hours during the 1^st or 2^nd 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 and/or spermicide, must be used in addition until NuvaRing has been in the vagina continuously for 7 days. The longer the time NuvaRing has been out of the vagina and the closer this is to the ring-free interval, the higher the risk of pregnancy.

During Week 3: If NuvaRing has been out of the vagina for more than 3 continuous hours during the 3^rd week of the three-week use period, contraceptive efficacy may be reduced. The woman should discard that ring, and one of the following two options should be chosen:

1. Insert a new ring immediately. Inserting a new ring will start the next three-week use period. The woman may not experience a withdrawal bleed from her previous cycle. However, breakthrough spotting or bleeding may occur.

   
   

2. Have a withdrawal bleeding and insert a new ring no later than 7 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 7 days.

   
   

A barrier method such as condoms and/or spermicides must be used until the new ring has been used continuously for seven days.

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 condoms and/or spermicide, must be used until NuvaRing has been used continuously for seven days. The longer the ring-free interval, the higher the risk of pregnancy.

estrogens increased, glucocorticoids increased, hypothyroidism.

Other rare adverse events which were observed in clinical trials were as follows:

hypertension, hypotension, oedema dependent.

In general, post-marketing data are in agreement with the expectations and conclusions based on the clinical development program, except for some unanticipated reports related to disconnected rings (<0.005%, see Warning and Precautions, Genitourinary).

cervical smear PAP II.

asthma, dyspnoea, rhinitis.

amenorrhoea, bleeding irregularity, breast enlargement, cervical dysplasia, cervicitis, cervix lesion, ectopy, endometritis, lactation nonpuerperal, mastitis, ovarian disorder, ovarian mass, ovarian pain, pelvic inflammation, premenstrual tension, uterine disorder nos, vulva discomfort, vulva disorder.

arthralgia, muscle weakness.

dehydration, hypercholesterolaemia, hypertriglyceridaemia, oedema generalised, xerophthalmia.

alopecia, dermatitis fungal, eczema, photosensitivity reaction, pigmentation abnormal, pruritus, pruritus genital, rash, rash maculo-papular, seborrhea, skin discolouration, skin disorder, skin dry.

infection viral.

abdomen enlarged, allergic reaction, asthenia, back pain, chest pain, fatigue, hot flushes, influenza-like symptoms, leg pain, malaise, oedema, oedema peripheral, pain, temperature changed sensation.

palpitation.

bladder discomfort, cystitis, dysuria, micturition frequency, micturition urgency, strangury, urinary incontinence, urinary tract infection.

anaemia.

anus disorder, change in bowel habits, colitis ulcerative aggravated, constipation, diarrhoea, dyspepsia, flatulence, haemorrhoids, rectal disorder, tenesmus, vomiting.

skin nodule.

breast fibroadenosis, breast neoplasm benign female, cervical smear test positive, cervical uterine polyp, haemangioma acquired, ovarian cyst, uterine fibroid, vaginal neoplasm benign.

cervical smear test PAP II.

conjunctivitis, vision abnormal.

An increased risk of the following serious adverse reactions has been associated with the use of combination hormonal contraceptives (including NuvaRing [etonogestrel/ethinyl estradiol slow release vaginal ring]): thrombophlebitis; pulmonary embolism; mesenteric thrombosis; neuro-ocular lesions, e.g., retinal thrombosis; myocardial infarction; cerebral thrombosis; cerebral hemorrhage; hypertension; benign hepatic tumours; gallbladder disease; congenital anomalies.

The following adverse reactions also have been reported in patients receiving combination hormonal contraceptives: Nausea and vomiting, usually the most common adverse reaction, occurs in approximately 10% or less of patients during the first cycle. Other reactions, as a general rule, are seen less frequently or only occasionally, as follows: gastrointestinal symptoms (such as abdominal cramps and bloating); breakthrough bleeding; spotting; change in menstrual flow; dysmenorrhea; amenorrhea during and after treatment; temporary infertility after discontinuance of treatment; edema; chloasma or melasma which may persist; breast changes: tenderness, enlargement, and secretion; change in weight (increase [5%] or decrease [0.1%]); endocervical hyperplasias; possible diminution in lactation when given immediately post-partum; cholestatic jaundice; migraine; increase in size of uterine leiomyomata; rash (allergic); mental depression; reduced tolerance to carbohydrates; vaginal candidiasis; premenstrual-like syndrome; intolerance to contact lenses; change in corneal curvature (steepening); cataracts; optic neuritis; retinal thrombosis; changes in libido; chorea; changes in appetite; cystitis-like syndrome; rhinitis; headache; nervousness; dizziness; hirsutism; loss of scalp hair; erythema multiforme; erythema nodosum; hemorrhagic eruption; vaginitis; porphyria; impaired renal function; Raynaud's phenomenon; auditory disturbances; hemolytic uremic syndrome; pancreatitis.

device related problems, penis disorders including pain, rash, bruises and abrasions.

cholelithiasis, AST increased.

thrombophlebitis, thrombophlebitis deep, thrombophlebitis superficial.

haematoma, purpura.

aphasia, cramps legs, dizziness, dysaesthesia, hypoaesthesia, migraine aggravated, paraesthesia, vertigo.

aggressive reaction, agitation, anorexia, anxiety, apathy, appetite increased, concentration impaired, depression aggravated, hallucination, insomnia, libido increased, nervousness.

There is an increased risk of post-surgery thromboembolic complications in combination hormonal contraceptive (including NuvaRing) users, after major surgery. If feasible, combination hormonal contraceptives should be discontinued and an alternative method substituted at least one month prior to major elective surgery. Combination hormonal contraceptives should not be resumed until the first menstrual period after hospital discharge following surgery.

Patients with a history of emotional disturbances, especially the depressive type, may be more prone to have a recurrence of depression while using combination hormonal contraceptives (including NuvaRing). In cases of a serious recurrence, a trial of an alternate method of contraception should be made which may help to clarify the possible relationship. Women with premenstrual syndrome (PMS) may have a varied response to combination hormonal contraceptives, ranging from symptomatic improvement to worsening of the condition.

Hepatic nodules (adenoma and focal nodular hyperplasia) have been reported, particularly in long-term users of combination hormonal contraceptives. Although these lesions are extremely rare, they have caused fatal intra-abdominal hemorrhage and should be considered in women presenting with an abdominal mass, acute abdominal pain, or evidence of intra-abdominal bleeding.

Women having a history of oligomenorrhea, secondary amenorrhea, or irregular cycles may remain anovulatory or become amenorrheic following discontinuation of estrogen-progestin combination therapy.

Amenorrhea, especially if associated with breast secretion, that continues for six months or more after withdrawal, warrants a careful assessment of hypothalamic-pituitary function.

Combination hormonal contraceptives (including NuvaRing) should not be used by pregnant women. However, if conception accidentally occurs while using combination hormonal contraceptives, there is no conclusive evidence that the estrogen and progestin contained in combination hormonal contraceptives will damage the developing child.

The extent of exposure in pregnancy during clinical trials: Very Limited: individual cases only.

A controlled open-label, multicenter trial was conducted to evaluate the effects of NuvaRing on bone mineral density (BMD) in healthy young women (n=105; 76 completers) over a 2 year period (26 cycles). The control group (n=39; 31 completers) consisted of women who did not use a hormonal method of contraception, and an IUD was offered as trial medication. The mean age of subjects was 27 years in the NuvaRing group and 29 years in the control group.

For the NuvaRing group, the BMD for lumbar spine and femoral neck were not statistically different from baseline after two years of follow-up (change in z-score was −0.093 and −0.048, respectively). In the control group, a slight increase of BMD for both the lumbar spine and femoral neck was observed (change in z-score of 0.257 and 0.223, respectively). At the end of 2 years, there was a statistically significant difference in the change of BMD from baseline, between the Nuvaring group and the control group.

Before combination hormonal contraceptives (including NuvaRing) are used, a thorough history and physical examination should be performed, including a blood pressure determination. Breasts, liver, extremities and pelvic organs should be examined. A Papanicolaou smear should be taken if the patient has been sexually active.

The first follow-up visit should be done three months after combination hormonal contraceptives are prescribed. Thereafter, examinations should be performed at least once a year or more frequently if indicated. At each annual visit, examination should include those procedures that were done at the initial visit as outlined above or per recommendations of the Canadian Task Force on the Periodic Health Examination.

Cigarette smoking increases the risk of serious cardiovascular side effects and mortality. Combination hormonal contraceptives (including NuvaRing), increase this risk, especially with increasing age.

Convincing data are available to support an upper age limit of 35 years for combination hormonal contraceptives use in women who smoke.

Other women who are independently at high risk for cardiovascular disease include those with diabetes, hypertension, abnormal lipid profile, or a family history of these. Whether combination hormonal contraceptives, accentuate this risk is unclear.

In low risk, non-smoking women of any age, the benefits of combination hormonal contraceptives use outweigh the possible cardiovascular risks associated with low dose formulations.

Consequently, combination hormonal contraceptives may be prescribed for these women up to the age of menopause.

NuvaRing (etonogestrel/ethinyl estradiol slow release vaginal ring) and other contraceptives that contain both an estrogen and a progestin are called combination hormonal contraceptives. Most of the warnings below are based on data obtained from the oral route of administration. There is no epidemiologic data available to determine whether the safety with the vaginal route of administration of combined hormonal contraceptives (such as NuvaRing) would be different than the oral route, and, in the absence of these comparable data, associated risks should be assumed to be similar for use through both routes.

Current low dose combination hormonal contraceptives (including NuvaRing) exert minimal impact on glucose metabolism. Diabetic patients, or those with a family history of diabetes, should be observed closely to detect any worsening of carbohydrate metabolism. Patients predisposed to diabetes who can be kept under close supervision may be given combination hormonal contraceptives. Young diabetic patients whose disease is of recent origin, well-controlled, and not associated with hypertension or other signs of vascular disease such as ocular fundal changes, should be monitored more frequently while using combination hormonal contraceptives.

Patients with fibroids (leiomyomata) should be carefully observed. Sudden enlargement, pain, or tenderness require discontinuation of the use of combination hormonal contraceptives (including NuvaRing).

The onset or exacerbation of migraine or the development of headache of a new pattern which is recurrent, persistent or severe, requires discontinuation of combination hormonal contraceptives (including NuvaRing) and evaluation of the cause.

Patients with essential hypertension whose blood pressure is well-controlled may be prescribed combination hormonal contraceptives (including NuvaRing) but only under close supervision. If a significant elevation of blood pressure in previously normotensive or hypertensive subjects occurs at any time during the administration of the drug, cessation of medication is necessary.

Persistent irregular vaginal bleeding requires assessment to exclude underlying pathology.

NuvaRing may not be suitable for women with conditions that make the vagina more susceptible to vaginal irritation or ulceration. In some cases, vaginal (fibrous) tissue may grow over the ring, necessitating removal by a healthcare provider.

After discontinuing combination hormonal contraceptive (including NuvaRing) therapy, the patient should delay pregnancy until at least one normal spontaneous cycle has occurred in order to date the pregnancy. An alternate contraceptive method should be used during this time.

Patients who are pregnant or are using combination hormonal contraceptives (including NuvaRing), may experience corneal edema that may cause visual disturbances and changes in tolerance to contact lenses, especially of the rigid type. Soft contact lenses usually do not cause disturbances. If visual changes or alterations in tolerance to contact lenses occur, temporary or permanent cessation of wear may be advised.

Persistent infection with the Human Papilloma Virus (HPV) is believed to be the most important risk factor for cervical cancer. Some epidemiological studies indicated that long-term use of combination oral contraceptives (COCs) may further contribute to this increased risk, but there continues to be controversy about the extent to which this finding may be confounded by other factors, e.g., cervical screening bias and sexual behaviour. It is unknown how this effect relates to NuvaRing.

Increasing age and a strong family history are the most significant risk factors for the development of breast cancer. Other established risk factors include obesity, nulliparity and late age at first full-term pregnancy. The identified groups of women that may be at increased risk of developing breast cancer before menopause are long-term users (more than 8 years) of combination hormonal contraceptives (including NuvaRing) and starters at early age. In a few women, the use of combination hormonal contraceptives (including NuvaRing) may accelerate the growth of an existing but undiagnosed breast cancer. Since any potential increased risk related to combination hormonal contraceptives (including NuvaRing) use is small, there is no reason to change prescribing habits at present.

Women receiving combination hormonal contraceptives (including NuvaRing) should be instructed in self-examination of their breasts. Their physicians should be notified whenever any masses are detected. A yearly clinical breast examination is also recommended because, if a breast cancer should develop, estrogen-containing drugs may cause a rapid progression.

Patients who have had jaundice including a history of cholestatic jaundice during pregnancy should be given combination hormonal contraceptives (including NuvaRing) with great care and under close observation.

The development of severe generalized pruritus or icterus requires that the medication be withdrawn until the problem is resolved.

If the jaundice should prove to be cholestatic in type, the use of combination hormonal contraceptives should not be resumed. In patients taking combination hormonal contraceptives, changes in the composition of the bile may occur and an increased incidence of gallstones has been reported.

Very rarely it has been reported that NuvaRing was inadvertently inserted in the urethra and possibly ended up in the bladder. Healthcare providers should assess for incorrect placement of NuvaRing in the urethra or bladder in those users presenting with persistent urinary symptoms and who are unable to locate the ring.

Epidemiological studies have suggested an association between the use of combination oral contraceptives (COCs) and an increased risk of venous thrombotic and thromboembolic diseases.

As NuvaRing is a new contraceptive product with a new (vaginal) route of administration delivering ethinyl estradiol and etonogestrel (the biological active metabolite of desogestrel) the following should be noted:

• Venous thromboembolism (VTE), manifesting as deep vein thrombosis and/or pulmonary embolism, may occur during the use of all combined hormonal contraceptives, including NuvaRing. The approximate incidence of VTE in users of low estrogen dose (<0.05 mg EE) oral contraceptives is up to 4 per 10 000 woman years compared to 0.5-3 per 10 000 woman years in non-oral contraceptive users. The incidence of VTE associated with pregnancy is 6 per 10 000 woman years.

  
  

• Several epidemiological studies indicate that third generation oral contraceptives, including those containing desogestrel (etonogestrel, the progestin component released by NuvaRing is the biologically active metabolite of desogestrel) are associated with a higher risk of venous thromboembolism than certain second generation oral contraceptives. These studies indicate an approximate 2-fold difference in risk, which corresponds to 1-2 cases of venous thromboembolism per 10 000 women-years of use. However, data from additional studies have not shown this difference in risk. It should be noted, however, that the incidence of venous thromboembolism in oral contraceptive users is rare.

The extent and possible pharmacological role of exposure of male sexual partners to ethinyl estradiol and etonogestrel through absorption through the penis have not been determined.

On rare occasions, NuvaRing has been reported to disconnect at the weld joint. Since the core of NuvaRing is solid, its contents will remain intact and release of hormone is unlikely to occur. In the event of a disconnected ring, expulsion (slipping out) is likely to occur (see Drug Interactions, Drug-Lifestyle Interactions, Expulsion). If a woman discovers that her NuvaRing has disconnected, she should discard the ring and replace it with a new ring.

Thromboembolic and Cardiovascular Disorders such as: thrombophlebitis, pulmonary embolism, cerebrovascular disorders, myocardial ischemia, mesenteric thrombosis, and retinal thrombosis.

The effects of NuvaRing in nursing mothers have not been evaluated and are unknown. In breast-feeding women, the use of combination hormonal contraceptives results in the hormonal components being excreted in breast milk and may reduce its quantity and quality. If the use of combination hormonal contraceptives is initiated after the establishment of lactation, there does not appear to be any effect on the quantity and quality of the milk. There is no evidence that low dose combination hormonal contraceptives are harmful to the nursing infant. However, women who are breast feeding should be advised not to use CHC’s (including NuvaRing) but to use other forms of contraception until the child is weaned.

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 patients with impaired liver function (see Warnings and Precautions).

Etonogestrel: Etonogestrel: Etonogestrel was found to be 98% protein bound, primarily to albumin and sex hormone-binding globulin (SHBG). The apparent volume of distribution of etonogestrel is 2.3 L/kg.

Ethinyl Estradiol: Ethinyl estradiol is highly but not specifically bound to serum albumin (approximately 98.5%) and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of about 15 L/kg has been determined.

Combination hormonal contraceptives (including NuvaRing) act by suppression of gonadotropins. Although the primary mechanism 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 reduces the likelihood of implantation).

No formal studies were conducted to evaluate the effect of race on the pharmacokinetics of NuvaRing.

Etonogestrel and ethinyl estradiol are primarily eliminated in urine, bile and feces.

No formal studies were conducted to evaluate the effect of renal disease on the pharmacokinetics, safety, and efficacy of NuvaRing.

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.

Etonogestrel, the progestogen component of NuvaRing, displays low androgenic activity in relation to its progestogenic effects and may increase the HDL₁-, HDL₂-, and HDL₃-cholesterol and apoprotein A-1/B ratio without affecting LDL. Like other hormonal contraceptives, these changes in lipid profile can be associated with an increase in triglycerides.

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

Serum ethinyl estradiol levels were measured in a comparative randomized trial (n=24) with NuvaRing (daily vaginal EE release of 0.015 mg), a transdermal patch (norelgestromin/EE; daily EE release of 0.020 mg) and a COC (levonorgestrel/EE; daily EE release of 0.030 mg) during one cycle in healthy female subjects. The monthly systemic ethinyl estradiol exposure (AUC_0-∞) of NuvaRing was 10.9 ng·h/mL.