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