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e. Persistence of risk of vascular disease There are two studies that have shown persistence of risk of vascular disease for ever-users of combination
hormonal contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing combination hormonal contraceptives persists for at least 9 years for women 40-49 years who had used combination hormonal contraceptives for five or more years, but this increased risk was not demonstrated in other age groups8. In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of combination hormonal contraceptives, although excess risk was very small34. However, both studies were performed with combination hormonal contraceptive formulations containing 50 micrograms or higher of estrogens. It is unknown whether ORTHO EVRAŽ is distinct from other combination hormonal contraceptives with regard to the occurrence of venous and arterial thrombosis. 2. Estimates Of Mortality From Combination Hormonal Contraceptive Use Text Continues Below
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 3). 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 combination oral contraceptive users 35 and older who smoke, and 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 combination oral contraceptive users is based on data gathered in the 1970s but not reported until 198335. Current clinical recommendation involves the use of lower estrogen dose formulations and a careful consideration of risk factors. In 1989, the Fertility and Maternal Health Drugs Advisory Committee was asked to review the use of combination hormonal contraceptivesin women 40 years of age and over. The Committee concluded that although cardiovascular disease risks may be increased with combination hormonal 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 that may be necessary if such women do not have access to effective and acceptable means of contraception. The Committee recommended that the benefits of low-dose combination hormonal contraceptive use by healthy nonsmoking women over 40 may outweigh the possible risks 36, 37. Although the data are mainly obtained with oral contraceptives, this is likely to apply to ORTHO EVRAŽ as well. Women of all ages who use combination hormonal contraceptives, should use the lowest possible dose
formulation that is effective and meets the individual patient needs. Table 3: Annual Number of Birth-Related or Method-Related Deaths Associated With Control of Fertility Per 100,000 Non-Sterile Women, by Fertility Control Method According to Age
Method of control
and outcome 15-19 20-24 25-29 30-34 35-39 40-44
No fertility control
methods* 7.0 7.4 9.1 14.8 25.7 28.2
Oral contraceptives,
non-smoker** 0.3 0.5 0.9 1.9 13.8 31.6
Oral contraceptives,
smoker** 2.2 3.4 6.6 13.5 51.1 117.2
IUD** 0.8 0.8 1.0 1.0 1.4 1.4
Condom* 1.1 1.6 0.7 0.2 0.3 0.4
Diaphragm/
spermicide* 1.9 1.2 1.2 1.3 2.2 2.8
Periodic abstinence* 2.5 1.6 1.6 1.7 2.9 3.6
*Deaths are birth-related
**Deaths are method-related
Adapted from H.W. Ory, ref. # 35. 3. Carcinoma Of The Reproductive Organs And Breasts Numerous epidemiological studies give conflicting reports on the relationship between breast cancer and COC use. The risk of having breast cancer diagnosed may be slightly increased among current and recent users of combination oral contraceptives. However, this excess risk appears to decrease over time after COC discontinuation and by 10 years after cessation the increased risk disappears. Some studies report an increased risk with duration of use while other studies do not and no consistent relationships have been found with dose or type of steroid. Some studies have found a small increase in risk for women who first use COCs before age 20. Most studies show a similar pattern of risk with COC use regardless of a womans reproductive history or her family breast cancer history. In addition, breast cancers diagnosed in current or ever oral contraceptive users may be less clinically advanced than in never-users. Women who currently have or have had breast cancer should not use hormonal contraceptives because breast cancer is usually a hormonally 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 women45-48. 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 not known whether ORTHO EVRAŽ is distinct from oral contraceptives with regard to the above statements. 4. Hepatic Neoplasia Benign hepatic adenomas are associated with hormonal 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/100,000 for users, a risk that increases after four or more years of use, especially with hormonal contraceptives containing 50 micrograms or more of estrogen49. Rupture of benign, hepatic adenomas may cause death through intra-abdominal hemorrhage 50,51. Studies from Britain and the US have shown an increased risk of developing hepatocellular carcinoma in long term (= 8 years)52-54,96 oral contraceptive users. However, these cancers are extremely rare in the U.S. 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 ORTHO EVRAŽ 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 hormonal contraceptives. ORTHO EVRAŽ 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 Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy56,57. Studies also do not indicate a teratogenic effect, particularly in so far as cardiac anomalies and limb reduction defects are concerned 55,56,58,59, when oral contraceptives are taken
inadvertently during early pregnancy. Combination hormonal contraceptives such as ORTHO EVRAŽ should not be used to induce withdrawal bleeding as a test for pregnancy. ORTHO EVRAŽ should not be used during pregnancy to treat threatened or habitual abortion. It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out. If the patient has not adhered to the prescribed schedule for the use of ORTHO EVRAŽ the possibility of pregnancy should be considered at the time of the first missed period. Hormonal contraceptive use should be discontinued if pregnancy is confirmed. 7. Gallbladder Disease Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of hormonal contraceptives and estrogens60,61. More recent studies, however, have shown that the relative risk of developing gallbladder disease among hormonal contraceptive users may be minimal62-64. The recent findings of minimal risk may be related to the use of hormonal contraceptive formulations containing lower hormonal doses of estrogens and progestins. Combination hormonal contraceptives such as ORTHO EVRAŽ 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 users17. However, in the non-diabetic woman, combination hormonal contraceptives appear to have no effect on fasting blood glucose67. Prediabetic and diabetic women in particular should be carefully monitored while taking combination hormonal contraceptives such as ORTHO EVRAŽ. In clinical trials with oral contraceptives containing ethinyl estradiol and norgestimate there were no clinically significant changes in fasting blood glucose levels. There were no clinically significant changes in glucose levels over 24 cycles of use. Moreover, glucose tolerance tests showed no clinically significant changes from baseline to cycles 3, 12 and 24. In a 6-cycle clinical trial with ORTHO EVRAŽ there were no clinically significant changes in fasting blood glucose from baseline to end of treatment. A small proportion of women will have persistent hypertriglyceridemia while taking hormonal contraceptives. As discussed earlier (see WARNINGS 1a and 1d), changes in serum triglycerides and lipoprotein levels have been reported in hormonal contraceptive users. 9. Elevated Blood Pressure Women with significant hypertension should not be started on hormonal contraception103. Women with a history of hypertension or hypertension-related diseases, or renal disease70 should be encouraged to use another method of contraception. If women elect to use ORTHO EVRAŽ, they should be monitored closely and if a clinically significant elevation of blood pressure occurs, ORTHO EVRAŽ should be discontinued. For most women, elevated blood pressure will return to normal after stopping hormonal contraceptives, and there is non difference in the occurrence of hypertension between former and never users68-71. An increase in blood pressure has been reported in women taking hormonal contraceptives68 and this increase is more likely in older hormonal contraceptive users69 and with extended duration of use61. Data from the Royal College of General Practitioners12 and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity. 10. Headache The onset or exacerbation of migraine headache or the development of headache with a new pattern that is recurrent, persistent or severe requires discontinuation of ORTHO EVRAŽ and evaluation of the cause. 11. Bleeding Irregularities Breakthrough bleeding and spotting are sometimes encountered in women using ORTHO EVRAŽ. Nonhormonal causes should be considered and adequate diagnostic measures taken to rule out malignancy, other pathology, or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another contraceptive product may resolve the bleeding. In the event of amenorrhea, pregnancy should be ruled out before initiating use of ORTHO EVRAŽ. Some women may encounter amenorrhea or oligomenorrhea after discontinuation of hormonal contraceptive use, especially when such a condition was pre-existent. Bleeding Patterns: In the clinical trials most women started their withdrawal bleeding on the fourth day of the drug-free interval, and the median duration of withdrawal bleeding was 5 to 6 days. On average 26% of women per cycle had 7 or more total days of bleeding and/or spotting (this includes both withdrawal flow and breakthrough bleeding and/or spotting). 12. Ectopic Pregnancy Ectopic as well as intrauterine pregnancy may occur in contraceptive failures.
PRECAUTIONS
Women should be counseled that ORTHO EVRAŽ does not protect against HIV infection (AIDS) and other sexually transmitted infections. 1. Body Weight =198 lbs. (90 kg)
Results of clinical trials suggest that ORTHO EVRAŽ may be less effective in women with body weight =198 lbs. (90 kg) than in women with lower body weights. 2. Physical Examination And Follow-Up
It is good medical practice for women using ORTHO EVRAŽ, as for all women, to have annual medical evaluation and physical examinations. The physical examination, however, may be deferred until after initiation of hormonal contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy or other pathology. Women with a strong 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 ORTHO EVRAŽ. Some progestins may elevate LDL levels and may render the control of hyperlipidemias more difficult. 4. Liver Function
If jaundice develops in any woman using ORTHO EVRAŽ, the medication should be discontinued. The hormones in ORTHO EVRAŽ may be poorly metabolized in patients with impaired liver function. 5. Fluid Retention
Steroid hormones like those in ORTHO EVRAŽ may cause some degree of fluid retention. ORTHO EVRAŽ should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention. 6. Emotional Disorders
Women who become significantly depressed while using combination hormonal contraceptives such as ORTHO EVRAŽ should stop the medication and use another 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 ORTHO EVRAŽ discontinued if significant depression occurs. 7. Contact Lenses
Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist. 8. Drug Interactions
Changes in Contraceptive Effectiveness Associated with Co-Administration of Other Drugs:
Contraceptive effectiveness may be reduced when hormonal contraceptives are co-administered with some antibiotics, 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 possibly with ampicillin. The proposed mechanism of interaction of antibiotics is different from that of liver enzyme-inducing drugs. Literature suggests possible interactions with the concomitant use of hormonal contraceptives and ampicillin or tetracycline. In a pharmacokinetic drug interaction study, oral administration of tetracycline HCl, 500 mg q.i.d. for 3 days prior to and 7 days during wear of ORTHO EVRAŽ did not significantly affect the pharmacokinetics of norelgestromin or EE. Several of the anti-HIV protease inhibitors have been studied with co-administration 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 ORTHO EVRAŽ. Healthcare professionals should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information. Herbal products containing St. Johns 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. 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. 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. Although norelgestromin and its metabolites inhibit a variety of P450 enzymes in human liver microsomes, the clinical consequence of such an interaction on the levels of other concomitant medications is likely to be insignificant. Under the recommended dosing regimen, the in vivo concentrations of norelgestromin and its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant (Ki) (based on results of in vitro studies). Health care professionals are advised to also refer to prescribing information of co-administered drugs for recommendations regarding management of concomitant therapy. 9. Interactions With Laboratory Tests
Certain endocrine and liver function tests and blood components may be affected by hormonal contraceptives: a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrineinduced platelet aggregability. b. 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. c. Other binding proteins may be elevated in serum. d. Sex hormone binding globulins are increased and result in elevated levels of total circulating endogenous sex steroids and corticoids; however, free or biologically active levels either decrease or remain unchanged. e. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected. f. Glucose tolerance may be decreased. g. Serum folate levels may be depressed by hormonal contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing ORTHO EVRAŽ. 10. Carcinogenesis No carcinogenicity studies were conducted with norelgestromin. However, bridging PK studies were conducted using doses of NGM/EE which were used previously in the 2-year rat carcinogenicity study and 10-year monkey toxicity study to support the approval of ORTHO-CYCLENŽ and ORTHO TRI-CYCLENŽ under NDAs 19-653 and 19-697, respectively. The PK studies demonstrated that rats and monkeys were exposed to 16 and 8 times the human exposure, respectively, with the proposed ORTHO EVRAŽ transdermal contraceptive system. Norelgestromin was tested in in-vitro mutagenicity assays (bacterial plate incorporation mutation assay, CHO/HGPRT mutation assay, chromosomal aberration assay using cultured human peripheral lymphocytes) and in one in-vivo test (rat micronucleus assay) and found to have no genotoxic potential.
See WARNINGS Section. 11. Pregnancy
Pregnancy Category X.
See CONTRAINDICATIONS and WARNINGS Sections.
Norelgestromin was tested for its reproductive toxicity in a rabbit developmental toxicity study by the SC route of administration. Doses of 0, 1, 2, 4 and 6 mg/kg body weight, which gave systemic exposure of approximately 25 to 125 times the human exposure with ORTHO EVRAŽ, were administered daily on gestation days 719. Malformations reported were paw hyperflexion at 4 and 6 mg/kg and paw hyperextension and cleft palate at 6 mg/kg. 12. Nursing Mothers
The effects of ORTHO EVRAŽ in nursing mothers have not been evaluated and are unknown. Small amounts of combination hormonal 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, combination hormonal contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. Long-term follow-up of infants whose mothers used combination hormonal contraceptives while breast feeding has shown no deleterious effects. However, the nursing mother should be advised not to use ORTHO EVRAŽ but to use other forms of contraception until she has completely weaned her child. 13. Pediatric Use
Safety and efficacy of ORTHO EVRAŽ have been established in women of reproductive age. Safety and efficacy are expected to be the same for post-pubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated. 14. Geriatric Use
This product has not been studied in women over 65 years of age and is not indicated in this population. 15. Sexually Transmitted Diseases
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases. 16. Patch Adhesion
Experience with more than 70,000 ORTHO EVRAŽ patches worn for contraception for 6-13 cycles showed that 4.7% of patches were replaced because they either fell off (1.8%) or were partly detached (2.9%). Similarly, in a small study of patch wear under conditions of physical exertion and variable temperature and humidity, less than 2% of patches were replaced for complete or partial detachment. If the ORTHO EVRAŽ patch becomes partially or completely detached and remains detached, insufficient drug delivery occurs. A patch should not be re-applied if it is no longer sticky, if it has become stuck to itself or another surface, if it has other material stuck to it, or if it has become loose or fallen off before. If a patch cannot be re-applied, a new patch should be applied immediately. Supplemental adhesives or wraps should not be used to hold the ORTHO EVRAŽ patch in place. If a patch is partially or completely detached for more than one day (24 hours or more) OR if the woman is not sure how long the patch has been detached, she may not be protected from pregnancy. She should stop the current contraceptive cycle and start a new cycle immediately by applying a new patch. Back-up contraception, such as condoms, spermicide, or diaphragm, must be used for the first week of the new cycle. GENERAL PRECAUTIONS 1. Weight > 198 lbs. (90 kg)
Clinical trials suggest that ORTHO EVRAŽ may be less effective in women weighing more than 198 lbs. (90 kg) compared with its effectiveness in women with lower body weights. If you weigh more than 198 lbs. (90 kg) you should talk to your health care professional about which method of birth control may be best for you. 2. Missed periods and use of ORTHO EVRAŽ before or during early pregnancy There may be times when you may not menstruate regularly during your patch-free week. If you have used ORTHO EVRAŽ correctly and miss one menstrual period, continue using your contraceptive patches for the next cycle but be sure to inform your health care professional before doing so. If you have not used ORTHO EVRAŽ as instructed and missed a menstrual period, or if you missed two menstrual periods in a row, you could be pregnant. Check with your health care professional immediately to determine whether you are pregnant. Stop using ORTHO EVRAŽ if you are pregnant. There is no conclusive evidence that hormonal contraceptive use causes birth defects when taken accidentally during early pregnancy. Previously, a few studies had reported that oral contraceptives might be associated with
birth defects, but these findings have not been seen in more recent studies. Nevertheless, hormonal contraceptives, including ORTHO EVRAŽ, should not be used during pregnancy. You should check with your healthcare professional about risks to your unborn child from any medication taken during pregnancy. 3. While breast-feeding
If you are breast-feeding, consult your health care professional before starting ORTHO EVRAŽ. Hormonal contraceptives are passed on to the child in the milk. A few adverse effects on the child have been reported, including yellowing of the skin (jaundice) and breast enlargement. In addition, combination hormonal contraceptives may decrease the amount and quality of your milk. If possible, do not use combination hormonal contraceptives such as ORTHO EVRAŽ while breast-feeding. You should use a barrier method of contraception since breast-feeding provides only partial protection from becoming pregnant and this partial protection decreases significantly as you breast-feed for longer periods of time. You should consider starting ORTHO EVRAŽ only after you have weaned your child completely. 4. Laboratory tests
If you are scheduled for any laboratory tests, tell your doctor you are using ORTHO EVRAŽ since certain blood tests may be affected by hormonal contraceptives. 5. Drug interactions
Certain drugs may interact with hormonal contraceptives, including ORTHO EVRAŽ, 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), anticonvulsants such as topiramate (TOPAMAX), carbamazepine (Tegretol is one brand of this drug), phenytoin (Dilantin is one brand of this drug), phenylbutazone (Butazolidin is one brand), certain drugs used in the treatment of HIV or AIDS, and possibly certain antibiotics. Tetracycline has been shown not to interact with ORTHO EVRAŽ. Pregnancies and breakthrough bleeding have been reported by users of combined hormonal contraceptives who also used some form of St. Johns Wort. As with all prescription products, you should notify your health care professional of any other medications you are taking. You may need to use a barrier contraceptive when you take drugs that can make ORTHO EVRAŽ
less effective. 6. Sexually transmitted diseases
ORTHO EVRAŽ is intended to prevent pregnancy. It does not protect against HIV (AIDS) or other sexually transmitted diseases such as chlamydia, genital herpes, genital warts, gonorrhea, hepatitis B, and syphilis. Page: << Prev | 1 | 2 | 3 | 4 | 5
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