Dosage Form: patch, extended release
Ortho Evra®
(norelgestromin / ethinyl estradiol
TRANSDERMAL SYSTEM)
Cigarette Smoking and Serious Cardiovascular Risks
Cigarette smoking increases the risk of serious cardiovascular events from hormonal contraceptive use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, hormonal contraceptives, including Ortho Evra®, should not be used by women who are over 35 years of age and smoke.
Risk of Venous Thromboembolism
The risk of venous thromboembolism (VTE) among women aged 15–44 who used the Ortho Evra® patch compared to women who used oral contraceptives containing 30–35 mcg of ethinyl estradiol (EE) and either levonorgestrel or norgestimate was assessed in four U.S. case-control studies using electronic healthcare claims data. The odds ratios ranged from 1.2 to 2.2; one of the studies found a statistically significant increased risk of VTE for current users of Ortho Evra® (see WARNINGS - Table 5).
Pharmacokinetic Profile of Ethinyl Estradiol
The pharmacokinetic (PK) profile for the Ortho Evra® patch is different from the PK profile for oral contraceptives in that it has higher steady state concentrations and lower peak concentrations. Area under the time-concentration curve (AUC) and average concentration at steady state for ethinyl estradiol (EE) are approximately 60% higher in women using Ortho Evra® compared with women using an oral contraceptive containing 35 mcg of EE. In contrast, peak concentrations for EE are approximately 25% lower in women using Ortho Evra®. It is not known whether there are changes in the risk of serious adverse events based on the differences in PK profiles of EE in women using Ortho Evra® compared with women using oral contraceptives containing 30–35 mcg of EE. Increased estrogen exposure may increase the risk of adverse events, including venous thromboembolism. (See WARNINGS and CLINICAL PHARMACOLOGY, Transdermal versus Oral Contraceptives.)
Patients should be counseled that this product does not protect against HIV infection (AIDS) and other sexually transmitted diseases.
Ortho Evra Description
Ortho Evra® is a combination transdermal contraceptive patch with a contact surface area of 20 cm2. It contains 6.00 mg norelgestromin (NGMN) and 0.75 mg ethinyl estradiol (EE). Systemic exposures (as measured by area under the curve [AUC] and steady state concentration [Css]) of NGMN and EE during use of Ortho Evra® are higher and peak concentrations (Cmax) are lower than those produced by an oral contraceptive containing norgestimate 250 mcg / EE 35 mcg. (See BOLDED WARNING; CLINICAL PHARMACOLOGY, Transdermal versus Oral Contraceptives).
Ortho Evra® is a thin, matrix-type transdermal contraceptive patch consisting of three layers. The backing layer is composed of a beige flexible film consisting of a low-density pigmented polyethylene outer layer and a polyester inner layer. It provides structural support and protects the middle adhesive layer from the environment. The middle layer contains polyisobutylene/polybutene adhesive, crospovidone, non-woven polyester fabric and lauryl lactate as inactive components. The active components in this layer are the hormones, norelgestromin and ethinyl estradiol. The third layer is the release liner, which protects the adhesive layer during storage and is removed just prior to application. It is a transparent polyethylene terephthalate (PET) film with a polydimethylsiloxane coating on the side that is in contact with the middle adhesive layer.
The outside of the backing layer is heat-stamped "Ortho Evra®."
The structural formulas of the components are:
Molecular weight, norelgestromin: 327.47
Molecular weight, ethinyl estradiol: 296.41
Chemical name for norelgestromin: 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-,3-oxime,(17α)
Chemical name for ethinyl estradiol: 19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol,(17α)
Ortho Evra - Clinical Pharmacology
Pharmacodynamics
Norelgestromin is the active progestin largely responsible for the progestational activity that occurs in women following application of Ortho Evra®. Norelgestromin is also the primary active metabolite produced following oral administration of norgestimate (NGM), the progestin component of the oral contraceptive products ORTHO-CYCLEN® and ORTHO TRI-CYCLEN®.
Combination oral contraceptives 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 reduce the likelihood of implantation).
Receptor and human sex hormone-binding globulin (SHBG) binding studies, as well as studies in animals and humans, have shown that both NGM and NGMN exhibit high progestational activity with minimal intrinsic androgenicity.90–93 Transdermally-administered norelgestromin, in combination with ethinyl estradiol, does not counteract the estrogen-induced increases in SHBG, resulting in lower levels of free testosterone in serum compared to baseline.
One clinical trial assessed the return of hypothalamic-pituitary-ovarian axis function post-therapy and found that FSH, LH, and estradiol mean values, though suppressed during therapy, returned to near baseline values during the 6 weeks post therapy.
Pharmacokinetics
Absorption
Following a single application of Ortho Evra®, both NGMN and EE reach a plateau by approximately 48 hours. Pooled data from the 3 clinical studies have demonstrated that steady state is reached within 2 weeks of application. The mean steady state Css concentrations ranged from 0.305–1.53 ng/mL for NGMN and from 11.2–137 pg/mL for EE.
Absorption of NGMN and EE following application of Ortho Evra® to the buttock, upper outer arm, abdomen and upper torso (excluding breast) was examined. While absorption from the abdomen was slightly lower than from other sites, absorption from these anatomic sites was considered to be therapeutically equivalent.
The mean (%CV) pharmacokinetic parameters Css and AUC0–168 for NGMN and EE following a single buttock application of Ortho Evra® are summarized in Table 1.
In multiple dose studies, AUC0–168 for NGMN and EE was found to increase over time (Table 1). In a three-cycle study, these pharmacokinetic parameters reached steady state conditions during Cycle 3 (Figures 1 and 2). Upon removal of the patch, serum levels of EE and NGMN reach very low or non-measurable levels within 3 days.
| Analyte | Parameter | Cycle 1 Week 1 | Cycle 3 Week 1 | Cycle 3 Week 2 | Cycle 3 Week 3 |
|---|---|---|---|---|---|
| nc = not calculated, | |||||
| |||||
| NGMN | Css (ng/mL) | 0.70 (39.4) | 0.70 (41.8) | 0.80 (28.7) | 0.70 (45.3) |
| AUC0–168 (ng∙h/mL) | 107 (44.2) | 105 (43.2) | 132 (43.4) | 120 (43.9) | |
| t1/2 (h) | nc | nc | nc | 32.1 (40.3) | |
| EE | Css (pg/mL) | 46.4 (38.5) | 47.6 (36.4) | 59.0 (42.5) | 49.6 (54.4) |
| AUC0–168 (pg∙h/mL) | 6796 (39.3) | 7160 (40.4) | 10054 (41.8) | 8840 (58.6) | |
| t1/2 (h) | nc | nc | nc | 21.0 (43.2) | |
Figure 1: Mean Serum NGMN Concentrations (ng/mL) in Healthy Female Volunteers Following Application of Ortho Evra® on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal)
Figure 2: Mean Serum EE Concentrations (pg/mL) in Healthy Female Volunteers Following Application of Ortho Evra® on the Buttock for Three Consecutive Cycles (Vertical arrow indicates time of patch removal.)
The absorption of NGMN and EE following application of Ortho Evra® was studied under conditions encountered in a health club (sauna, whirlpool and treadmill) and in a cold water bath. The results indicated that for NGMN there were no significant treatment effects on Css or AUC when compared to normal wear. For EE, increased exposures were observed due to sauna, whirlpool and treadmill. There was no significant effect of cold water on these parameters.
Results from a study of consecutive Ortho Evra® wear for 7 days and 10 days indicated that serum concentrations of NGMN and EE dropped slightly during the first 6 hours after the patch replacement, and recovered within 12 hours. By Day 10 of patch administration, both NGMN and EE concentrations had decreased by approximately 25% when compared to Day 7 concentrations.
Metabolism
Since Ortho Evra® is applied transdermally, first-pass metabolism (via the gastrointestinal tract and/or liver) of NGMN and EE that would be expected with oral administration is avoided. Hepatic metabolism of NGMN occurs and metabolites include norgestrel, which is highly bound to SHBG, and various hydroxylated and conjugated metabolites. Ethinyl estradiol is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.
Distribution
NGMN and norgestrel (a serum metabolite of NGMN) are highly bound (>97%) to serum proteins. NGMN is bound to albumin and not to SHBG, while norgestrel is bound primarily to SHBG, which limits its biological activity. Ethinyl estradiol is extensively bound to serum albumin and induces an increase in the serum concentrations of SHBG (see CLINICAL PHARMACOLOGY, Transdermal versus Oral Contraceptives, Table 3).
Elimination
Following removal of patches, the elimination kinetics of NGMN and EE were consistent for all studies with half-life values of approximately 28 hours and 17 hours, respectively. The metabolites of NGMN and EE are eliminated by renal and fecal pathways.
Transdermal versus Oral Contraceptives
The Ortho Evra® transdermal patch was designed to deliver EE and NGMN over a seven-day period while oral contraceptives (containing NGM 250 mcg / EE 35 mcg) are administered on a daily basis. Figures 3 and 4 present mean pharmacokinetic (PK) profiles for EE and NGMN following administration of an oral contraceptive (containing NGM 250 mcg / EE 35 mcg) compared to the 7-day transdermal Ortho Evra® patch (containing NGMN 6.0 mg / EE 0.75 mg) during cycle 2 in 32 healthy female volunteers.
Figure 3: Mean Serum Concentration-Time Profiles of NGMN Following Once-Daily Administration of an Oral Contraceptive for 2 Cycles or Application of Ortho Evra® for 2 Cycles to the Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15–21, Ortho Evra®: Cycle 2, Week 3]
Figure 4: Mean Serum Concentration-Time Profiles of EE Following Once-Daily Administration of an Oral Contraceptive for 2 Cycles or Application of Ortho Evra® for 2 Cycles to the Buttock in Healthy Female Volunteers. [Oral contraceptive: Cycle 2, Days 15–21, Ortho Evra®: Cycle 2, Week 3]
Table 2 provides the mean (%CV) for NGMN and EE pharmacokinetic (PK) parameters.
| Parameter | Ortho Evra®* | ORAL CONTRACEPTIVE† |
|---|---|---|
| ||
| NGMN‡ | ||
| Cmax (ng/mL) | 1.12 (33.6) | 2.16 (25.2) |
| AUC0–168 (ng∙h/mL) | 145 (36.8) | 123 (30.2)§ |
| Css (ng/mL) | 0.888 (36.6) | 0.732 (30.2)¶ |
| EE | ||
| Cmax (pg/mL) | 97.4 (31.6) | 133 (27.7) |
| AUC0–168 (pg∙h/mL) | 12971 (33.1) | 8281(26.9)§ |
| Css (pg/mL) | 80.0 (33.5) | 49.3 (26.9)¶ |
In general, overall exposure for NGMN and EE (AUC and Css) was higher in subjects treated with Ortho Evra® for both Cycle 1 and Cycle 2, compared to that for the oral contraceptive, while Cmax values were higher in subjects administered the oral contraceptive. Under steady state conditions, AUC0–168 and Css for EE were approximately 55% and 60% higher, respectively, for the transdermal patch, and the Cmax was about 35% higher for the oral contraceptive, respectively. Inter-subject variability (%CV) for the PK parameters following delivery from Ortho Evra® was higher relative to the variability determined from the oral contraceptive. The mean pharmacokinetic profiles are different between the two products and caution should be exercised when making a direct comparison of these PK parameters.
In Table 3, percent change in concentrations (%CV) of markers of systemic estrogenic activity (Sex Hormone Binding Globulin [SHBG] and Corticosteroid Binding Globulin [CBG]) from Cycle 1 Day 1 to Cycle 1 Day 22 is presented. Percent change in SHBG concentrations was higher for Ortho Evra® users compared to women taking the oral contraceptive; percent change in CBG concentrations was similar for Ortho Evra® and oral contraceptive users. Within each group, the absolute values for SHBG were similar for Cycle 1, Day 22 and Cycle 2, Day 22.
| Parameter | Ortho Evra® | ORAL CONTRACEPTIVE |
|---|---|---|
| (% change from Day 1 to Day 22) | (% change from Day 1 to Day 22) | |
| SHBG | 334 (39.3) | 200 (43.2) |
| CBG | 153 (40.2) | 157 (33.4) |
Special Populations
Effects of Age, Body Weight, Body Surface Area and Race
The effects of age, body weight, body surface area and race on the pharmacokinetics of NGMN and EE were evaluated in 230 healthy women from nine pharmacokinetic studies of single 7-day applications of Ortho Evra®. For both NGMN and EE, increasing age, body weight and body surface area each were associated with slight decreases in Css and AUC values. However, only a small fraction (10–25%) of the overall variability in the pharmacokinetics of NGMN and EE following application of Ortho Evra® may be associated with any or all of the above demographic parameters. There was no significant effect of race with respect to Caucasians, Hispanics and Blacks.
Renal and Hepatic Impairment
No formal studies were conducted with Ortho Evra® to evaluate the pharmacokinetics, safety, and efficacy in women with renal or hepatic impairment. Steroid hormones may be poorly metabolized in patients with impaired liver function (see PRECAUTIONS).
Patch Adhesion
In the clinical trials with Ortho Evra®, approximately 2% of the cumulative number of patches completely detached. The proportion of subjects with at least 1 patch that completely detached ranged from 2% to 6%, with a reduction from Cycle 1 (6%) to Cycle 13 (2%). For instructions on how to manage detachment of patches, refer to the DOSAGE AND ADMINISTRATION section.
Indications and Usage for Ortho Evra
Ortho Evra® is indicated for the prevention of pregnancy in women who elect to use a transdermal patch as a method of contraception.
The pharmacokinetic profile for the Ortho Evra® transdermal patch is different from that of an oral contraceptive. Healthcare professionals should balance the higher estrogen exposure and the possible increased risk of venous thromboembolism with Ortho Evra® against the chance of pregnancy if a contraceptive pill is not taken daily. (See BOLDED WARNING; WARNINGS; CLINICAL PHARMACOLOGY, Transdermal versus Oral Contraceptives).
Like oral contraceptives, Ortho Evra® is highly effective if used as recommended in this label.
In 3 large clinical trials in North America, Europe and South Africa, 3,330 women (ages 18–45) completed 22,155 cycles of Ortho Evra® use, pregnancy rates were approximately 1 per 100 women-years of Ortho Evra® use. The racial distribution was 91% Caucasian, 4.9% Black, 1.6% Asian, and 2.4% Other.
With respect to weight, 5 of the 15 pregnancies reported with Ortho Evra® use were among women with a baseline body weight ≥ 198 lbs. (90kg), which constituted < 3% of the study population. The greater proportion of pregnancies among women at or above 198 lbs. was statistically significant and suggests that Ortho Evra® may be less effective in these women.
Healthcare professionals who consider Ortho Evra® for women at or above 198 lbs. should discuss the patient's individual needs in choosing the most appropriate contraceptive option.
Table 4 lists the accidental pregnancy rates for users of various methods of contraception. The efficacy of these contraceptive methods, except sterilization, IUD, and Norplant® depends upon the reliability with which they are used. Correct and consistent use of methods can result in lower failure rates.
| % of Women Experiencing an Unintended Pregnancy within the First Year of Use | % of Women Continuing Use at One Year* | ||
|---|---|---|---|
| Method | Typical Use† | Perfect Use‡ | |
| (1) | (2) | (3) | (4) |
| Hatcher et al, 1998, Ref. # 1. Emergency Contraceptive Pills: Treatment initiated within 72 hours after unprotected intercourse reduces the risk of pregnancy by at least 75%.§ Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.¶ Source: Trussell J, Contraceptive efficacy. In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Kowal D, Guest F. Contraceptive Technology: Seventeenth Revised Edition. New York, NY: Irvington Publishers, 1998. | |||
| |||
| Chance# | 85 | 85 | |
| SpermicidesÞ | 26 | 6 | 40 |
| Periodic abstinence | 25 | 63 | |
| Calendar | 9 | ||
| Ovulation Method | 3 | ||
| Sympto-Thermalß | 2 | ||
| Post-Ovulation | 1 | ||
| Capà | |||
| Parous Women | 40 | 26 | 42 |
| Nulliparous Women | 20 | 9 | 56 |
| Sponge | |||
| Parous Women | 40 | 20 | 42 |
| Nulliparous Women | 20 | 9 | 56 |
| Diaphragmà | 20 | 6 | 56 |
| Withdrawal | 19 | 4 | |
| Condomè | |||
| Female (Reality®) | 21 | 5 | 56 |
| Male | 14 | 3 | 61 |
| Pill | 5 | 71 | |
| Progestin Only | 0.5 | ||
| Combined | 0.1 | ||
| IUD | |||
| Progesterone T | 2.0 | 1.5 | 81 |
| Copper T380A | 0.8 | 0.6 | 78 |
| LNG 20 | 0.1 | 0.1 | 81 |
| Depo-Provera® | 0.3 | 0.3 | 70 |
| Norplant® and Norplant-2® | 0.05 | 0.05 | 88 |
| Female Sterilization | 0.5 | 0.5 | 100 |
| Male Sterilization | 0.15 | 0.10 | 100 |
Ortho Evra® has not been studied for and is not indicated for use in emergency contraception.
Contraindications
Ortho Evra® should not be used in women who currently have the following conditions:
- Thrombophlebitis, thromboembolic disorders
- A past history of deep vein thrombophlebitis or thromboembolic disorders
- Known thrombophilic conditions
- Cerebrovascular or coronary artery disease (current or past history)
- Valvular heart disease with complications103
- Persistent blood pressure values of ≥ 160 mm Hg systolic or ≥ 100 mg Hg diastolic103, 112
- Diabetes with vascular involvement103
- Headaches with focal neurological symptoms
- Major surgery with prolonged immobilization
- Known or suspected carcinoma of the breast or personal history of breast cancer
- Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia
- Undiagnosed abnormal genital bleeding
- Cholestatic jaundice of pregnancy or jaundice with prior hormonal contraceptive use
- Acute or chronic hepatocellular disease with abnormal liver function103
- Hepatic adenomas or carcinomas
- Known or suspected pregnancy
- Hypersensitivity to any component of this product
Warnings
Cigarette smoking increases the risk of serious cardiovascular events from hormonal contraceptive use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, hormonal contraceptives, including Ortho Evra®, should not be used by women who are over 35 years of age and smoke.
The pharmacokinetic (PK) profile for the Ortho Evra® patch is different from the PK profile for oral contraceptives in that it has higher steady state concentrations and lower peak concentrations. Area under the time-concentration curve (AUC) and average concentration at steady state for ethinyl estradiol (EE) are approximately 60% higher in women using Ortho Evra® compared with women using an oral contraceptive containing EE 35 mcg. In contrast, peak concentrations for EE are approximately 25% lower in women using Ortho Evra®. Inter-subject variability results in increased exposure to EE in some women using either Ortho Evra® or oral contraceptives. However, inter-subject variability in women using Ortho Evra® is higher. It is not known whether there are changes in the risk of serious adverse events based on the differences in pharmacokinetic profiles of EE in women using Ortho Evra® compared with women using oral contraceptives containing 30–35 mcg of EE. Increased estrogen exposure may increase the risk of adverse events, including venous thromboembolism. (See CLINICAL PHARMACOLOGY, Transdermal versus Oral Contraceptives).
Four epidemiologic, case-control studies107–111,113–115 were conducted in the U.S. using electronic healthcare claims data to evaluate the risk of venous thromboembolism (VTE) among women aged 15–44 who used Ortho Evra® compared to women who used oral contraceptives containing 30–35 mcg of ethinyl estradiol (EE) and either levonorgestrel (LNG) or norgestimate (NGM). NGM is the prodrug for norelgestromin, the progestin in Ortho Evra®.
These studies (see Table 5) used slightly different designs and reported odds ratios ranging from 1.2 to 2.2. The interpretations of these odds ratios range from no increase in risk to an approximate doubling of risk. One of the studies found a statistically significant increased risk of VTE for current users of Ortho Evra®.
The four studies are:
- The i3 Ingenix study with NGM-containing oral contraceptives as the comparator, including a 24-month extension, based on the Ingenix Research Datamart; only this study included patient chart review to confirm the VTE occurrence.
- The Boston Collaborative Drug Surveillance Program (BCDSP) with NGM-containing oral contraceptives as the comparator (BCDSP NGM), including two extensions of 17 and 14 months, respectively, based on the Pharmetrics database
- BCDSP with LNG-containing oral contraceptives as the comparator, based on the Pharmetrics database
- BCDSP with LNG-containing oral contraceptives as the comparator, based on the Marketscan database
The i3 Ingenix and BCDSP NGM studies have provided data on additional cases identified in study extensions; however, each study extension was not powered to provide independent estimates of risk. The pooled estimates provide the most reliable estimates of VTE risk. Odds ratios from the original and various extensions of the i3 Ingenix and BCDSP NGM studies are provided in the footnotes to Table 5.
| Epidemiologic Study | Comparator Product | Odds Ratio (95% CI) |
|---|---|---|
| ||
| i3 Ingenix NGM Study in Ingenix Research Datamart107,113,114,115 | NGM/35 mcg EE* | 2.2† (1.2–4.0)‡ |
| BCDSP§ NGM Study in Pharmetrics database108,109,111 | NGM/35 mcg EE | 1.2 (0.9–1.8)¶ |
| BCDSP LNG Study in Pharmetrics database110 | LNG#/30 mcg EE | 2.0 (0.9–4.1)Þ |
| BCDSP LNG Study in Marketscan database110 | LNG/30 mcg EE | 1.3 (0.8–2.0)ß |
In 3 large clinical trials (N= 3,330 with 1,704 women-years of exposure), one case of non-fatal pulmonary embolism occurred during Ortho Evra® use, and one case of post-operative non-fatal pulmonary embolism was reported following Ortho Evra® use.
Ortho Evra® and other contraceptives that contain both an estrogen and a progestin are called combination hormonal contraceptives. As with any combination hormonal contraceptive, the clinician should be alert to the earliest manifestations of thromboembolic disorders (thrombophlebitis, VTE including pulmonary embolism, cerebrovascular disorders, and retinal thrombosis). Should any of these occur or be suspected, Ortho Evra® should be discontinued immediately.
Practitioners prescribing Ortho Evra® should be familiar with the following information relating to risks:
The use of combination hormonal contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, 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 hypertension, hyperlipidemias, obesity and diabetes.
The information that follows in this section of the package insert is principally based on studies carried out in women who used combination oral contraceptives with higher formulations of estrogens and progestins than those in common use today. The effect of long-term use of combination hormonal contraceptives with lower doses of both estrogen and progestin administered by any route remains to be determined.
Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and cohort studies. Case control studies provide an estimate of the relative risk or odds for developing a disease, namely, a ratio of the disease among oral contraceptive users to that among nonusers or users of a comparator drug product. The odds ratio does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of the incidence of a disease in an exposed population. The relative risk is the ratio of the incidence density in the exposed population relative to the incidence density in a comparator population. Cohort studies also provide a measure of attributable risk, which is the difference in the incidence of disease between hormonal contraceptive users and nonusers or comparator drug products. The attributable risk does provide information about the actual occurrence of a disease in the population (adapted from refs. 2 and 3 with the author's permission). For further information, the reader is referred to a text on epidemiological methods.
1. Thromboembolic Disorders and Other Vascular Problems
a. Thromboembolism
An increased risk of thromboembolic and thrombotic disease associated with the use of hormonal contraceptives is well established. Case control studies have found the relative risk of users compared to nonusers to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease.2,3,19–24 Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization.25 The risk of thromboembolic disease associated with hormonal contraceptives is not related to length of use and disappears after hormonal contraceptive use is stopped.2 A two- to four-fold increase in relative risk of post-operative thromboembolic complications has been reported with the use of hormonal contraceptives.9,26 The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions.9,26 If feasible, hormonal contraceptives 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, hormonal contraceptives should be started no earlier than four weeks after delivery in women who elect not to breastfeed.
b. Myocardial Infarction
An increased risk of myocardial infarction has been attributed to hormonal 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 hormonal contraceptive users has been estimated to be two to six4–10 compared to non-users. The risk is very low under the age of 30.
Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases.11 Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older among women who use oral contraceptives. (See Figure 5.)
Figure 5: Circulatory Disease Mortality Rates Per 100,000 Women-Years by Age, Smoking Status and Oral Contraceptive Use
Hormonal contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity.13 In particular, some progestins are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism.14–18 Hormonal contraceptives have been shown to increase blood pressure among some users (see section 9 in WARNINGS). Similar effects on risk factors have been associated with an increased risk of heart disease. Hormonal contraceptives, including Ortho Evra®, must be used with caution in women with cardiovascular disease risk factors.
Norgestimate and norelgestromin have minimal androgenic activity (see CLINICAL PHARMACOLOGY). There is some evidence that the risk of myocardial infarction associated with hormonal contraceptives is lower when the progestin has minimal androgenic activity than when the activity is greater.97
c. Cerebrovascular Diseases
Hormonal 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 nonusers, for both types of strokes, and smoking interacted to increase the risk of stroke.27–29
In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension.30 The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used hormonal contraceptives, 2.6 for smokers who did not use hormonal contraceptives, 7.6 for smokers who used hormonal contraceptives, 1.8 for normotensive users and 25.7 for users with severe hypertension.30 The attributable risk is also greater in older women.3
d. Dose-Related Risk of Vascular Disease from Hormonal Contraceptives
A positive association has been observed between the amount of estrogen and progestin in hormonal contraceptives and the risk of vascular disease.31–33 A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents.14–16 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 a hormonal contraceptive depends on a balance achieved between doses of estrogen and progestin and the activity of the progestin used in the contraceptives. The activity and amount of both hormones should be considered in the choice of a hormonal contraceptive.
e. Persistence of Risk of Vascular
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