Absorption

Norethindrone acetate (NA) is completely and rapidly deacetylated to norethindrone after oral administration, and the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate and ethinyl estradiol (EE) are rapidly absorbed from norethindrone acetate and ethinyl estradiol tablets, with maximum plasma concentrations of norethindrone and ethinyl estradiol generally occurring 1 to 2 hours postdose. Both are subject to first-pass metabolism after oral dosing, resulting in an absolute bioavailability of approximately 64% for norethindrone and 55% for ethinyl estradiol. Bioavailability of norethindrone acetate and ethinyl estradiol tablets is similar to that from solution for norethindrone and slightly less for ethinyl estradiol. Administration of norethindrone acetate and ethinyl estradiol tablets with a high fat meal decreases rate but not extent of ethinyl estradiol absorption. The extent of norethindrone absorption is increased by 27% following administration of norethindrone acetate and ethinyl estradiol tablets with food.

The full pharmacokinetic profile of norethindrone acetate and ethinyl estradiol tablets was not characterized due to assay sensitivity limitations. However, the multiple-dose pharmacokinetics were studied at a dose of 1 mg NA/10 mcg EE in 18 post-menopausal women. Mean plasma concentrations are shown below (Figure 1) and pharmacokinetic parameters are found in Table 1. Based on a population pharmacokinetic analysis, mean steady-state concentrations of norethindrone for 1 mg NA/5 mcg EE and 1/10 are slightly more than proportional to dose when compared to 0.5 mg NA/2.5 mcg EE tablets. It can be explained by higher sex hormone binding globulin (SHBG) concentrations. Mean steady-state plasma concentrations of ethinyl estradiol for the norethindrone acetate and ethinyl estradiol 0.5/2.5 tablets and norethindrone acetate and ethinyl estradiol 1/5 tablets are proportional to dose, but there is a less than proportional increase in steady-state concentrations for the NA/EE 1/10 tablet.

Figure 1: Mean Steady-State (Day 87) Plasma Norethindrone and Ethinyl Estradiol Concentrations Following Continuous Oral Administration of 1 mg NA/10 mcg EE Tablets

 Based on a population pharmacokinetic analysis, average steady-state concentrations (Css) of norethindrone and ethinyl estradiol for norethindrone acetate and ethinyl estradiol 1/5 tablets are estimated to be 2.6 ng/mL and 11.4 pg/mL, respectively. Css values of norethindrone and ethinyl estradiol for norethindrone acetate and ethinyl estradiol 0.5/2.5 tablets are estimated to be 1.1 ng/mL and 5.4 ng/mL, respectively.

The pharmacokinetics of ethinyl estradiol and norethindrone acetate were not affected by age, (age range 40-62 years), in the postmenopausal population studied.

Distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

Volume of distribution of norethindrone and ethinyl estradiol ranges from 2 to 4 L/kg. Plasma protein binding of both steroids is extensive (>95%); norethindrone binds to both albumin and sex hormone binding globulin (SHBG), whereas ethinyl estradiol binds only to albumin. Although ethinyl estradiol does not bind to SHBG, it induces SHBG synthesis.

Metabolism

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Norethindrone undergoes extensive biotransformation, primarily via reduction, followed by sulfate and glucuronide conjugation. The majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites. A small amount of norethindrone acetate is metabolically converted to ethinyl estradiol, such that exposure to ethinyl estradiol following administration of 1 mg of norethindrone acetate is equivalent to oral administration of 2.8 mcg ethinyl estradiol. Ethinyl estradiol is also extensively metabolized, both by oxidation and by conjugation with sulfate and glucuronide. Sulfates are the major circulating conjugates of ethinyl estradiol and glucuronides predominate in urine. The primary oxidative metabolite is 2-hydroxy ethinyl estradiol, formed by the CYP3A4 isoform of cytochrome P450. Part of the first-pass metabolism of ethinyl estradiol is believed to occur in gastrointestinal mucosa. Ethinyl estradiol may undergo enterohepatic circulation.

Excretion

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Norethindrone and ethinyl estradiol are excreted in both urine and feces, primarily as metabolites. Plasma clearance values for norethindrone and ethinyl estradiol are similar (approximately 0.4 L/hr/kg). Steady-state elimination half-lives of norethindrone and ethinyl estradiol following administration of 1 mg NA/10 mcg EE tablets are approximately 13 hours and 24 hours, respectively.

Pediatric

Norethindrone acetate and ethinyl estradiol is not indicated in children.

Geriatrics

The pharmacokinetics of norethindrone acetate and ethinyl estradiol have not been studied in a geriatric population.

Race

The effect of race on the pharmacokinetics of norethindrone acetate and ethinyl estradiol has not been studied.

Patients with Renal Insufficiency

The effect of renal disease on the disposition of norethindrone acetate and ethinyl estradiol has not been evaluated. In premenopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma ethinyl estradiol concentrations were higher and norethindrone concentrations were unchanged compared to concentrations in premenopausal women with normal renal function (see PRECAUTIONS, Fluid Retention).

Patients with Hepatic Impairment

The effect of hepatic disease on the disposition of norethindrone acetate and ethinyl estradiol has not been evaluated. However, ethinyl estradiol and norethindrone may be poorly metabolized in patients with impaired liver function (see PRECAUTIONS).

Effects on Vasomotor Symptoms

A 12-week placebo-controlled, multicenter, randomized clinical trial was conducted in 266 symptomatic women who had at least 56 moderate to severe hot flushes during the week prior to randomization. On average, patients had 12 hot flushes per day upon study entry.

A total of 66 women were randomized to receive norethindrone acetate and ethinyl estradiol  1/5, 67 women were randomized to receive norethindrone acetate and ethinyl estradiol 0.5/2.5 and 66 women were randomized to the placebo group. Norethindrone acetate and ethinyl estradiol 1/5 and norethindrone acetate and ethinyl estradiol 0.5/2.5 were shown to be statistically better than placebo at weeks 4 and 12 for relief of the frequency of moderate to severe vasomotor symptoms. See Table 2. In Table 3, norethindrone acetate and ethinyl estradiol 1/5 was shown to be statistically better than placebo at weeks 4 and 12 for relief of the severity of moderate to severe vasomotor symptoms; norethindrone acetate and ethinyl estradiol 0.5/2.5 was shown to be statistically better than placebo at weeks 5 and 12 for relief of the severity of moderate to severe vasomotor symptoms.

[1] The baseline number of moderate to severe vasomotor symptoms (MSVS) is the weekly average number of MSVS during the two week prerandomization observation period.

[2] ANCOVA - Analysis of Covariance model where the observation variable is change from baseline; independent variables include treatment, center and baseline as covariate. The 95% CI-Mann-Whitney confidence interval for the difference between means (not stratified by center).

ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval

2 randomized subjects (1 in Placebo and 1 in norethindrone acetate and ethinyl estradiol) did not return diaries.

[1] The baseline severity of moderate to severe vasomotor symptoms (MSVS) is the daily severity score of MSVS during the two week prerandomization observation period.

[2] ANCOVA - Analysis of Covariance model where the observation variable is change from baseline; independent variables include treatment, center and baseline as covariate. The 95% CI- Mann-Whitney confidence interval for the difference between means (not stratified by center).

ITT = intent to treat; LOCF = last observation carried forward; CI = confidence interval

2 randomized subjects (1 in Placebo and 1 in norethindrone acetate and ethinyl estradiol) did not return diaries.

Endometrial Hyperplasia

A 2-year, placebo-controlled, multicenter, randomized clinical trial was conducted to determine the safety and efficacy of norethindrone acetate and ethinyl estradiol on maintaining bone mineral density, protecting the endometrium, and to determine effects on lipids. A total of 1265 women were enrolled and randomized to either placebo, 0.2 mg NA/1 mcg EE, norethindrone acetate and ethinyl estradiol 0.5/2.5, norethindrone acetate and ethinyl estradiol 1/5 and 1 mg NA/10 mcg EE or matching unopposed EE doses (1, 2.5, 5, or 10 mcg) for a total of 9 treatment groups. All participants received 1000 mg of calcium supplementation daily. Of the 1265 women randomized to the various treatment arms of this study, 137 were randomized to placebo, 146 to norethindrone acetate and ethinyl estradiol 1/5, 136 to norethindrone acetate and ethinyl estradiol 0.5/2.5 and 141 to EE 5 mcg and 137 to EE 2.5 mcg. Of these, 134 placebo, 143 norethindrone acetate and ethinyl estradiol 1/5, 136 norethindrone acetate and ethinyl estradiol 0.5/2.5, 139 EE 5 mcg and 137 EE 2.5 mcg had a baseline endometrial result. Baseline biopsies were classified as normal (in approximately 95% of subjects), or insufficient tissue (in approximately 5% of subjects). Follow-up biopsies were obtained in approximately 70-80% of patients in each arm after 12 and 24 months of therapy. Results are shown in Table 4.

Irregular Bleeding/Spotting

The cumulative incidence of amenorrhea, defined as no bleeding or spotting obtained from subject recall, was evaluated over 12 months for norethindrone acetate and ethinyl estradiol 0.5/2.5, norethindrone acetate and ethinyl estradiol 1/5 and placebo arms. Results are shown in Figure 2.

Effect on Bone Mineral Density

In the 2 year study, trabecular bone mineral density (BMD) was assessed at lumbar spine using quantitative computed tomography. A total of 419 postmenopausal primarily Caucasian women, aged 40 to 64 years, with intact uteri and non-osteoporotic bone mineral densities were randomized (1:1:1) to norethindrone acetate and ethinyl estradiol 1/5, norethindrone acetate and ethinyl estradiol 0.5/2.5 or placebo. Approximately 75% of the subjects in each group completed the two-year study. All patients received 1000 mg calcium in divided doses. Vitamin D was not supplemented.

As shown in Figure 3, women treated with norethindrone acetate and ethinyl estradiol 1/5 had an average increase of 3.1% in lumbar spine BMD from baseline to Month 24. Women treated with norethindrone acetate and ethinyl estradiol 0.5/2.5 and placebo had average decreases of –0.8% and –6.3%, respectively, in spinal BMD from baseline to Month 24. The differences in the changes from baseline to Month 24 in the two norethindrone acetate and ethinyl estradiol groups compared with the placebo group were statistically significant.

It should be noted that when measured by QCT, BMD gains and losses are greater than when measured by dual X-ray absorptiometry (DXA). Therefore, the differences in the changes in BMD between the placebo and active drug treated groups will be larger when measured by QCT compared with DXA. Changes in BMD measured by DXA should not be compared with changes in BMD measured by QCT.

Figure 3: Mean Percent Change (+ SE) From Baseline in Volumetric Bone Mineral Density* at Lumbar Spine Measured by Quantitative Computed Tomography after 12 and 24 Months of Treatment (Intent-to-Treat Population)

*It should be noted that when measured by QCT, BMD gains and losses are greater than when measured by dual X-ray absorptiometry (DXA). Therefore, the differences in the changes in BMD between the placebo and active drug treated groups will be larger when measured by QCT compared with DXA. Changes in BMD measured by DXA should not be compared with changes in BMD measured by QCT.

a. Coronary Heart Disease and Stroke

In the Women’s Health Initiative (WHI) study, an increase in the number of strokes was observed in women receiving CE compared to placebo.

In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as non-fatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 women-years). The increase in risk was observed in year one and persisted. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

In postmenopausal women with documented heart disease (n=2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA-0.625 mg/2.5 mg per day demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall.

Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.

b. Venous Thromboembolism (VTE)

In the Women’s Health Initiative (WHI) study, an increase in VTE was observed in women receiving CE compared to placebo.

In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 woman-years in the CE/MPA group compared to 16 per 10,000 woman-years in the placebo group. The increase in VTE risk was observed during the first year and persisted. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

If feasible, estrogens should be discontinued at least 4-6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

a. Breast Cancer

The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women’s Health Initiative (WHI) substudy of CE/MPA (See CLINICAL PHARMACOLOGY, Clinical Studies). The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration.

The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy.

In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs 33 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs 25 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups.

The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a health care provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

b. Endometrial Cancer

The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

1. Addition of a Progestin When a Woman Has Not Had a Hysterectomy

A daily dose of norethindrone acetate and ethinyl estradiol contains a progestin.

Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.

There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone treatment. These include a possible increased risk of breast cancer.

2. Elevated Blood Pressure

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.

3. Hypertriglyceridemia

In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.

4. Impaired Liver Function and Past History of Cholestatic Jaundice

Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.

5. Hypothyroidism

Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

6. Fluid Retention

Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.

7. Hypocalcemia

Estrogens should be used with caution in individuals with severe hypocalcemia.

8. Ovarian Cancer

The CE/MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95% confidence interval 0.77 – 3.24) but was not statistically significant. The absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.

9. Exacerbation of Endometriosis

Endometriosis may be exacerbated with administration of estrogens. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.

10. Exacerbation of Other Conditions

Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

The Effect of Ethinyl Estradiol on Other Drugs

Drug products containing ethinyl estradiol may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporin, prednisolone, and theophylline have been reported with concomitant administration of certain drugs containing ethinyl estradiol (e.g., oral contraceptives containing ethinyl estradiol). In addition, drugs containing ethinyl estradiol may induce the conjugation of other compounds.

Decreased plasma concentrations of acetaminophen and increased clearance of temazapam, salicylic acid, morphine, and clofibric acid have been noted when these drugs were administered with certain ethinyl-estradiol containing drug products (e.g., oral contraceptives containing ethinyl estradiol).