Jinteli

CLINICAL PHARMACOLOGY

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites estrone and estriol at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. The pharmacologic effects of ethinyl estradiol are similar to those of endogenous estrogens.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, bone, skeletal tissue and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone.

Pharmacokinetics

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 firstpass 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

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

Table 1: Mean (SD) Single-Dos e (Day 1) and Steady-State (Day 87) Pharmacokinetic Parameters Following Adminis tration of 1 mg NA/10 mcg EE Tablets

Norethindrone Cmax ng/mL tmax hr AUC(0-24) ng-hr/mL CL/F mL/min t½ hr
Day 1 6.0 (3.3) 1.8 (0.8) 29.7 (16.5) 588 (416) 10.3 (3.7)
Day 87 10.7 (3.6) 1.8 (0.8) 81.8 (36.7) 226 (139) 13.3 (4.5)
Ethinyl Estradiol pg/mL hr pg•hr/mL mL/min hr
Day 1 33.5 (13.7) 2.2 (1.0) 339 (113) ND† ND†
Day 87 38.3 (11.9) 1.8 (0.7) 471 (132) 383 (119) 23.9 (7.1)
*C max = Maximum plasma concentration; t max = time of C max; AUC(0-24)= Area under the plasma concentration-time curve over the dosing interval; and CL/F = Apparent oral clearance; t ½= Elimination half-life
†ND = Not determined

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.

Special Populations

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).

Drug Interactions

See PRECAUTIONS: DRUG INTERACTIONS.

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

Clinical Studies

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.

Table 2: Mean Change from Baseline in the Number of Moderate to Severe Vas omotor Symptoms per Week-ITT Population, LOCF

Visit Placebo
(N=66)
Norethindrone Acetate and Ethinyl Estradiol 0.5/2.5
(N=67)
Norethindrone Acetate and Ethinyl Estradiol 1/5
(N=66)
Baseline1
Mean (SD) 76.5 (21.4) 77.6 (26.5) 70.0 (16.6)
Week 4
Mean (SD) 39.4 (27.6) 30.2 (26.1) 20.4 (22.7)
Mean Change from Baseline (SD) -37.0 (26.6) -47.4* (26.1) -49.6* (22.1)
p-Value vs. Placebo (95% CI) 2   0.041 (-20.0, -1.0) < 0.001 (-22.0,-6.0)
Week 12
Mean (SD) 31.1 (27.0) 13.8 (20.4) 11.3 (18.9)
Mean Change from Baseline (SD) -45.3 (30.2) -63.8* (27.5) -58.7* (23.1)
p-Value vs. Placebo (95%CI)2   < 0.001 (-27.0, -7.0) < 0.001 (-25.0, -5.0)
*Denotes statistical significance at the 0.05 level
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.

Table 3: Mean Change from Baseline in the Daily Severity Score of Moderate to Severe Vasomotor Symptoms per Week-ITT Population, LOCF

Visit Placebo
(N=66)
Norethindrone Acetate and Ethinyl Estradiol 0.5/2.5
(N=67)
Norethindrone Acetate and Ethinyl Estradiol
1/5
(N=66)
Baseline1
Mean (SD) 2.49 (0.26) 2.48 (0.22) 2.47 (0.23)
Week 4
Mean (SD) 2.13 (0.74) 1.88 (0.89) 1.45 (1.03)
Mean Change from Baseline (SD) -0.36 (0.68) -0.59 (0.83) -1.02* (1.06)
p-Value vs. Placebo (95% CI)2 - 0.130 (-0.3, 0.0) < 0.001 (-0.9, - 0.2)
Week 5
Mean (SD) 2.06 (0.79) 1.68 (0.99) 1.23 (1.03)
Mean Change from Baseline (SD) -0.44 (0.74) -0.80* (0.94) -1.24* (1.07)
p-Value vs. Placebo (95% CI)2 0.041 (-0.4, -0.0) < 0.001 (-1.2, -0.3)
Week 12
Mean (SD) 1.82 (1.03) 1.22 (1.11) 1.02 (1.16)
Mean Change from Baseline (SD) -0.67 (1.02) -1.26* (1.08) -1.45* (1.19)
p-Value vs. Placebo (95% CI)2 0.002 (-0.9, -0.2) < 0.001 (-1.4, -0.3)
*Denotes statistical significance at the 0.05 level
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.

Table 4: Endometrial Biops y Res ults After 12 and 24 Months of Treatment (CHART Study, 376-359)

Endometrial Status Placebo Norethindrone Acetate and Ethinyl Estradiol EE Alone
0.5/2.5 1/5 2.5 mcg 5 mcg
Number of Patients Biopsied at Baseline N= 134 N=136 N= 143 N=137 N=139
MONTH 12 (% Patients)
Patients Biopsied (%) 113 (84) 103 (74) 110 (77) 100 (73) 114 (82)
Insufficient Tissue 30 34 45 20 20
Atrophic Tissue 60 41 41 15 2
Proliferative Tissue 23 28 24 65 91
Endometrial Hyperplasia* 0 0 0 0 1
MONTH 24 (%Patients)
Patients Biopsied (%) 94 (70) 99 (73) 102 (71) 89 (65) 107 (77)
Insufficient Tissue 35 42 37 23 17
Atrophic Tissue 38 30 33 6 2
Proliferative Tissue 20 27 32 60 86
Endometrial Hyperplasia* 1 0 0 0 2
* All patients with endometrial hyperplasia were carried forward for all time Points

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.

Figure 2: Patients With Cumulative Amenorrhea Over Time: Intent-to-Treat Population, Last Observation Carried Forward

Patients With Cumulative Amenorrhea Over Time: Intent-to-Treat Population, Last Observation Carried Forward - Illustration

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)

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 - Illustration

*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.

Women's Health Initiative Studies

The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of oral 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 5 below:

Table 5: RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY OF WHI*

Eventt Relative Risk CE/MPA vs placebo at 5.2 Years (95% CI*) Placebo
n = 8102
CE/MPA
n = 8506
Absolute Risk per 10,000 Women-years
CHD events 1.29 (1.02-1.63) 30 37
Non-fatal MI 1.32 (1.02-1.72) 23 30
CHD death 1.18 (0.70-1.97) 6 7
Invasive breast cancer‡ 1.26 (1.00-1.59) 30 38
Stroke 1.41 (1.07-1.85) 21 29
Pulmonary embolism 2.13 (1.39-3.25) 8 16
Colorectal cancer 0.63 (0.43-0.92) 16 10
Endometrial cancer 0.83 (0.47-1.47) 6 5
Hip fracture 0.66 (0.45-0.98) 15 10
Death due to causes other than the events above 0.92 (0.74-1.14) 40 37
Global Index† 1.15 (1.03-1.28) 151 170
Deep vein thrombosis§ 2.07 (1.49-2.87) 13 26
Vertebral fractures§ 0.66 (0.44-0.98) 15 9
Other osteoporotic fractures§ 0.77 (0.69-0.86) 170 131
*nominal confidence intervals unadjusted for multiple looks and multiple comparisons
*adapted from JAMA, 2002; 288:321-333
†subset of the events was combined in a “global index”, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes
‡includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer
§not included in Global Index

For those outcomes included in the “global index,” the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. There was no difference between the groups in terms of allcause mortality. (See BOXED WARNING, WARNINGS, and PRECAUTIONS.)

Women's Health Initiative Memory Study

The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNING and WARNINGS, Dementia.)

Last reviewed on RxList: 3/31/2014
This monograph has been modified to include the generic and brand name in many instances.

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