Nora-BE (Norethindrone) - Summary

NORA-BE SUMMARY

Each white Nora-BE^® tablet provides a continuous oral contraceptive regimen of 0.

1. Indications. Progestin-only oral contraceptives are indicated for the prevention of pregnancy.

2. Efficacy. If used perfectly, the first-year failure rate for progestin-only oral contraceptives is 0.5%. However, the typical failure rate is estimated to be closer to 5%, due to late or omitted pills. The following table lists the pregnancy rates for users of all major methods of contraception.

Table 1. Percentage of Women Experiencing an Unintended Pregnancy During the First Year of Typical Use and the First Year of Perfect Use of Contraception and the Percentage Continuing Use at the End of the First Year. United States.

		% of Women Experiencing an		% of Women
		Unintended Pregnancy within the		Continuing Use
		First Year of Use		at One Year3
Method		Typical Use 1	Perfect Use 2
(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%.9
Lactational Amenorrhea Method: LAM is a highly effective, temporary method of contraception.10
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.
1 Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any reason.
2 Among couples who initiate use of a method (not necessarily for the first time), and who use it perfectly (both consistently and correctly), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.
3 Among couples attempting to avoid pregnancy, the percentage who continue to use a method for one year.
4 The percentage of women becoming pregnant noted in columns (2) and (3) are based on data from populations where contraception is not used and from women who cease using contraception in order to become pregnant. Among such populations, about 89% become pregnant within one year. This estimate was lowered slightly (to 85%) to represent the percentage that would become pregnant within one year among women now relying on reversible methods of contraception if they abandoned contraception altogether.
5 Foams, creams, gels, vaginal suppositories, and vaginal film.
6 Cervical mucus (ovulation) method supplemented by calendar in the pre-ovulatory and basal body temperature in the post-ovulatory phases.
7 With spermicidal cream or jelly.
8 Without spermicides.
9 The treatment schedule is one dose within 72 hours after unprotected intercourse, and a second dose 12 hours after the first dose. The Food and Drug Administration has declared the following brands of oral contraceptives to be safe and effective for emergency contraception: Ovral (1 dose is 2 white pills), Alesse (1 dose is 5 pink pills), Nordette or Levlen (1 dose is 2 light-orange pills), Lo/Ovral (1 dose is 4 white pills), Triphasil or Tri-Levlen (1 dose is 4 yellow pills).
10 However, to maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breastfeeds is reduced, bottle feeds are introduced, or the baby reaches six months of age.
Chance4		85	85
Spermicides5		26	6	40
Periodic abstinence		25		63
	Calendar		9
	Ovulation Method		3
	Sympto-Thermal6		2
	Post-Ovulation		1
Cap7
	Parous Women	40	26	42
	Nulliparous Women	20	9	56
Sponge
	Parous Women	40	20	42
	Nulliparous Women	20	9	56
Diaphragm7		20	6	56
Withdrawal		19	4
Condom8
	Female (Reality)	21	5	56
	Male	14	3	61
Pill		5		71
	Progestin only		0.5
	Combined		0.1
IUDs
	Progesterone T	2.0	1.5	81
	Copper T 380A	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

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NEWS HIGHLIGHTS

Published Studies Related to Nora-BE (Norethindrone)

Distribution of HLA-B alleles in a Ugandan HIV-infected adult population: NORA pharmacogenetic substudy of DART. [2011.02]
OBJECTIVES: To determine the frequencies of HLA-B alleles in Ugandan patients in the NORA substudy of the DART trial and to compare HLA-B allele frequencies in those with and without clinically diagnosed hypersensitivity reaction (HSR)... CONCLUSION: The rate of clinical HSR was low, which may reflect the expected 2-3% clinical false-positive rate seen in previous double-blind randomized studies. The presumption that these cases may be false-positive abacavir HSR is supported by the fact that no HLA-B*5701 alleles were found in the abacavir group. Implementation of prospective HLA-B*5701 screening must be based on benefit/risk considerations within local practice. Clinical risk management remains paramount. (c) 2010 Blackwell Publishing Ltd.

Distribution of HLA-B alleles in a Ugandan HIV-infected adult population: NORA pharmacogenetic substudy of DART. [2011]
those with and without clinically diagnosed hypersensitivity reaction (HSR)... CONCLUSION: The rate of clinical HSR was low, which may reflect the expected 2-3%

Effect of the bile acid sequestrant colesevelam on the pharmacokinetics of pioglitazone, repaglinide, estrogen estradiol, norethindrone, levothyroxine, and glyburide. [2010.05]
The purpose of this study was to assess effects of colesevelam on the pharmacokinetics of glyburide, levothyroxine, estrogen estradiol (EE), norethindrone (NET), pioglitazone, and repaglinide in healthy volunteers. Six drugs with a potential to interact with colesevelam were studied in open-label, randomized clinical studies.

Does hormone therapy improve age-related skin changes in postmenopausal women? A randomized, double-blind, double-dummy, placebo-controlled multicenter study assessing the effects of norethindrone acetate and ethinyl estradiol in the improvement of mild to moderate age-related skin changes in postmenopausal women. [2008.09]
BACKGROUND: In postmenopausal women, declining estrogen levels are associated with a variety of skin changes, many of which are reportedly improved by estrogen supplementation. OBJECTIVE: A study was conducted to assess the effects of continuous combined norethindrone acetate (NA) and ethinyl estradiol (EE) in the control of mild to moderate age-related skin changes in postmenopausal women... CONCLUSION: Low-dose hormone therapy for 48 weeks in postmenopausal women did not significantly alter mild to moderate age-related facial skin changes.

Combined continuous ethinyl estradiol/norethindrone acetate does not improve forearm blood flow in postmenopausal women at risk for cardiovascular events: a pilot study. [2007.09]
OBJECTIVE: This study sought to determine whether combined continuous ethinyl estradiol and norethindrone acetate, a postmenopausal hormone therapy (HT) combination designed to have fewer side effects than cyclical therapies and therapies using medroxyprogesterone acetate (MPA), could improve vascular endothelial function in postmenopausal women with risk factors for cardiovascular disease (CVD)... CONCLUSIONS: In this older postmenopausal population with at least one cardiovascular risk factor, treatment with combined continuous ethinyl estradiol and norethindrone acetate failed to improve vascular endothelial function. The agent's proinflammatory effect or subclinical atherosclerosis in this population may have contributed to this finding.

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Clinical Trials Related to Nora-BE (Norethindrone)

Nexplanon Observational Risk Assessment Study (NORA) [Active, not recruiting]

Cortisol and Nutritional Sympathetic Responsiveness [Recruiting]
This project will examine whether short-term (over a 12-hour period) pharmacological lowering of the stress hormone 'cortisol' improves the nervous system response to food intake in overweight or obese individuals who have metabolic syndrome. The investigators know from our previous research that overweight/obese persons who are insulin resistant, have a blunted sympathetic nervous response to carbohydrate ingestion. This means that they are less able to dissipate energy from caloric intake, which would favour the maintenance of the obese state. Cortisol adversely impacts on insulin action and transport into the brain and cortisol levels are often elevated in persons with central (abdominal) obesity. A randomized, double-blind, placebo controlled, cross-over design will be used to compare the effects of overnight treatment with metyrapone (15 mg/kg at midnight and 15 mg/kg at 6 am) versus placebo on sympathetic nervous system activity in response to a standard 75-g oral sugar (glucose) tolerance test. A 2 week washout will separate treatments. Metyrapone is a drug that reversibly inhibits the enzyme 11beta-hydroxylase, and therefore the production of cortisol. It is used clinically to test the activity of the adrenal gland (the key site of cortisol production) and the pituitary gland. The investigators anticipate that at the dosage used, it will lower blood cortisol concentration by 44 to 64% during the experimental morning. The study protocol comprises two screening visits and two experimental mornings. Key procedures will include:

- Assessment of insulin action (sensitivity) using the gold standard 'clamp' method.

- Measurement of sympathetic nervous system activity by both biochemical methods (isotope

dilution which provides a measure of the apparent rate of release of 'noradrenaline'-the key neurotransmitter in the sympathetic nervous system) and direct intra-neuronal nerve recordings from the peroneal nerve in the lower leg.

- Indirect calorimetry to assess resting metabolic rate and the response to sugar

ingestion.

- DEXA scan to quantify fat and lean mass.

- Assessment of arterial elasticity and calf blood flow by non-invasive methods.

- A standard 75g oral sugar tolerance test.

The results will provide important new information regarding the role of cortisol on nervous system function in overweight/obese individuals.

Sympathetic Activity in Individuals With the Metabolic Syndrome: Benefits of Lifestyle Interventions [Recruiting]
An abdominal distribution of fat is associated with the greatest heart disease risk, because commonly, several risk factors of metabolic origin (high blood pressure, unfavourable cholesterol profile, elevated blood sugar, impaired insulin action) cluster in these individuals. When this occurs the condition is called the 'metabolic syndrome' (MetS). The cause of the MetS is yet to be fully elucidated. Increased activity of the nervous system resulting in enhanced release of the stress hormone 'norepinephrine', may be one mechanism by which adverse cardiovascular and metabolic sequelae of the MetS might be mediated. Dietary weight loss, and exercise are first-line treatments for the MetS and provide an opportunity to prevent or delay the development of type 2 diabetes and heart disease in this high risk group. However, there is a paucity of data regarding the effects of these lifestyle factors on the nervous system. Furthermore, it is also unknown whether active weight loss ('negative energy balance') or a stable lower weight (weight loss maintenance) is more important in modifying MetS components and nervous system activity. The aims of the proposed project are: 1. To determine whether dietary weight loss in combination with aerobic exercise is more beneficial than dietary weight loss alone in reducing nervous system activity and improving metabolic and cardiovascular parameters in middle-aged men and women with abdominal obesity and the MetS. 2. To determine whether weight loss maintenance four months after active weight loss is associated with a preservation of clinical benefits. 3. To study biological determinants of successful weight loss and weight loss maintenance.

The Effects of Weight Loss on Neuroadrenergic Function [Not yet recruiting]
Elevated subconscious nervous system activity is a characteristic of the obese state and contributes importantly to the risk of heart disease and diabetes. This project will compare sympathetic nervous system activity and function in a group of obese persons with differing levels of sugar tolerance (normal, impaired and type 2 diabetic). Inter-relationships with insulin action, blood pressure, heart and kidney function will be determined before and after a 4-month weight loss and 3-month weight loss maintenance program. It is hypothesized that the transition from normal sugar tolerance to impaired sugar tolerance to type 2 diabetes will be accompanied by escalating sympathetic nervous system dysfunction. Furthermore, that weight loss will favorably improve sympathetic function, with greatest benefits occurring in those subjects who are insulin resistant with high blood insulin concentration.

Safety and Efficacy of Gardasil in Females With Juvenile Idiopathic Arthritis (JIA)/Seronegative Arthritis [Recruiting]
The purpose of this research study is to see if patients with juvenile idiopathic arthritis or seronegative arthritis (and related conditions) mount protective immune responses to the human papillomavirus (HPV) vaccine called Gardasil. The researchers also want to monitor for any increase in disease activity following receipt of the vaccine.

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