Norethindrone Acetate

NORETHINDRONE ACETATE- norethindrone acetate tablet
Glenmark Pharmaceuticals Inc., USA

DESCRIPTION

Norethindrone acetate tablets USP — 5 mg oral tablets Norethindrone acetate USP, (17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one acetate), a synthetic, orally active progestin, is the acetic acid ester of norethindrone. It is a white, or creamy white, crystalline powder.

norethindrone-acetate-structure
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Norethindrone acetate tablets USP, 5 mg contain the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose and talc.

CLINICAL PHARMACOLOGY

Norethindrone acetate induces secretory changes in an estrogen-primed endometrium. On a weight basis, it is twice as potent as norethindrone.

Pharmacokinetics

Absorption:

Norethindrone acetate is completely and rapidly deacetylated to norethindrone (NET) after oral administration, and the disposition of norethindrone acetate is indistinguishable from that of orally administered norethindrone. Norethindrone acetate is rapidly absorbed from norethindrone acetate tablets, with maximum plasma concentration of norethindrone generally occurring at about 2 hours post-dose. The pharmacokinetic parameters of norethindrone following single oral administration of norethindrone acetate in 29 healthy female volunteers are summarized in Table 1.

Table 1 Pharmacokinetic Parameters after a Single Dose of Norethindrone Acetate in Healthy Women

Norethindrone Acetate (n=29) Arithmetic Mean ± SD

Norethindrone (NET)

AUC (0-inf) (ng/ml*h)

166.90 ± 56.28

Cmax (ng/ml)

26.19 ± 6.19

tmax (h)

1.83 ± 0.58

t1/2 (h)

8.51 ± 2.19

AUC = area under the curve,

Cmax = maximum plasma concentration,

tmax = time at maximum plasma concentration,

t1/2 = half-life,

SD = standard deviation

Figure 1
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Figure 1. Mean Plasma Concentration Profile after a Single Dose of 5 mg Administered to 29 Healthy Female Volunteers under Fasting Conditions

Effect of Food:

The effect of food administration on the pharmacokinetics of norethindrone acetate has not been studied.

Distribution:

Norethindrone is 36% bound to sex hormone-binding globulin (SHBG) and 61% bound to albumin. Volume of distribution of norethindrone is about 4 L/kg.

Metabolism:

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.

Excretion:

Plasma clearance value for norethindrone is approximately 0.4 L/hr/kg. Norethindrone is excreted in both urine and feces, primarily as metabolites. The mean terminal elimination half- life of norethindrone following a single dose administration of norethindrone acetate is approximately 9 hours.

Special Populations

Geriatrics:

The effect of age on the pharmacokinetics of norethindrone after norethindrone acetate administration has not been evaluated.

Race:

The effect of race on the disposition of norethindrone after norethindrone acetate administration has not been evaluated.

Renal Insufficiency:

The effect of renal disease on the disposition of norethindrone after norethindrone acetate administration has not been evaluated. In pre-menopausal women with chronic renal failure undergoing peritoneal dialysis who received multiple doses of an oral contraceptive containing ethinyl estradiol and norethindrone, plasma norethindrone concentration was unchanged compared to concentrations in pre-menopausal women with normal renal function.

Hepatic Insufficiency:

The effect of hepatic disease on the disposition of norethindrone after norethindrone acetate administration has not been evaluated. However, norethindrone acetate is contraindicated in markedly impaired liver function or liver disease.

Drug Interactions:

No pharmacokinetic drug interaction studies investigating any drug-drug interactions with norethindrone acetate have been conducted.

INDICATIONS AND USAGE

Norethindrone acetate is indicated for the treatment of secondary amenorrhea, endometriosis, and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as submucous fibroids or uterine cancer. Norethindrone acetate is not intended, recommended or approved to be used with concomitant estrogen therapy in postmenopausal women for endometrial protection.

CONTRAINDICATIONS

Known or suspected pregnancy. There is no indication for norethindrone acetate in pregnancy. (See PRECAUTIONS ).
Undiagnosed vaginal bleeding
Known, suspected or history of cancer of the breast
Active deep vein thrombosis, pulmonary embolism or history of these conditions
Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction)
Impaired liver function or liver disease
As a diagnostic test for pregnancy
Hypersensitivity to any of the drug components

WARNINGS

1. Cardiovascular disorders

Patients with risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

2. Visual abnormalities

Discontinue medication pending examination if there is a sudden partial or complete loss of vision or if there is sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, medication should be discontinued.

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