Norethindrone acetate

ADVERSE REACTIONS See WARNINGS and PRECAUTIONS The following adverse reactions have been observed in women taking progestins: Breakthrough bleeding Spotting Change in menstrual flow Amenorrhea Edema Changes in weight (decreases, increases) Changes in the cervical squamo-columnar junction and cervical secretions Cholestatic jaundice Rash (allergic) with and without pruritus Melasma or chloasma Clinical depression Acne Breast enlargement/tenderness Headache/migraine Urticaria Abnormalities of liver tests (i.e., AST, ALT, Bilirubin) Decreased HDL cholesterol and increased LDL/HDL ratio Mood swings Nausea Insomnia Anaphylactic/anaphylactoid reactions Thrombotic and thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, retinal vascular thrombosis, cerebral thrombosis and embolism) Optic neuritis (which may lead to partial or complete loss of vision) To report SUSPECTED ADVERSE REACTIONS, please call Ingenus Pharmaceuticals, LLC toll-free at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CONTRAINDICATIONS Known or suspected pregnancy. There is no indication for norethindrone acetate tablets 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

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 to yellowish-white, crystalline powder. Norethindrone acetate tablets, USP contain the following inactive ingredients: lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Meets USP dissolution Test 2. structure

DOSAGE AND ADMINISTRATION Therapy with norethindrone acetate tablets must be adapted to the specific indications and therapeutic response of the individual patient. Secondary amenorrhea, abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology: 2.5 to 10 mg norethindrone acetate tablets may be given daily for 5 to 10 days to produce secretory transformation of an endometrium that has been adequately primed with either endogenous or exogenous estrogen. Progestin withdrawal bleeding usually occurs within three to seven days after discontinuing norethindrone acetate tablets therapy. Patients with a past history of recurrent episodes of abnormal uterine bleeding may benefit from planned menstrual cycling with norethindrone acetate tablets. Endometriosis: Initial daily dosage of 5 mg norethindrone acetate tablets for two weeks. Dosage should be increased by 2.5 mg per day every two weeks until 15 mg per day of norethindrone acetate tablets is reached. Therapy may be held at this level for six to nine months or until annoying breakthrough bleeding demands temporary termination.

INDICATIONS AND USAGE Norethindrone acetate tablets are 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 tablets are not intended, recommended or approved to be used with concomitant estrogen therapy in postmenopausal women for endometrial protection.

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.

3 Drug/Laboratory Tests Interactions The following laboratory test results may be altered by the use of estrogen/progestin combination drugs: Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor X a and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T 4 levels (by column or by radio immunoassay) or T 3 levels by radio immunoassay. T 3 resin uptake is decreased, reflecting the elevated TBG. Free T 4 and free T 3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone. Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG)) leading to increased circulating corticosteroid and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). Increased plasma HDL and HDL 2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels. Impaired glucose metabolism. Reduced response to metyrapone test.

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 tablets in 29 healthy female volunteers are summarized in Table 1. Table 1 Pharmacokinetic Parameters after a Single Dose of norethindrone acetate tablets in Healthy Women Norethindrone acetate tablets (n=29) Arithmetic Mean ± SD Norethindrone (NET) AUC(0-inf)(ng/mL*h) 166.90±56.28 C max (ng/mL) 26.19±6.19 t max (h) 1.83±0.58 t 1/2 (h) 8.51±2.19 AUC= area under the curve C max = maximum plasma concentration t max = time at maximum plasma concentration t 1/2 = half-life SD = standard deviation 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 tablets 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 tablets is approximately 9 hours. figure 1 SPECIAL POPULATIONS Geriatrics The effect of age on the pharmacokinetics of norethindrone after norethindrone acetate tablets administration has not been evaluated. Race The effect of race on the disposition of norethindrone after norethindrone acetate tablets administration has not been evaluated. Renal Insufficiency The effect of renal disease on the disposition of norethindrone after norethindrone acetate tablets administration 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 norethindrone concentration was unchanged compared to concentrations in premenopausal women with normal renal function. Hepatic Insufficiency The effect of hepatic disease on the disposition of norethindrone after norethindrone acetate tablets administration has not been evaluated. However, norethindrone acetate tablets are contraindicated in markedly impaired liver function or liver disease. Drug Interactions No pharmacokinetic drug interaction studies investigating any drug-drug interactions with norethindrone acetate tablets have been conducted.

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 tablets in 29 healthy female volunteers are summarized in Table 1. Table 1 Pharmacokinetic Parameters after a Single Dose of norethindrone acetate tablets in Healthy Women Norethindrone acetate tablets (n=29) Arithmetic Mean ± SD Norethindrone (NET) AUC(0-inf)(ng/mL*h) 166.90±56.28 C max (ng/mL) 26.19±6.19 t max (h) 1.83±0.58 t 1/2 (h) 8.51±2.19 AUC= area under the curve C max = maximum plasma concentration t max = time at maximum plasma concentration t 1/2 = half-life SD = standard deviation 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 tablets 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 tablets is approximately 9 hours. figure 1

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Norethindrone acetate norethindrone acetate NORETHINDRONE ACETATE NORETHINDRONE LACTOSE MONOHYDRATE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE white to off-white flat, beveled-edge P658

4 Carcinogenesis, Mutagenesis, and Impairment of Fertility Some beagle dogs treated with medroxyprogesterone acetate developed mammary nodules. Although nodules occasionally appeared in control animals, they were intermittent in nature, whereas nodules in treated animals were larger and more numerous, and persisted. There is no general agreement as to whether the nodules are benign or malignant. Their significance with respect to humans has not been established.

ANDA206490

Norethindrone acetate

norethindrone acetate

50742-267

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL ingenus NDC 50742-267-50 Norethindrone Acetate Tablets, USP 5 mg ORALLY ACTIVE PROGESTIN PHARMACIST: PLEASE DISPENSE WITH ATTACHED PATIENT INFORMATION LEAFLET Rx only 50 Tablets 50's Count Container Label

2 Information for the Patient Healthcare providers are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe norethindrone acetate tablets.

6 Nursing Mothers Detectable amounts of progestins have been identified in the milk of mothers receiving them. Caution should be exercised when progestins are administered to a nursing woman.

7 Pediatric Use Norethindrone acetate tablets are not indicated in children.

5 Pregnancy Category X Norethindrone acetate is contraindicated during pregnancy as it may cause fetal harm when administered to pregnant women. Several reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and congenital abnormalities in male and female fetuses. Some progestational drugs induce mild virilization of the external genitalia of female fetuses.

HOW SUPPLIED Norethindrone acetate tablets, USP are available as: 5 mg: White to off-white, oval, flat beveled edged tablet. 'P658' is engraved on one side, and a breakline on the reverse. Available as follows: Bottle of 50 NDC 50742-267-50 Bottle of 500 NDC 50742-267-05 Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature]. Rx Only Revised: 05/2019 I0093 Rev B Manufactured for: Ingenus Pharmaceuticals, LLC Orlando, FL 32839-6408 Made in China ingenus

1 General Precautions Because this drug may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, cardiac or renal dysfunctions, require careful observation In cases of breakthrough bleeding, and in all cases of irregular bleeding per vagina, nonfunctional causes should be borne in mind. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures are indicated Patients who have a history of clinical depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree Data suggest that progestin therapy may have adverse effects on lipid and carbohydrate metabolism. The choice of progestin, its dose, and its regimen may be important in minimizing these adverse effects, but these issues will require further study before they are clarified. Women with hyperlipidemias and/or diabetes should be monitored closely during progestin therapy The pathologist should be advised of progestin therapy when relevant specimens are submitted

PRECAUTIONS 1 General Precautions Because this drug may cause some degree of fluid retention, conditions which might be influenced by this factor, such as epilepsy, migraine, cardiac or renal dysfunctions, require careful observation In cases of breakthrough bleeding, and in all cases of irregular bleeding per vagina, nonfunctional causes should be borne in mind. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures are indicated Patients who have a history of clinical depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree Data suggest that progestin therapy may have adverse effects on lipid and carbohydrate metabolism. The choice of progestin, its dose, and its regimen may be important in minimizing these adverse effects, but these issues will require further study before they are clarified. Women with hyperlipidemias and/or diabetes should be monitored closely during progestin therapy The pathologist should be advised of progestin therapy when relevant specimens are submitted 2 Information for the Patient Healthcare providers are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe norethindrone acetate tablets. 3 Drug/Laboratory Tests Interactions The following laboratory test results may be altered by the use of estrogen/progestin combination drugs: Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor X a and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T 4 levels (by column or by radio immunoassay) or T 3 levels by radio immunoassay. T 3 resin uptake is decreased, reflecting the elevated TBG. Free T 4 and free T 3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone. Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG)) leading to increased circulating corticosteroid and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin). Increased plasma HDL and HDL 2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels. Impaired glucose metabolism. Reduced response to metyrapone test. 4 Carcinogenesis, Mutagenesis, and Impairment of Fertility Some beagle dogs treated with medroxyprogesterone acetate developed mammary nodules. Although nodules occasionally appeared in control animals, they were intermittent in nature, whereas nodules in treated animals were larger and more numerous, and persisted. There is no general agreement as to whether the nodules are benign or malignant. Their significance with respect to humans has not been established. 5 Pregnancy Category X Norethindrone acetate is contraindicated during pregnancy as it may cause fetal harm when administered to pregnant women. Several reports suggest an association between intrauterine exposure to progestational drugs in the first trimester of pregnancy and congenital abnormalities in male and female fetuses. Some progestational drugs induce mild virilization of the external genitalia of female fetuses. 6 Nursing Mothers Detectable amounts of progestins have been identified in the milk of mothers receiving them. Caution should be exercised when progestins are administered to a nursing woman. 7 Pediatric Use Norethindrone acetate tablets are not indicated in children.