ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. See WARNINGS and PRECAUTIONS.The following adverse reactions have been observed in women taking progestins:oBreakthrough bleedingoSpottingoChange in menstrual flowoAmenorrheaoEdemaoChanges in weight (decreases, increases)oChanges in the cervical squamo-columnar junction and cervical secretionsoCholestatic jaundiceoRash (allergic) with and without pruritusoMelasma or chloasmaoClinical depressionoAcneoBreast enlargement/tendernessoHeadache/migraineoUrticariaoAbnormalities of liver tests (i.e., AST, ALT, Bilirubin)oDecreased HDL cholesterol and increased LDL/HDL ratiooMood swingsoNauseaoInsomniaoAnaphylactic/anaphylactoid reactionsoThrombotic and thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, retinal vascular thrombosis, cerebral thrombosis and embolism)oOptic neuritis (which may lead to partial or complete loss of vision). oBreakthrough bleeding. oSpotting. oChange in menstrual flow. oAmenorrhea. oEdema. oChanges in weight (decreases, increases). oChanges in the cervical squamo-columnar junction and cervical secretions. oCholestatic jaundice. oRash (allergic) with and without pruritus. oMelasma or chloasma. oClinical depression. oAcne. oBreast enlargement/tenderness. oHeadache/migraine. oUrticaria. oAbnormalities of liver tests (i.e., AST, ALT, Bilirubin). oDecreased HDL cholesterol and increased LDL/HDL ratio. oMood swings. oNausea. oInsomnia. oAnaphylactic/anaphylactoid reactions. oThrombotic and thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, retinal vascular thrombosis, cerebral thrombosis and embolism). oOptic neuritis (which may lead to partial or complete loss of vision).

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Norethindrone acetate induces secretory changes in an estrogen-primed endometrium. On 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 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 1Pharmacokinetic Parameters after Single Dose of Norethindrone Acetate Tablets in Healthy WomenNorethindrone acetate tablets (n=29) Arithmetic Mean +- SD Norethindrone (NET) AUC (0-inf)(ng/mlh) 166.9 +- 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. Mean Plasma Concentration Profile after Single Dose of mg Administered to 29 Healthy Female Volunteers under Fasting ConditionsEffect 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 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 single dose administration of norethindrone acetate tablets is approximately hours.. Graph. SPECIAL POPULATIONS. GeriatricsThe effect of age on the pharmacokinetics of norethindrone after norethindrone acetate tablets administration has not been evaluated.RaceThe effect of race on the disposition of norethindrone after norethindrone acetate tablets administration has not been evaluated.Renal InsufficiencyThe 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 InsufficiencyThe 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 InteractionsNo pharmacokinetic drug interaction studies investigating any drug-drug interactions with norethindrone acetate tablets have been conducted.

PHARMACOKINETICS SECTION.

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 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 1Pharmacokinetic Parameters after Single Dose of Norethindrone Acetate Tablets in Healthy WomenNorethindrone acetate tablets (n=29) Arithmetic Mean +- SD Norethindrone (NET) AUC (0-inf)(ng/mlh) 166.9 +- 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. Mean Plasma Concentration Profile after Single Dose of mg Administered to 29 Healthy Female Volunteers under Fasting ConditionsEffect 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 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 single dose administration of norethindrone acetate tablets is approximately hours.. Graph.

PRECAUTIONS SECTION.

PRECAUTIONS. 1. General PrecautionsoBecause 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 observationoIn 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 indicatedoPatients who have history of clinical depression should be carefully observed and the drug discontinued if the depression recurs to serious degreeoData 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 therapyoThe pathologist should be advised of progestin therapy when relevant specimens are submitted2. Information for the PatientHealthcare providers are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe norethindrone acetate tablets.3. Drug/Laboratory Tests InteractionsThe following laboratory test results may be altered by the use of estrogen/progestin combination drugs: 1. 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 Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity. 2. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radio immunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone. 3. 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). 4. Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglycerides levels. 5. Impaired glucose metabolism. 6. Reduced response to metyrapone test.4. Carcinogenesis, Mutagenesis, and Impairment of FertilitySome 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 XNorethindrone 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 MothersDetectable amounts of progestins have been identified in the milk of mothers receiving them. Caution should be exercised when progestins are administered to nursing woman.7. Pediatric UseNorethindrone acetate tablets are not indicated in children.. oBecause 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. oIn 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. oPatients who have history of clinical depression should be carefully observed and the drug discontinued if the depression recurs to serious degree. oData 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. oThe pathologist should be advised of progestin therapy when relevant specimens are submitted.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONNorethindrone Acetate Tablets USP, mgRead this PATIENT INFORMATION before you start taking norethindrone acetate tablets and read what you get each time you refill norethindrone acetate tablets. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition.What is the most important information should know about Norethindrone Acetate (A Progestin Hormone) tablets Do not use norethindrone acetate tablets if you are pregnant, breast-feeding or are trying to conceive. Do not use norethindrone acetate tablets if you have had previous blood clot, stroke, or heart attack. Do not use norethindrone acetate tablets if you are postmenopausal. What are Norethindrone Acetate TabletsNorethindrone acetate tablets are similar to the progesterone hormones naturally produced by the body. Your healthcare provider may provide norethindrone acetate tablets as individual tablets.What are Norethindrone Acetate Tablets used for Norethindrone acetate tablets are used for the treatment of secondary amenorrhea (absence of menstrual periods in women who have previously had menstrual period who are not pregnant), the treatment of endometriosis, and the treatment of irregular menstrual periods due to hormone imbalance.Who should not take Norethindrone Acetate TabletsYou should not take norethindrone acetate tablets if you are postmenopausal, pregnant or breast-feeding.You should not take norethindrone acetate tablets if you have the following conditions: Known or suspected pregnancy. Norethindrone acetate tablets are not indicated during pregnancy as it may cause fetal harm when administered to pregnant women. There is an increased risk of minor birth defects in children whose mothers take norethindrone acetate tablets during the first months of pregnancy (mild masculinization of the external genitalia of the female fetus, as well as hypospadias in the male fetus). If you take norethindrone acetate tablets and later find out you were pregnant, talk with your healthcare provider right away History of blood clots in the legs, lungs, eyes, brain, or elsewhere, or past history of these conditions Liver impairment or disease Known or suspected cancer of the breast. If you have or had cancer of the breast, talk with your healthcare provider about whether you should take norethindrone acetate tablets. Undiagnosed vaginal bleeding Hypersensitivity to norethindrone acetate tablets. See the end of this leaflet for list of all of the ingredients in norethindrone acetate tablets.What are the risks associated with Norethindrone Acetate Tablets Risk to the Fetus: Norethindrone acetate tablets should not be used if you are pregnant. Norethindrone acetate tablets are contraindicated during pregnancy as it may cause fetal harm when administered to pregnant women. There is an increased risk of minor birth defects in children whose mothers take this drug during the first months of pregnancy. Several reports suggest an association between mothers who take these drugs in the first trimester of pregnancy and congenital abnormalities in male and female babies. Although it is not clear that these events were drug related, you should check with your healthcare provider about the risks to your unborn child of any medication taken during pregnancy. You should avoid using norethindrone acetate tablets during pregnancy. If you take norethindrone acetate tablets and later find you were pregnant when you took it, be sure to discuss this with your healthcare provider as soon as possible. Abnormal Blood Clotting: Use of progestational drugs, such as norethindrone acetate tablets, has been associated with changes in the blood-clotting system. These changes allow the blood to clot more easily, possibly allowing clots to form in the bloodstream. If blood clots do form in your bloodstream, they can cut off the blood supply to vital organs, causing serious problems. These problems may include stroke (by cutting off blood to part of the brain), heart attack (by cutting off blood to part of the heart), pulmonary embolus (by cutting off blood to part of the lungs), visual loss or blindness (by cutting off blood vessels in the eye), or other problems. Any of these conditions may cause death or serious long-term disability. Call your healthcare provider right away if you suspect you have any of these conditions. He or she may advise you to stop using the drug. Eye Abnormalities: Discontinue norethindrone acetate tablets and call your healthcare provider right away if you experience sudden partial or complete loss of vision, blurred vision, or sudden onset of bulging eyes, double vision, or migraine.These are some of the warning signs of serious side effects with progestin therapy:oBreast lumpsoDizziness and faintnessoChanges in speechoSevere headachesoChest painoShortness of breathoPains in your legsoChanges in visionCall your healthcare provider right away if you get any of these warning signs, or any other unusual symptom that concerns you.Common side effects include:oHeadacheoBreast painoIrregular vaginal bleeding or spottingoStomach/abdominal cramps/bloatingoNausea and vomitingoHair lossOther side effects include:oHigh blood pressureoLiver problemsoHigh blood sugaroFluid retentionoEnlargements of benign tumors of the uterus (fibroids)oVaginal yeast infectionsoMental depressionThese are not all the possible side effects of progestin and/or estrogen therapy. For more information, ask your healthcare provider or pharmacist.What can do to lower my chances of getting serious side effect with Norethindrone Acetate Tablets Talk with your healthcare provider regularly about whether you should continue taking norethindrone acetate tablets. Have breast exam and mammogram (breast x-ray) every year unless your healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease. Ask your healthcare provider for ways to lower your chances of getting heart attacksGeneral information about the safe and effective use of Norethindrone Acetate Tablets Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take norethindrone acetate tablets for conditions for which it was not prescribed. Do not give norethindrone acetate tablets to other people, even if they have the same symptoms you have. It may harm them.Keep Norethindrone Acetate Tablets out of the reach of children.This leaflet provides summary of the most important information about progestin and/or estrogen therapy. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about norethindrone acetate tablets that is written for health professionals.What are the ingredients in Norethindrone Acetate TabletsNorethindrone acetate tablets contain the following inactive ingredients: anhydrous lactose, lactose monohydrate, magnesium stearate, and microcrystalline celluloseManufactured for:Mylan Pharmaceuticals Inc.Morgantown, WV 26505 U.S.A.Manufactured by:Mylan Laboratories LimitedAhmedabad 382 213, IndiaCode No.: GUJ-DRUGS/G/28/129775076124Revised: 6/2020FC:PIL:7291:R3pt. oBreast lumps. oDizziness and faintness. oChanges in speech. oSevere headaches. oChest pain. oShortness of breath. oPains in your legs. oChanges in vision. oHeadache. oBreast pain. oIrregular vaginal bleeding or spotting. oStomach/abdominal cramps/bloating. oNausea and vomiting. oHair loss. oHigh blood pressure. oLiver problems. oHigh blood sugar. oFluid retention. oEnlargements of benign tumors of the uterus (fibroids). oVaginal yeast infections. oMental depression.