Label: AYGESTIN- norethindrone acetate tablet

AYGESTIN® (norethindrone acetate tablets USP) - 5 mg oral tablets.

AYGESTIN® (norethindrone acetate tablets 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. The structural formula is as follows:

C22H28O3 M.W. 340.46

AYGESTIN® (norethindrone acetate tablets USP) contain the following inactive ingredients: anhydrous lactose, magnesium stearate, and microcrystalline cellulose.

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 AYGESTIN 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 AYGESTIN in 29 healthy female volunteers are summarized in Table 1.

Table 1 Pharmacokinetic Parameters after a Single Dose of AYGESTIN® in Healthy Women
AYGESTIN® (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. 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 AYGESTIN 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 AYGESTIN is approximately 9 hours.

AYGESTIN (norethindrone acetate tablets USP) 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. AYGESTIN (norethindrone acetate tablets USP) is not intended, recommended or approved to be used with concomitant estrogen therapy in postmenopausal women for endometrial protection.

• Known or suspected pregnancy. There is no indication for AYGESTIN 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

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.

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)

Therapy with AYGESTIN must be adapted to the specific indications and therapeutic response of the individual patient.

AYGESTIN® (norethindrone acetate tablets USP) is available as:

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature].

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

TEVA WOMEN’S HEALTH, INC.

Subsidiary of TEVA PHARMACEUTICALS USA, INC.
North Wales, PA 19454

Rev. A 10/2015

AYGESTIN®
(norethindrone acetate tablets USP)

Read this PATIENT INFORMATION before you start taking AYGESTIN and read what you get each time you refill AYGESTIN. 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 I should know about AYGESTIN (A Progestin Hormone)?

• Do not use AYGESTIN if you are pregnant, breastfeeding or are trying to conceive.
• Do not use AYGESTIN if you have had a previous blood clot, stroke, or heart attack.
• Do not use AYGESTIN if you are postmenopausal.

What is AYGESTIN?

AYGESTIN is similar to the progesterone hormones naturally produced by the body. Your healthcare provider may provide AYGESTIN as individual tablets.

What are AYGESTIN used for?

AYGESTIN are used for the treatment of secondary amenorrhea (absence of menstrual periods in women who have previously had a 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 AYGESTIN?

You should not take AYGESTIN if you are postmenopausal, pregnant or breastfeeding.

You should not take AYGESTIN if you have the following conditions:

• Known or suspected pregnancy. AYGESTIN 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 AYGESTIN during the first 4 months of pregnancy (mild masculinization of the external genitalia of the female fetus, as well as hypospadias in the male fetus). If you take AYGESTIN 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 a 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 AYGESTIN.
• Undiagnosed vaginal bleeding
• Hypersensitivity to AYGESTIN. See the end of this leaflet for a list of all of the ingredients in AYGESTIN.

What are the risks associated with AYGESTIN?

• Risk to the Fetus

AYGESTIN should not be used if you are pregnant. AYGESTIN 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 4 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 AYGESTIN during pregnancy. If you take AYGESTIN 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 AYGESTIN, 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 a stroke (by cutting off blood to part of the brain), a heart attack (by cutting off blood to part of the heart), a 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 AYGESTIN 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

• Breast lumps
• Dizziness and faintness
• Changes in speech
• Severe headaches
• Chest pain
• Shortness of breath
• Pains in your legs
• Changes in vision

Call 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

• Headache
• Breast pain
• Irregular vaginal bleeding or spotting
• Stomach/abdominal cramps/bloating
• Nausea and vomiting
• Hair loss

Other side effects include

• High blood pressure
• Liver problems
• High blood sugar
• Fluid retention
• Enlargements of benign tumors of the uterus (“fibroids”)
• Vaginal yeast infections
• Mental depression

These are not all the possible side effects of progestin and/or estrogen therapy. For more information, ask your healthcare provider or pharmacist.

What can I do to lower my chances of getting a serious side effect with AYGESTIN?

• Talk with your healthcare provider regularly about whether you should continue taking AYGESTIN.
• Have a 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 attacks.

General information about the safe and effective use of AYGESTIN

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not take AYGESTIN for conditions for which it was not prescribed. Do not give AYGESTIN tablets to other people, even if they have the same symptoms you have. It may harm them.

Keep AYGESTIN out of the reach of children.

This leaflet provides a 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 AYGESTIN that is written for health professionals.

What are the ingredients in AYGESTIN?

AYGESTIN contain the following inactive ingredients: anhydrous lactose, magnesium stearate, and microcrystalline cellulose.

TEVA WOMEN’S HEALTH, INC.

Subsidiary of TEVA PHARMACEUTICALS USA, INC.
North Wales, PA 19454

Rev. A 10/2015

NDC 51285-424-10

Aygestin®

(norethindrone acetate

tablets USP)

ORALLY ACTIVE PROGESTIN

5 mg

PHARMACIST: PLEASE DISPENSE WITH
ATTACHED PATIENT INFORMATION LEAFLET.

Rx only

50 TABLETS

TEVA WOMEN’S HEALTH