Ogen

Estropipate is a form of estrogen. Estrogen is a female sex hormone necessary for many processes in the body.

Estropipate is used to treat symptoms of menopause such as hot flashes, and vaginal dryness, burning, and irritation. It is also used to prevent osteoporosis.

Estropipate may also be used for purposes other than those listed in this medication guide.

Take the medication as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your medicine at the next regularly scheduled time. Do not take extra medicine to make up the missed dose.

Ogen (estropipate tablets), (formerly piperazine estrone sulfate), is a natural estrOgenic substance prepared from purified crystalline estrone, solubilized as the sulfate and stabilized with piperazine. It is appreciably soluble in water and has almost no odor or taste properties which are ideally suited for oral administration. The amount of piperazine in Ogen is not sufficient to exert a pharmacological action. Its addition ensures solubility, stability, and uniform potency of the estrone sulfate. Chemically estropipate, molecular weight: 436.56, is represented by estra-1,3,5(10)-trien-17-one,3-(sulfooxy)-, compound with piperazine (1:1). The structural formula may be represented as follows:

Ogen is available as tablets for oral administration containing either 0.75 mg (Ogen .625), 1.5 mg (Ogen 1.25), or 3 mg (Ogen 2.5) estropipate (Calculated as sodium estrone sulfate 0.625 mg, 1.25 mg, and 2.5 mg, respectively).

Inactive Ingredients

Each tablet contains: Colloidal silicon dioxide, dibasic potassium phosphate, hydrOgenated vegetable oil wax, hydroxypropyl cellulose, lactose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate and tromethamine.
Ogen .625 also contains: D&C Yellow No. 10 and FD&C Yellow No. 6.
Ogen 1.25 also contains: FD&C Yellow No. 6.
Ogen 2.5 also contains: FD&C Blue No. 2.

EndOgenous estrOgens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrOgens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrOgen and is substantially more potent than its metabolites, estrone and estriol at the receptor level.

The primary source of estrOgen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endOgenous estrOgen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrOgens in postmenopausal women.

EstrOgens act through binding to nuclear receptors in estrOgen-responsive tissues. To date, two estrOgen receptors have been identified. These vary in proportion from tissue to tissue.

Circulating estrOgens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. EstrOgens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Pharmacokinetics

EstrOgens are well absorbed through the skin and gastrointestinal tract. When applied for a local action, absorption is usually sufficient to cause systemic effects.

The distribution of exOgenous estrOgens is similar to that of endOgenous estrOgens. EstrOgens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. EstrOgens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

ExOgenous estrOgens are metabolized in the same manner as endOgenous estrOgens. Circulating estrOgens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. EstrOgens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrOgens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrOgens.

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

In vitro and in vivo studies have shown that estrOgens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrOgen drug metabolism. Inducers of CYP3A4 such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrOgens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrOgens and may result in side effects.

Clinical Studies

The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of 0.625 mg conjugated estrOgens (CE) per day alone or the use of oral 0.625 mg conjugated estrOgens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index." Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 1 below:

For those outcomes included in the "global index," the absolute excess risks per 10,000 person-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the "global index" was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS.)

The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625mg conjugated estrOgens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 4 years, 40 women in the estrOgen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia.)

The results of a double-blind, placebo-controlled two-year study have shown that treatment with one tablet of Ogen .625 daily for 25 days (of a 31-day cycle per month) prevents vertebral bone mass loss in postmenopausal women. When estrOgen therapy is discontinued, bone mass declines at a rate comparable to that of the immediate postmenopausal period. There is no evidence that estrOgen replacement therapy restores to premenopausal levels.

Serious ill effects have not been reported following acute ingestion of large doses of estrOgen-containing oral contraceptives by young children. Overdosage of estrOgen may cause nausea and vomiting, and withdrawal bleeding may occur in females.

Read this PATIENT INFORMATION before you start taking Ogen and read what you get each time you refill Ogen. There may be new information. This information does not take the place of talking to your health care provider about your medical condition or your treatment.

• EstrOgens increase the chances of getting cancer of the uterus.

Report any unusual vaginal bleeding right away while you are taking estrOgens. Vaginal bleeding after menopause may be a warning sign of cancer of the uterine (womb). Your health care provider should check any unusual vaginal bleeding to find out the cause.

• Do not use estrOgens with or without progestins to prevent heart disease, heart attacks or strokes.

Using estrOgens with or without progestins may increase your chances of getting heart attacks, strokes, breast cancer and blood clots. You and your health care provider should talk regularly about whether you still need treatment with Ogen.

What is Ogen?

Ogen is a medicine that contains estrOgen hormones.

What is Ogen used for?

Ogen is used during and after menopause to:

• reduce moderate or severe hot flashes.

EstrOgens are hormones made by a woman's ovaries. The ovaries normally stop making estrOgens when a woman is between 45 to 55 years old. This drop in body estrOgen levels causes the "change of life" or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrOgen levels causes "surgical menopause".

When the estrOgen levels begin dropping, some women develop very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest, or sudden strong feelings of heat and sweating ("hot flashes" or "hot flushes"). In some women, the symptoms are mild, and they do not need to use estrOgens. In other women, symptoms can be more severe. You and your health care provider should talk regularly about whether you still need treatment with Ogen.

• treat moderate to severe dryness, itching, and burning in and around the vagina.

You and your health care provider should talk regularly about whether you still need treatment with Ogen to control these problems. If you use Ogen only to treat your dryness, itching, and burning in and around your vagina, talk with your health care provider about whether a topical vaginal product would be better for you.

• help reduce your chances of getting osteoporosis (thin weak bones).

Osteoporosis from menopause is a thinning of the bones that makes them weaker and easier to break. If you use Ogen only to prevent osteoporosis from menopause, talk with your health care provider about whether a different treatment or medicine without estrOgens might be better for you. You and your health care provider should talk regularly about whether you should continue with Ogen.

Weight-bearing exercise, like walking or running, and taking calcium and vitamin D supplements may also lower your chances of getting postmenopausal osteoporosis. It is important to talk about exercise and supplements with your health care provider before starting them.

Ogen is also used to:

treat certain conditions in women before menopause if their ovaries do not make enough estrOgen naturally.

Who should not take Ogen?

Do not start taking Ogen if you:

• have unusual vaginal bleeding.
• currently have or have had certain cancers.

EstrOgens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or had cancer, talk with your health care provider about whether you should take Ogen.

• had a stroke or heart attack in the past year.
• currently have or have had blood clots.
• currently have or have had liver problems.
• are allergic to Ogen or any of its ingredients.

See the end of this leaflet for a list of ingredients in Ogen.

• think you may be pregnant.

Tell your health care provider:

• if you are breastfeeding.

The hormone in Ogen can pass into your milk.

• about all of your medical problems.

Your health care provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.

• about all the medicines you take.

This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how Ogen works. Ogen may also affect how your other medicines work.

• if you are going to have surgery or will be on bed rest.

You may need to stop taking estrOgens.

How should I take Ogen?

Take Ogen as directed by your health care provider. Ogen comes in three strengths. Check with your health care provider periodically to make sure you are using the appropriate dose.

1. Start at the lowest dose and talk to your health care provider about how well that dose is working for you.
2. EstrOgens should be used at the lowest dose possible for your treatment only as long as needed. The lowest effective dose of Ogen has not been determined. You and your health care provider should talk regularly (for example, every 3 to 6 months) about whether you still need treatment with Ogen.

What are the possible side effects of estrOgens?

Less common but serious side effects include:

• Breast cancer
• Cancer of the uterus
• Stroke
• Heart attack
• Blood clots
• Gallbladder disease
• Ovarian cancer

These are some of the warning signs of serious side effects:

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

Call your health care 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

Other side effects include:

• High blood pressure
• Liver problems
• High blood sugar
• Fluid retention
• Enlargement of benign tumors of the uterus ("fibroids")
• Vaginal yeast infections
• Hair loss

These are not all the possible side effects of Ogen. For more information, ask your health care provider or pharmacist.

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

Talk with your health care provider regularly about whether you should continue taking Ogen. If you have a uterus, talk to your health care provider about whether the addition of a progestin is right for you. See your health care provider right away if you get vaginal bleeding while taking Ogen. Have a breast exam and mammogram (breast X-ray) every year unless your health care 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 examinations 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 health care provider for ways to lower your chances for getting heart disease.

General information about safe and effective use of Ogen

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

This leaflet provides a summary of the most important information about Ogen. If you would like more information, talk with your health care provider or pharmacist. You can ask for information about Ogen that is written for health professionals. You can get more information by calling the toll free number 1-888-691-6813.

What are the ingredients in Ogen?

Ogen contains estropipate as the active ingredient. Ogen also contains colloidal silicon dioxide, dibasic potassium phosphate, hydrOgenated vegetable oil wax, hydroxypropyl cellulose, lactose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate and tromethamine.

The color ingredients are:
Ogen .625 (yellow tablet): D&C Yellow No. 10 and FD&C Yellow No. 6.
Ogen 1.25 (peach tablet): FD&C Yellow No. 6.
Ogen 2.5 (blue tablet): FD&C Blue No. 2.

LAB-0090-4.0
July 2006

NDC 0009-3773-01

100 Tablets Divide-Tab®
Rx only

Ogen® 1.25
estropipate
tablets, USP
1.5

1.5 mg*

Pfizer
Distributed by
Pharmacia & Upjohn Co
Division of Pfizer Inc, NY, NY 10017

NDC 0009-3774-01

100 Tablets Divide-Tab®
Rx only

Ogen® 2.5
estropipate
tablets, USP
3

3 mg*

Pfizer
Distributed by
Pharmacia & Upjohn Co
Division of Pfizer Inc, NY, NY 10017