Label: CENESTIN- synthetic conjugated estrogens, a tablet, film coated

Pharmacokinetics

Absorption

Synthetic conjugated estrogens, A are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. The Cenestin tablet releases the synthetic conjugated estrogens, A slowly over a period of several hours. The effect of food on the bioavailability of synthetic conjugated estrogens, A from Cenestin has not been studied.

Table 1 PHARMACOKINETIC  PARAMETERS FOR UNCONJUGATED AND CONJUGATED ESTROGENS IN HEALTHY POSTMENOPAUSAL WOMEN UNDER FASTING CONDITIONS

Pharmacokinetic Parameters of Unconjugated Estrogens Following a Dose of 2 x 0.625 mg Cenestin
Drug	Cmax (pg/mL) CV%	Tmax (h) CV%	AUC0-72h (pg•hr/mL) CV%
Baseline-corrected estrone	84.5 (41.7)	8.25 (35.6)	1749 (43.8)
Equilin	45.6 (47.3)	7.78 (28.8)	723 (67.9)

Pharmacokinetic Parameters of Conjugated Estrogens Following a Dose of 2 x 0.625 mg Cenestin
Drug	Cmax (pg/mL) CV%	Tmax (h) CV%	t ½ (h) CV%	AUC0-72h (pg•hr/mL) CV%
Baseline-corrected estrone	4.43 (40.4)	7.7 (30.3)	10.6 (25.4)	69.89 (39.2)
Equilin	3.27 (43.5)	5.8 (31.1)	9.7 (23.0)	46.46 (47.5)

Special Populations

Cenestin was investigated in postmenopausal women. No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.

Drug Interactions

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers and 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

Effects on vulvar and vaginal atrophy

The effects of 0.3 mg Cenestin on moderate to severe symptoms of vulvar and vaginal atrophy were confirmed in a 16-week, randomized, placebo-controlled, multicenter clinical study in 72 postmenopausal women between 30 and 77 years of age (53% were Caucasian). Patients were randomized to receive either placebo or 0.3 mg Cenestin daily for 16 weeks. Efficacy was assessed at weeks 12 and 16 for vaginal wall cytology and week 16 for vaginal pH. Results for percent of superficial cells from a maturation index of the vaginal mucosa are shown in Figure 2. Mean vaginal pH decreased from a baseline of 6.20 to 5.14 for Cenestin and increased to 6.15 from a baseline of 6.03 for placebo.

 1. Cardiovascular disorders.

Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately.

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. Malignant neoplasms.

3. Dementia

In the Women’s Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 years of age and older were studied, of whom 35% were 70 to 74 years of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n = 2,229) and 21 women in the placebo group (0.9%, n = 2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21 – 3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use.)

4. Gallbladder disease

A 2 to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

5. Hypercalcemia

Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

6. Visual abnormalities

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or renal vascular lesions, estrogens should be permanently discontinued.

A. General

1. Addition of a progestin when a woman has not had a hysterectomy. Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.
   There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer.
2. Elevated blood pressure. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.
3. Hypertriglyceridemia. In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.
4. Impaired liver function and past history of cholestatic jaundice. Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.
5. Hypothyroidism. Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.
6. Fluid retention. Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.
7. Hypocalcemia. Estrogens should be used with caution in individuals with severe hypocalcemia.
8. Ovarian cancer. The CE/MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95% confidence interval 0.77-3.24) but was not statistically significant. The absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.
9. Exacerbation of endometriosis. Endometriosis may be exacerbated with administration of estrogens. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.
10. Exacerbation of other conditions. Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

B. Patient Information

Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Cenestin.

C. Laboratory Tests

Estrogen administration should be initiated at the lowest dose for the approved indication and then guided by clinical response, rather than by serum hormone levels (e.g., estradiol, FSH).

D. Drug/Laboratory Test Interactions

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 anti-factor 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 radioimmunoassay. 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 total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. 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 triglyceride levels.
5. Impaired glucose tolerance.
6. Reduced response to metyrapone test.

E. Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term continuous administration of estrogen, with and without progestin, in women, with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS.)

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

F. Pregnancy

Cenestin should not be used during pregnancy. (See CONTRAINDICATIONS.)

G. Nursing Mothers

Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving this drug. Caution should be exercised when Cenestin is administered to a nursing woman.

H. Pediatric Use

Cenestin is not indicated in children.

I. Geriatric Use

There have not been sufficient numbers of geriatric patients involved in studies utilizing Cenestin to determine whether those over 65 years of age differ from younger subjects in their response to Cenestin.
In the Women’s Health Initiative Memory Study, including 4,532 women 65 years of age and older, followed for an average of 4 years, 82% (n = 3,729) were 65 to 74 while 18% (n = 803) were 75 and over. Most women (80%) had no prior hormone therapy use. Women treated with conjugated estrogens plus medroxyprogesterone acetate were reported to have a two-fold increase in the risk of developing probable dementia. Alzheimer’s disease was the most common classification of probable dementia in both the conjugated estrogens plus medroxyprogesterone acetate group and the placebo group. Ninety percent of the cases of probable dementia occurred in the 54% of women that were older than 70. (See WARNINGS, Dementia.)

What is Cenestin?

Cenestin is a medicine that contains a mixture of synthetic estrogens made from a plant source.

What is Cenestin used for?

Cenestin is used 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 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 will not need estrogens. In other women, symptoms can be more severe. You and your healthcare provider should talk regularly about whether you still need treatment with Cenestin.
• treat moderate to severe dryness, itching, and burning in and around the vagina. You and your healthcare provider should talk regularly about whether you still need treatment with Cenestin to control these problems. If you use Cenestin only to treat your dryness, itching, and burning in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you.

Who Should Not Take Cenestin?

Do not start taking Cenestin if you:

• have unusual vaginal bleeding.
• currently have or have had certain cancers.
  Estrogens may increase the risk of certain types of cancers, including cancer of the breast or uterus. If you have or had cancer, talk with your healthcare provider about whether you should take Cenestin.
• 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 Cenestin or any of its ingredients.
  See the end of this leaflet for a list of ingredients in Cenestin.
• if you think you may be pregnant.

Tell your healthcare provider:

• if you are breastfeeding.
  The synthetic estrogen hormones in Cenestin can pass into your milk.
• about all of your medical problems.
  Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), migraine, endometriosis, lupus, 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 Cenestin works. Cenestin may also affect how your other medicines work.
• if you are going to have surgery or will be on bedrest.
  You may need to stop taking estrogens.

How Should I Take Cenestin?

Take one Cenestin tablet each day at about the same time. If you miss a dose, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your normal schedule. Do not take 2 doses at the same time.

Start at the lowest dose and talk to your healthcare provider about how well that dose is working for you. Estrogens should be used only as long as needed. You and your healthcare provider should talk regularly (for example every 3 to 6 months) about whether you still need treatment with Cenestin.

What are the possible side effects of estrogens?

Less common but serious side effects include:

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

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

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

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

Other side effects include:

• High blood pressure
• Fluid retention
• Liver problems
• Enlargement of benign tumors of the uterus (“fibroids”)
• High blood sugar
• Vaginal yeast infection

These are not all the possible side effects of Cenestin. For more information, ask your healthcare provider or pharmacist.

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

• Talk with your healthcare provider regularly about whether you should continue taking Cenestin.
• If you have a uterus, talk to your healthcare provider about whether the addition of a progestin is right for you.
• See your healthcare provider right away if you get vaginal bleeding while taking Cenestin.
• 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 for getting heart disease.

General information about safe and effective use of Cenestin.

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

Keep Cenestin out of the reach of children.

This leaflet provides a summary of the most important information about Cenestin. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about Cenestin that is written for health professionals. You can get more information by calling the toll free number 877-405-0369.

What are the ingredients in Cenestin?

Tablets for oral administration, are available in 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg and 1.25 mg strengths of synthetic conjugated estrogens, A. Tablets also contain the following inactive ingredients: ethylcellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80, pregelatinized starch, titanium dioxide, and triethyl citrate.

-0.3 mg tablets also contain FD&C Blue No. 2 aluminum lake and D&C Yellow No. 10 aluminum lake.

-0.45 mg tablets also contain FD&C Yellow No. 6/Sunset Yellow FCF lake.

-0.625 mg tablets also contain FD&C Red No. 40 aluminum lake.

-0.9 mg tablets do not contain any additional color additives.

-1.25 mg tablets also contain FD&C Blue No. 2 aluminum lake.

Manufactured By:

Duramed Pharmaceuticals, Inc.

Subsidiary of Barr Pharmaceuticals, Inc.

Pomona, New York 10970

Revised SEPTEMBER 2004

BR - 41, 46, 42, 43, 44

Relabeling and Repackaging by:
Physicians Total Care, Inc.
Tulsa, OK      74146