Professional Information — Covaryx

Indications and Usage

COVARYXT® and COVARYX® H.S. are indicated in the treatment of

Moderate to severe vasomotor symptoms associated with the menopause in those patients not improved by estrogens alone. (There is no evidence that estrogens are effective for nervous symptoms or depression without associated vasomotor symptoms, and they should not be used to treat such conditions.)

COVARYXT® and COVARYX® H.S. HAVE NOT BEEN SHOWN TO BE EFFECTIVE FOR ANY PURPOSE DURING PREGNANCY AND ITS USE MAY CAUSE SEVERE HARM TO THE FETUS (See BOXED WARNINGS).

Dosage and Administration

Given cyclically for short-term use only

For treatment of moderate to severe vasomotor symptoms associated with the menopause in patients not improved by estrogen alone. The lowest dose that will control symptoms should be chosen and medication should be discontinued as promptly as possible. Administration should be cyclic (e.g., three weeks on and one week off). Attempts to discontinue or taper medication should be made at three to six month intervals.

Usual Dosage Range

1 capsule-shaped tablet of COVARYX® (1.25 mg/2.5 mg) or 1 to 2 capsule shaped tablets of COVARYX® H.S. (0.625 mg/1.25 mg) daily as recommended by the physician. Treated patients with an intact uterus should be monitored closely for signs of endometrial cancer and appropriate diagnostic measures should be taken to rule out malignancy in the event of persistent or recurring abnormal vaginal bleeding.

Contraindications

Estrogens should not be used in women with any of the following conditions:

1. Known or suspected cancer of the breast except in appropriately selected patients being treated for metastatic disease.
2. Known or suspected estrogen-dependent neoplasia.
3. Known or suspected pregnancy (See BOXED WARNINGS).
4. Undiagnosed abnormal genital bleeding.
5. Active thrombophlebitis or thromboembolic disorders.
6. A past history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use (except when in treatment of breast malignancy).

Methyltestosterone should not be used in:

1. The presence of severe liver damage.
2. Pregnancy and in breast-feeding mothers because of the possibility of masculinization of the female fetus or breast-fed infant.

Adverse Reactions

Associated with Estrogens

(See WARNINGS regarding induction of neoplasia, adverse effects on the fetus, increased incidence of gallbladder disease, and adverse effects similar to those of oral contraceptives, including thromboembolism). The following additional adverse reactions have been reported with estrogenic therapy, including oral contraceptives:

1.Genitourinary system: Breakthrough bleeding; spotting; change in menstrual flow; dysmenorrhea; premenstrual-like syndrome; amenorrhea during and after treatment; increase in size of urerine fibromyomata; vaginal candidiasis; change in cervical erosion and in degree of cervical secretion; cystitis-like syndrome.
2. Breasts: Tenderness: enlargement; secretion.
3. Gastrointestinal: Nausea; vomiting; abdominal cramps; bloating; cholestatic jaundice.
4. Skin: Chloasma or melasma which may persist when drug is discontinued; erythema multiforme; erythema nodosum; hemorrhagic eruption; loss of scalp hair; hirsutism.
5. Eyes: Steepening of corneal curvature; intolerance to contact lenses.
6. Central Nervous System: Headache, migraine, dizziness; mental depression; chorea.
7. Miscellaneous: Increase or decrease in weight; reduced carbohydrate tolerance; aggravation of porphyria; edema; changes in libido.

Associated with Methyltestosterone

1. Endocrine and Urogenital.

Female: The most common side effects of androgen therapy are amenorrhea and other menstrual irregularities, inhibition of gonadotropin secretion, and virilization, including deepening of the voice and clitoral enlargement. The latter usually is not reversible after androgens are discontinued. When administered to a pregnant woman androgens cause virilization of external genitalia of the female fetus.

2. Skin and Appendages: Hirsutism, male pattern of baldness, and acne.
3. Fluid and Electrolyte Disturbances: Retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates.
4. Gastrointestinal: Nausea, cholestatic jaundice, alterations in liver function test, rarely hepatocellular neoplasms, and peliosis hepatis (See WARNINGS).
5. Hematologic: Suppression of clotting factors II, V, VII, and X, bleeding in patients on concomitant anticoagulant therapy, and polycythemia.
6. Nervous System. Increased or decreased libido, headache, anxiety, depression, and generalized paresthesia.
7. Metabolic: Increased serum cholesterol.
8. Miscellaneous: Inflammation and pain at the site of intramuscular injection or subcutaneous implantation of testosterone containing pellets, stomatitis with buccal preparatons, and rarely anaphylactoid reactions.

To report SUSPECTED ADVERSE REACTIONS, contact Syntho Pharmaceuticals or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

Overdosage

Numerous reports of ingestion of large doses of estrogen-containing oral contraceptives by young children indicate that serious ill effects do not occur. Overdosage of estrogen may cause nausea, and withdrawal bleeding may occur in females. There have been no reports of acute overdosage with the androgens.

Description

COVARYX®: Each light yellow, capsule-shaped, film coated tablet debossed "C010" on obverse and plain on the reverse contains 1.25 mg of Esterified Estrogens, USP and 2.5 mg of Methyltestosterone, USP.

COVARYX® H.S. (Half-Strength): Each light pink, capsule-shaped, film coated tablet debossed "C020" on obverse and plain on the reverse contains 0.625 mg of Esterified Estrogens, USP and 1.25 mg of Methyltestosterone, USP.

Esterified Estrogens

Esterified Estrogens, USP is a mixture of the sodium salts of the sulfate esters of the estrogenic substances, principally estrone, that are of the type excreted by pregnant mares. Esterified Estrogens contain not less than 75.0 percent and not more than 85.0 percent of sodium estrone sulfate, and not less than 6.0 percent and not more than 15.0 percent of sodium equilin sulfate, in such proportion that the total of these two components is not less than 90.0 percent.

Category: Estrogens

Methyltestosterone

Methyltestosterone, USP is an androgen. Androgens are derivatives of cyclopentano-perhydrophenanthrene. Endogenous androgens are C-19 steroids with a side chain at C-17, and with two angular methyl groups.

Testosterone is the primary endogenous androgen. Fluoxymesterone and methyltestosterone are synthetic derivatives of testosterone. Methyltestosterone is a white to light yellow crystalline substance that is virtually insoluble in water but soluble in organic solvents. It is stable in air but decomposes in light. Methyltestosterone structural formula:

COVARYX® and COVARYX® H.S. Tablets contain the following inactive ingredients: Microcrystalline Cellulose, Colloidal Silicon Dioxide, Lactose, Sodium Bicarbonate, Sodium Citrate, Magnesium Stearate, Polyvinyl Alcohol, Polyethylene Glycol, Talc, Titanium Dioxide, FD&C Yellow #5 Tartrazine Aluminum Lake, FD&C Yellow #6 Sunset Yellow FCF Aluminum Lake, and D&C Red #30 Helendon Pink Aluminum Lake.

Clinical Pharmacology

Estrogens

Estrogens are important in the development and maintenance of the female reproductive system and secondary sex characteristics. They promote growth and development of the vagina, uterus, and fallopian tubes, and enlargement of the breasts. Indirectly, they contribute to the shaping of the skeleton, maintenance of tone and elasticity of urogenital structures, changes in the epiphyses of the long bones that allow for the pubertal growth spurt and its termination, growth of axillary and pubic hair, and pigmentation of the nipples and genitals. Decline of estrogenic activity at the end of the menstrual cycle can bring on menstruation, although the cessation of progesterone secretion is the most important factor in the mature ovulatory cycle. However, in the preovulatory or nonovulatory cycle, estrogen is the primary determinant in the onset of menstruation. Estrogens also affect the release of pituitary gonadotropins.

The pharmacologic effects of esterified estrogens are similar to those of endogenous estrogens. They are soluble in water and are well absorbed from the gastrointestinal tract.

In responsive tissues (female genital organs, breasts, hypothalamus, pituitary) estrogens enter the cell and are transported into the nucleus. As a result of estrogen action, specific RNA and protein synthesis occurs.

Estrogen Pharmacokinetics

Metabolism and inactivation occur primarily in the liver. Some estrogens are excreted into the bile; however they are reabsorbed from the intestine and returned to the liver through the portal venous system. Water soluble esterified estrogens are strongly acidic and are ionized in body fluids, which favor excretion through the kidneys since tubular reabsorption is minimal.

Androgens

Endogenous androgens are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as beard, pubic, chest, and axillary hair, laryngeal enlargement, vocal cord thickening, alterations in body musculature, and fat distribution. Drugs in this class also cause retention of nitrogen, sodium, potassium, phosphorus, and decreased urinary excretion of calcium. Androgens have been reported to increase protein anabolism and decrease protein catabolism. Nitrogen balance is improved only when there is sufficient intake of calories and protein. Androgens are responsible for the growth spurt of adolescence and for the eventual termination of linear growth which is brought about by fusion of the epiphyseal growth centers. In children, exogenous androgens accelerate linear growth rates, but may cause a disproportionate advancement in bone maturation. Use over long periods may result in fusion of the epiphyseal growth centers and terminaton of growth process. Androgens have been reported to stimulate the production of red blood cells by enhancing the production of erythropoietic stimulating factor.

Androgen Pharmacokinetics

Testosterone given orally is metabolized by the gut and 44 percent is cleared by the liver in the first pass. Oral doses as high as 400 mg per day are needed to achieve clinically effective blood levels for full replacement therapy. The synthetic androgens (methyltestosterone and fluoxymesterone) are less extensively metabolized by the liver and have longer half-lives. They are more suitable than testosterone for oral administration.

Testosterone in plasma is 98 percent bound to a specific testosterone-estradiol binding globulin, and about 2 percent is free. Generally, the amount of this sex-hormone binding globulin in the plasma will determine the distribution of testosterone between free and bound forms, and the free testosterone concentration will determine its half-life.

About 90 percent of a dose of testosterone is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6 percent of a dose is excreted in the feces, mostly in the unconjugated form. Inactivation of testosterone occurs primarily in the liver. Testosterone is metabolized to various 17-keto steroids through two different pathways. There are considerable variations of the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes. In many tissues the activity of testosterone appears to depend on reduction to dihydrotestosterone, which binds to cytosol receptor proteins. The steroid receptor complex is transported to the nucleus where it initiates transcription events and cellular changes related to androgen action.

How Supplied / Storage and Handling

COVARYX® is a combination of Esterified Estrogens and Methyltestosterone. COVARYX® is supplied in bottles of 100 Tablets. Each light yellow, capsule-shaped, film coated tablet debossed "C010" on obverse and plain on the reverse contains 1.25 mg of Esterified Estrogens, USP and 2.5 mg of Methyltestosterone, USP (NDC 11528-010-01).

COVARYX® H.S. (Half-Strength) is a combination of Esterified Estrogens and Methyltestosterone. COVARYX® H.S. is supplied in bottles of 100 Tablets. Each light pink, capsule-shaped, film coated tablet debossed "C020" on obverse and plain on the reverse contains 0.625 mg of Esterified Estrogens, USP and 1.25 mg of Methyltestosterone, USP (NDC 11528-020-01).

Store at 20º-25ºC (68º-77ºF); excursions permitted to 15º-30ºC (59º-86ºF).
[See USP Controlled Room Temperature.]

Patient Counseling Information

INFORMATION FOR THE PATIENT1

WHAT YOU SHOULD KNOW ABOUT ESTROGENS

Estrogens are female hormones produced by the ovaries. The ovaries make several different kinds of estrogens. In addition, scientists have been able to make a variety of synthetic estrogens. As far as we know, all these estrogens have similar properties and therefore much the same usefulness, side effects, and risks. This leaflet is intended to help you understand what estrogens are used for, the risks involved in their use, and how to use them as safely as possible. This leaflet includes the most important information about estrogens, but not all the information. If you want to know more, you can ask your doctor or pharmacist to let you read the package insert prepared for the doctor.

USES OF ESTROGEN

Estrogens are prescribed by doctors for a number of purposes, including:

1. To provide estrogen during a period of adjustment when a woman's ovaries no longer produce it, in order to prevent certain uncomfortable symptoms of estrogen deficiency. (All women normally stop producing estrogens, generally between the ages of 45 and 55; this is called the menopause).
2. To prevent symptoms of estrogen deficiency when a woman's ovaries have been removed surgically before the natural menopause.
3. To prevent pregnancy. (Estrogens are given along with a progestogen, another female hormone; these combinations are called oral contraceptives or birth control pills. Patient labeling is available to women taking oral contraceptives and they will not be discussed in this leaflet.)
4. To treat certain cancers in women and men.

THERE IS NO PROPER USE OF ESTROGENS IN A PREGNANT WOMAN.

ESTROGENS IN THE MENOPAUSE

In the natural course of their lives, all women eventually experience a decrease in estrogen production. This usually occurs between ages 45 and 55 but may occur earlier or later. Sometimes the ovaries may need to be removed before narural menopause by an operation, producing a "surgical menopause."

When the amount of estrogen in the blood begins to decrease, many women may develop typical symptoms: Feelings of warmth in the face, neck, and chest of sudden intense episodes of heat and sweating throughout the body (called "hot flashes" or "hot flushes"). These symptoms are sometimes very uncomfortable. A few women eventually develop changes in the vagina (called "atrophic vaginitis") which cause discomfort, especially during and after intercourse.

Estrogens can be prescribed to treat these symptoms of the menopause. It is estimated that considerably more than half of all women undergoing the menopause have only mild symptoms or no symptoms at all and therefore do not need estrogens. Other women may need estrogens for a few months, while their bodies adjust to lower estrogen levels. Sometimes the need will be for periods longer than six months. In an attempt to avoid overstimulation of the uterus (womb), estrogens are usually given cyclically during each month of use, that is three weeks of pills followed by one week without pills.

Sometimes women experience nervous symptoms or depression during menopause. There is no evidence that estrogens are effective for such symptoms and they should not be used to treat them, although other treatment may be needed. You may have heard that taking estrogens for long periods (years) after the menopause will keep your skin soft and supple and keep you feeling young. There is no evidence that this is so, however, and such long-term treatment carries important risks.

THE DANGERS OF ESTROGENS

1.Cancer of the Uterus:

If estrogens are used in the postmenopausal period for more than a year, there is an increased risk of endometrial cancer (cancer of the uterus). Women taking estrogens have roughly 5 to 10 times as great a chance of getting this cancer as women who take no estrogens. To put this another way, while a postmenopausal woman not taking estrogens has 1 chance in 1,000 each year of getting cancer of the uterus, a woman taking estrogens has 5 to 10 chances in 1,000 each year.

For this reason it is important to take estrogens only when you really need them.

The risk of this cancer is greater the longer estrogens are used and also seems to be greater when larger doses are taken. For this reason, it is important to take the lowest dose of estrogen that will control symptoms and to take it only as long as it is needed. If estrogens are needed for longer periods of time, your doctor will want to reevaluate your need for estrogens at least every six months.

Women using estrogens should report any irregular vaginal bleeding to their doctors; such bleeding may be of no importance, but it can be an early warning of cancer of the uterus. If you have undiagnosed vaginal bleeding, you should not use estrogens until a diagnosis is made and you are certain there is no cancer of the uterus.

2.Other Possible Cancers: Estrogens can cause development of other tumors in animals, such as tumors of the breast, cervix, vagina, or liver, when given for a long time. This is a further reason to use estrogens only when clearly needed. While you are taking estrogens, it is important that you go to your doctor at least once a year for a physical examination. Also, if members of your family have had breast cancer or if you have breast nodules or abnormal mammograms (breast x-rays), your doctor may wish to carry out more frequent examinations of your breasts.

3.Gallbladder Disease: Women who use estrogens after menopause are more likely to develop gallbladder disease needing surgery as women who do not use estrogens. Birth control pills have a similar effect.

4.Abnormal Blood Clotting: Oral contraceptives increase the risk of blood clotting in various parts of the body. This can result in a stroke (if the clot is in the brain), a heart attack (clot in a blood vessel of the heart), or pulmonary embolus (a clot which forms in the legs or pelvis, then breaks off and travels to the lungs). Any of these can be fatal. At this time use of estrogens in the menopause is not known to cause such blood clotting, but this has not been fully studied and there could still prove to be such a risk. It is recommended that if you have had clotting in the legs or lungs or a heart attack or stroke while you were using estrogens or birth control pills, you should not use estrogens (unless they are being used to treat cancer of the breast or prostate). If you have had a stroke or heart attack or if you have angina pectoris, estrogens should be used with great caution and only if clearly needed (for example, if you have severe symptoms of the menopause). The larger doses of estrogen used to prevent swelling of the breasts after pregnancy have been reported to cause clotting in the legs and lungs.

5.Other Potential Risks: Using estrogens and progestins may increase your chances of getting heart attacks, strokes, breast cancer, or blood clots.

SPECIAL WARNING ABOUT PREGNANCY

You should not receive estrogen if you are pregnant. If this should occur, there is a greater than usual chance that the developing child will be born with a birth defect, although the possibility remains fairly small. A female child may have an increased risk of developing cancer of the vagina or cervix later in life (in the teens or twenties). Every possible effort should be made to avoid exposure to estrogens during pregnancy. If exposure occurs, see your doctor.

OTHER EFFECTS OF ESTROGENS

In addition to the serious known risks of estrogens described above, estrogens have the following side effects and potential risks:

1. Nausea and vomiting: The most common side effect of estrogen therapy is nausea. Vomiting is less common.
2. Effects on breasts: Estrogens may cause breast tenderness or enlargement and may cause the breasts to secrete a liquid. These effects are not dangerous.
3. Effects on the uterus: Estrogens may cause benign fibroid tumors of the uterus to get larger. Some women will have menstrual bleeding when estrogens are stopped. But if the bleeding occurs on days you are still taking estrogens you should report this to your doctor.
4. Effects on liver: Women taking oral contraceptives develop on rare occasions a benign tumor of the liver which can rupture and bleed into the abdomen. So far, these tumors have not been reported in women using estrogens in the menopause, but you should report any swelling or unusual pain or tenderness in the abdomen to your doctor immediately. Women with a past history of jaundice (yellowing of the skin and white parts of the eyes) may get jaundice again during estrogen use. If this occurs, stop taking estrogens and see your doctor.
5. Other effects: Estrogens may cause excess fluid to be retained in the body. This may make some conditions worse, such as epilepsy, migraine, heart disease, or kidney disease.

SUMMARY

Estrogens have important uses, but they have serious risks as well. You must decide, with your doctor, whether the risks are acceptable to you in view of the benefits of the treatment. Except where your doctor has prescribed estrogens for use in special cases of cancer of the breast or prostate, you should not use estrogens if you have cancer of the breast or uterus, are pregnant, have undiagnosed abnormal vaginal bleeding, or have had a stroke, heart attack or angina, or clotting in the legs or lungs in the past while you were taking estrogens.

You can use estrogens as safely as possible by understanding that your doctor will require regular physical examinations while you are taking them and will try to discontinue the drug as soon as possible and use the smallest dose possible. Be alert for signs of trouble including:

1. Abnormal bleeding from the vagina.
2. Pains in the calves or chest or sudden shortness of breath, or coughing blood (indicating possible clots in the legs, heart, or lungs).
3. Severe headache, dizziness, faintness, or changes in vision (indicating possible developing clots in the brain or eye).
4. Breast lumps (you should ask your doctor how to examine your own breasts).
5. Jaundice (yellowing of the skin).
6. Mental depression.

Based on his or her assessment of your medical needs, your doctor has prescribed this drug for you. Do not give the drug to anyone else.

1
This product has not obtained FDA pre-market approval applicable for new drugs.