Covaryx

Covaryx is part of the drug classes:

• 3 oxoandrosten 4 derivatives

• Androgens and female sex hormones in combination with other drugs

Do not use this medication if you have any of the following conditions: liver disease, a recent history of heart attack, stroke or circulation problems, a hormone-related cancer such as breast or uterine cancer, abnormal vaginal bleeding, or if you are pregnant or breast-feeding. This medication should not be used to prevent heart disease or stroke.

This medication can cause birth defects in an unborn baby. Do not use if you are pregnant. Tell your doctor if you become pregnant during treatment.

Esterified estrogens and methyltestosterone increases your risk of developing endometrial hyperplasia, a condition that may lead to cancer of the uterus. Taking progestins while using esterified estrogens and methyltestosterone may lower this risk. If your uterus has not been removed, your doctor may prescribe a progestin for you to take while you are taking esterified estrogens and methyltestosterone.

Long-term esterified estrogens and methyltestosterone treatment may increase your risk of breast cancer, heart attack, or stroke. Talk with your doctor about your individual risks before using esterified estrogens and methyltestosterone long-term. Your doctor should check your progress on a regular basis (every 3 to 6 months) to determine whether you should continue this treatment.

Have regular physical exams and self-examine your breasts for lumps on a monthly basis while using esterified estrogens and methyltestosterone.

It is very important that your doctor check your progress at regular visits to make sure the medicine is working properly and to decide if you should continue to take it. These visits should be every 6 to 12 months or as otherwise directed by your doctor.

It is unlikely that a postmenopausal woman may become pregnant. But, you should know that using this medicine while you are pregnant could harm your unborn baby. If you think you have become pregnant while using the medicine, tell your doctor right away.

Very rarely, this medicine can cause serious side effects such as a heart attack or stroke. You are much more likely to have these side effects if you smoke cigarettes or are overweight, or if you have diabetes, high blood pressure, or a high blood cholesterol. Talk with your doctor if you think you might be at risk.

Using large doses of estrogen alone over a long period of time may increase the risk of some kinds of cancer (e.g., endometrial cancer). Talk with your doctor about this risk. If you have vaginal bleeding with this medicine, call your doctor right away.

This medicine may increase the risk of getting breast cancer. It is very important that you check your breasts on a regular basis for any unusual lumps or discharge, and that you have breast x-rays every year as directed by your doctor. These exams are very important if you have a family member with a history of breast cancer. Talk with your doctor about this risk.

This medicine may increase the risk of getting dementia in elderly women (above 65 years of age). Talk with your doctor if this concerns you.

Check with your doctor right away if blurred vision, difficulty with reading, or any other change in vision occurs during or after treatment. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

Using large doses of methyltestosterone over a long period of time may increase the risk of serious liver problems (e.g., peliosis hepatis or liver cancer). Talk with your doctor about this risk.

Before you have any medical tests, tell the medical doctor in charge that you are taking this medicine. The results of some tests may be affected by this medicine. Also, you may need to stop using this medicine for a few weeks before and after having surgery, or if you are inactive for a long period of time.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

• Absent, missed, or irregular menstrual periods
• acne or oily skin
• decreased breast size
• enlarging clitoris
• hoarseness or deepening of the voice
• menstrual changes
• stopping of menstrual bleeding
• unnatural hair growth or loss

Rare

• Continuing nausea
• cough
• dark-colored urine
• difficulty with swallowing
• dizziness
• fast heartbeat
• fever
• hives
• itching
• light-colored stools
• loss of appetite
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• purple or red-colored spots on the body or inside the mouth or nose
• shortness of breath
• skin rash
• sore throat
• tightness in the chest
• unusual tiredness or weakness
• vomiting
• wheezing

Incidence not known

• Abdominal or stomach bloating, cramps, or pain
• anxiety
• bleeding from gums or nose
• blistering, peeling, or loosening of the skin
• bloating
• bloody or cloudy urine
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• change in vaginal discharge
• changes in skin color, pain, or tenderness
• chest pain or discomfort
• chills
• clay-colored stools
• clear or bloody discharge from nipple
• confusion
• constipation
• convulsions
• darkening of urine
• decrease in amount of urine
• diarrhea
• difficult, burning, or painful urination
• difficulty with breathing
• difficulty with moving
• difficulty with speaking
• dimpling of the breast skin
• dizziness or lightheadedness
• double vision
• eye pain
• fainting
• fever
• fluid-filled skin blisters
• frequent urge to urinate
• headache
• heavy bleeding
• inability to move the arms, legs, or facial muscles
• inability to speak
• indigestion
• inverted nipple
• irregular heartbeats
• itching of the vagina or genital area
• joint or muscle pain
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• light-colored stools
• loss of appetite
• lump in the breast or under the arm
• mood or mental changes
• muscle cramps in the hands, arms, feet, legs, or face
• muscle pain or stiffness
• nausea
• noisy, rattling breathing
• numbness and tingling around the mouth, fingertips, or feet
• pain
• pain during sexual intercourse
• pain in the ankles or knees
• pain or discomfort in the arms, jaw, back, or neck
• pain or feeling of pressure in pelvis
• painful, red lumps under the skin, mostly on the legs
• pains in the stomach, side, or abdomen, possibly radiating to the back
• pelvic pain
• persistent crusting or scaling of the nipple
• pinpoint red or purple spots on the skin
• poor insight and judgment problems with memory or speech
• red, irritated eyes
• redness or swelling of the breast
• ringing in the ears
• sensitivity to the sun
• shortness of breath
• skin thinness
• slow speech
• sore on the skin of the breast that does not heal
• sore throat
• sores, ulcers, or white spots in the mouth or on the lips
• stomach pain
• sudden shortness of breath or troubled breathing
• sweating
• swelling
• swelling of the fingers, hands, feet, or lower legs
• tenderness of the breast
• thick, white curd-like vaginal discharge without odor or with mild odor
• tiredness
• tremor
• trouble recognizing objects
• trouble thinking and planning
• trouble walking
• troubled breathing at rest
• unexpected or excess milk flow from breasts
• unpleasant breath odor
• vaginal bleeding
• vision changes
• vomiting of blood
• weakness
• weight gain
• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Incidence not known

• Blemishes on the skin
• brown, blotchy spots on the exposed skin
• decreased interest in sexual intercourse
• depression
• headache, severe and throbbing
• inability to have or keep an erection
• increase or decrease in weight
• increased hair growth, especially on the face
• increased in sexual ability, desire, drive, or performance
• increased interest in sexual intercourse
• irritability
• leg cramps
• loss in sexual ability, desire, drive, or performance
• loss of hair
• mental depression
• pimples
• redness of the skin
• swelling or inflammation of the mouth
• twitching, uncontrolled movements of the tongue, lips, face, arms, or legs

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

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).

Associated with Estrogens

General Precautions

1. A complete medical and family history should be taken prior to the initiation of any estrogen therapy. The pretreatment and periodic physical examinations should include special reference to blood pressure, breasts, abdomen, and pelvic organs, and should include a Papanicolaou smear. As a general rule, estrogens should not be prescribed for longer than one year without another physical examination being performed.
2. Fluid retention-Because estrogens may cause some degree of fluid retention, conditions which might be influenced by this factor such as asthma, epilepsy, migraine, and cardiac or renal dysfunction, require careful observation.
3. Certain patients may develop undesirable manifestations of excessive estrogenic stimulation, such as abnormal or excessive uterine bleeding, mastodynia, etc.
4. Oral contraceptives appear to be associated with an increased incidence of mental depression.24 Although it is not clear whether this is due to the estrogenic or progestogenic component of the contraceptive, patients with a history of depression should be carefully observed.
5. Preexisting uterine leiomyomata may increase in size during estrogen use.
6. The pathologist should be advised of estrogen therapy when relevant specimens are submitted.
7. Patients with a past history of jaundice during pregnancy have an increased risk of recurrence of jaundice while receiving estrogen containing oral contraceptive therapy. If jaundice develops in any patient receiving estrogen, the medication should be discontinued while the cause is investigated.
8. Estrogens may be poorly metabolized in patients with impaired liver function and they should be administered with caution in such patients.
9. Because estrogens influence the metabolism of calcium and phosphorus, they should be used with caution in patients with metabolic bone diseases that are associated with hypercalcemia or in patients with renal insufficiency.
10. Because of the effects of estrogens on epiphyseal closure, they should be used judiciously in young patients in whom bone growth is not complete.
11. Certain endocrine and liver function tests may be affected by estrogen-containng oral contraceptives. The following similar changes may be expected with larger doses of estrogen:
    1. Increased sulfobromophthalein retention.
    2. Increased prothrombin and factors VII, VIII, IX and X; decreased antithrombin 3: increased norepinephrine induced platelet aggregability.
    3. Increased thyroxine-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by PBI, T4 by column, or T4 by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG; free T4 concentration is unaltered.
    4. Impaired glucose tolerance.
    5. Decreased pregnanediol excretion.
    6. Reduced response to metyrapone test.
    7. Reduced serum folate concentration.
    8. Increased serum triglyceride and phospholipid concentration.

Information for the Patient

(See INFORMATION FOR PATIENT after REFERENCES).

Pregnancy Category X

(See CONTRAINDICATIONS and BOXED WARNINGS).

Nursing Mothers

As a general principle, the administration of any drug to nursing mothers should be done only when clearly necessary since many drugs are excreted in human milk.

Associated with Methyltestosterone

General Precautions

1. Women should be observed for signs of virilization (deepening of the voice, hirsutism, acne, clitoromegaly, and menstrual irregularities). Discontinuation of drug therapy at the time of evidence of mild virilism is necessary to prevent irreversible virilization. Such virilization is usual following androgen use at high doses.
2. Prolonged dosage of androgen may result in sodium and fluid retention. This may present a problem, especially in patients with compromised cardiac reserve or renal disease.
3. Hypersensitivity may occur rarely.
4. PBI may be decreased in patients taking androgens.
5. Hypercalcemia may occur. If this does occur, the drug should be discontinued.

Information for the Patient

The physician should instruct patients to report any of the following side effects of androgens

Women: Hoarseness, acne, changes in menstrual periods, or more hair on the face.

All Patients: Any nausea, vomiting, changes in skin color or ankle swelling.

Laboratory Tests

1. Women with disseminated breast carcinoma should have frequent determination of urine and serum calcium levels during the course of androgen therapy (See WARNINGS).
2. Because of the hepatotoxicity associated with the use of 17-alpha alkylated androgens, liver function tests should be obtained periodically.
3. Hemoglobin and hematocrit should be checked periodically for polycythemia in patients who are receiving high doses of androgens.

Drug Interactions

1. Anticoagulants: C-17 substituted derivatives of testosterone, such as methandrostenolone, have been reported to decrease the anticoagulant requirements of patients receiving oral anticoagulants. Patients receiving oral anticoagulant therapy require close monitoring, especially when androgens are started or stopped.
2. Oxyphenbutazone: Concurrent administration of oxyphenbutazone and androgens may result in elevated serum levels of oxyphenbutazone.
3. Insulin: In diabetic patients, the metabolic effects of androgens may decrease blood glucose and insulin requirements.

Drug/Laboratory Test Interferences

Androgens may decrease levels of thyroxine-binding globulin, resulting in decreased T4 serum levels and increased resin uptake of T3 and T4. Free thyroid hormone levels remain unchanged, however, and there is no clinical evidence of thyroid dysfunction.

Carcinogenesis

Animal Data

Testosterone has been tested by subcutaneous injection and implantation in mice and rats. The implant induced cervical- uterine tumors in mice, which metastasized in some cases. There is suggestive evidence that injection of testosterone into some strains of female mice increases their susceptibility to hepatoma. Testosterone is also known to increase the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver in rats.

Human Data

There are rare reports of hepatocellular carcinoma in patients receiving long-term therapy with androgens in high doses. Withdrawal of the drugs did not lead to regression of the tumors in all cases. Geriatric patients treated with androgens may be at increased risk for the development of prostatic hypertrophy and prostatic carcinoma.

Pregnancy

Teratogenic Effects

Pregnancy Category X

(See CONTRAINDICATIONS).

Nursing Mothers

It is not known whether androgens are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from androgens, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

1. Ziel HK, et al. N Engl J Med. 1975;293:1167-1170.
2. Smith DC, et al. N Engl J Med. 1975;293:1164-1167.
3. Mack TM, et al. N Engl J Med. 1976;294:1262-1267.
4. Weiss NS, et al. N Engl J Med. 1976;294:1259-1262.
5. Herbst AL, et al. N Engl J Med. 1971;284:878-881.
6. Greenwald P, et al. N Engl J Med. 1971;285:390-392.
7. Lanier A, et al. Mayo Clin Proc. 1973;48:793-799.
8. Herbst A, et al. Obstet Gynecol. 1972;40:287-298.
9. Herbst A, et al. Am J Obstet Gynecol. 1974;118:607-615.
10. Herbst A, et al. N Engl J Med. 1975;292:334-339.
11. Stafl A, et al. Obstet Gynecol. 1974;43:118-128.
12. Sherman Al, et al. Obstet Gynecol. 1974;44:531-545.
13. Gal l, et al. Nature. 1967;216:83.
14. Levy EP, et al. Lancet. 1973;1:611.
15. Nora J, et al. Lancet. 1973;1:941-942.
16. Janerich DT, et al. N Engl J Med. 1974;291:697-700.
17. Boston Collaborative Drug Surveillance Program. N Engl J Med. 1974;290:15-19.
18. Hoover R, et al. N Engl J Med. 1976;295:401-405.
19. Boston Collaborative Drug Surveillance Program. Lancet.1973;1:1399-1404.
20. Daniel DG, et al. Lancet. 1967;2:287-289.
21. The Veterans Administration Cooperative Urological Research Group. J Urol. 1967;98:516-522.
22. Bailar JC, Lancet. 1967;2:560.
23. Blackard C, et al. Cancer. 1970;26:249-256.
24. Royal College of General Practitioners: J Coll Gen Practit. 1967;13:267-279.
25. Inman WHW, et al. Br Med J. 1968;2:193-199.
26. Vessey MP, et al. Br Med J. 1969;2:651-657.
27. Sartwell PE, et al. Am J Epidemiol. 1969;90:365-380.
28. Collaborative Group for the Study of Stroke in Young Women. N Engl J Med. 1973;288:871-878.
29. Collaborative Group for the Study of Stroke in Young Women. JAMA. 1975;231:718-722.
30. Mann Jl, et al. Br Med J. 1975;2:245-248.
31. Mann Jl. et al. Br Med J. 1975;2:241-245.
32. Inman WHW, et al. Br Med J. 1970;2:203-209.
33. Stolley PD, et al. Am J Epidemiol. 1975;102:197-208.
34. Vessey MP, et al. Br Med J. 1970;3:123-126.
35. Greene GR, et al. Am J Public Health. 1972;62:680-685.
36. Rosenberg L. et al. N Engl J Med. 1976;294:1256-1259.
37. Coronary Drug Project Research Group. JAMA. 1970;214:1303-1313.
38. Baum J, et al. Lancet. 1973;2:926-928.
39. Mays ET, et al. JAMA. 1976;235:730-732.
40. Edmondson HA, et al. N Engl J Med. 1976;294:470-472.
41. Pfeffer RI, et al. Am J Epidemiol. 1976;103:445-456.

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.

NDC 11528-010-01

Covaryx™
(esterified estrogens and
methyltestosterone tablets,
1.25mg/2.5mg)

Rx Only
100 Tablets

CP™ CENTRIX®
PHARMACEUTICAL, INC.

Applies to esterified estrogens / methyltestosterone: oral tablet

Along with its needed effects, esterified estrogens / methyltestosterone may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking esterified estrogens / methyltestosterone:

More common

• Absent, missed, or irregular menstrual periods
• acne or oily skin
• decreased breast size
• enlarging clitoris
• hoarseness or deepening of the voice
• menstrual changes
• stopping of menstrual bleeding
• unnatural hair growth or loss

Rare

• Continuing nausea
• cough
• dark-colored urine
• difficulty with swallowing
• dizziness
• fast heartbeat
• fever
• hives
• itching
• light-colored stools
• loss of appetite
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• purple or red-colored spots on the body or inside the mouth or nose
• shortness of breath
• skin rash
• sore throat
• tightness in the chest
• unusual tiredness or weakness
• vomiting
• wheezing

Incidence not known

• Abdominal or stomach bloating, cramps, or pain
• anxiety
• bleeding from gums or nose
• blistering, peeling, or loosening of the skin
• bloating
• bloody or cloudy urine
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• change in vaginal discharge
• changes in skin color, pain, or tenderness
• chest pain or discomfort
• chills
• clay-colored stools
• clear or bloody discharge from nipple
• confusion
• constipation
• convulsions
• darkening of urine
• decrease in amount of urine
• diarrhea
• difficult, burning, or painful urination
• difficulty with breathing
• difficulty with moving
• difficulty with speaking
• dimpling of the breast skin
• dizziness or lightheadedness
• double vision
• eye pain
• fainting
• fever
• fluid-filled skin blisters
• frequent urge to urinate
• headache
• heavy bleeding
• inability to move the arms, legs, or facial muscles
• inability to speak
• indigestion
• inverted nipple
• irregular heartbeats
• itching of the vagina or genital area
• joint or muscle pain
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• light-colored stools
• loss of appetite
• lump in the breast or under the arm
• mood or mental changes
• muscle cramps in the hands, arms, feet, legs, or face
• muscle pain or stiffness
• nausea
• noisy, rattling breathing
• numbness and tingling around the mouth, fingertips, or feet
• pain
• pain during sexual intercourse
• pain in the ankles or knees
• pain or discomfort in the arms, jaw, back, or neck
• pain or feeling of pressure in pelvis
• painful, red lumps under the skin, mostly on the legs
• pains in the stomach, side, or abdomen, possibly radiating to the back
• pelvic pain
• persistent crusting or scaling of the nipple
• pinpoint red or purple spots on the skin
• poor insight and judgment problems with memory or speech
• red, irritated eyes
• redness or swelling of the breast
• ringing in the ears
• sensitivity to the sun
• shortness of breath
• skin thinness
• slow speech
• sore on the skin of the breast that does not heal
• sore throat
• sores, ulcers, or white spots in the mouth or on the lips
• stomach pain
• sudden shortness of breath or troubled breathing
• sweating
• swelling
• swelling of the fingers, hands, feet, or lower legs
• tenderness of the breast
• thick, white curd-like vaginal discharge without odor or with mild odor
• tiredness
• tremor
• trouble recognizing objects
• trouble thinking and planning
• trouble walking
• troubled breathing at rest
• unexpected or excess milk flow from breasts
• unpleasant breath odor
• vaginal bleeding
• vision changes
• vomiting of blood
• weakness
• weight gain
• yellow eyes or skin

Some side effects of esterified estrogens / methyltestosterone may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Incidence not known

• Blemishes on the skin
• brown, blotchy spots on the exposed skin
• decreased interest in sexual intercourse
• depression
• headache, severe and throbbing
• inability to have or keep an erection
• increase or decrease in weight
• increased hair growth, especially on the face
• increased in sexual ability, desire, drive, or performance
• increased interest in sexual intercourse
• irritability
• leg cramps
• loss in sexual ability, desire, drive, or performance
• loss of hair
• mental depression
• pimples
• redness of the skin
• swelling or inflammation of the mouth
• twitching, uncontrolled movements of the tongue, lips, face, arms, or legs

Applies to esterified estrogens / methyltestosterone: oral tablet

Cardiovascular

Cardiovascular side effects have included increased risks of myocardial infarction, pulmonary embolism, deep and superficial venous thrombosis, stroke, and increased blood pressure.[Ref]

Oncologic

Oncologic side effects have included increase risk of breast cancer[Ref]

Genitourinary

Genitourinary side effects have included changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, dysmenorrhea, increase in size of uterine leiomyomata, vaginitis, including vaginal candidiasis, change in amount of cervical secretion, changes in cervical ectropion, ovarian cancer, endometrial hyperplasia, endometrial cancer, and cystitis-like syndrome. Side effects involving the breasts have included tenderness, enlargement, pain, nipple discharge, galactorrhea, and fibrocystic breast changes. Side effects of androgen therapy are amenorrhea and other menstrual irregularities, and virilization, including deepening of the voice and clitoral enlargement. The latter usually is not reversible after androgens are discontinued.[Ref]

Gastrointestinal

Gastrointestinal side effects have included nausea, vomiting, abdominal cramps, bloating, cholestatic jaundice, increased incidence of gallbladder disease, pancreatitis, and enlargement of hepatic hemangiomas. Additional side effects have included alterations in liver function test, rarely hepatocellular neoplasms, and peliosis hepatis.[Ref]

Dermatologic

Dermatologic side effects have included chloasma or melasma that may persist when drug is discontinued, erythema multiforme, erythema nodosum, hemorrhagic eruption, loss of scalp hair, hirsutism, pruritus, acne, and rash.[Ref]

Ocular

Ocular side effects have included retinal vascular thrombosis, steepening of corneal curvature, and intolerance to contact lenses.[Ref]

Nervous system

Nervous system side effects have included headache, migraine, dizziness, mental depression, chorea, nervousness, mood disturbances, irritability, exacerbation of epilepsy, and dementia. Additional side effects have included increased or decreased libido, headache, anxiety, depression, and generalized paresthesia.[Ref]

Hematologic

Hematologic side effects have included suppression of clotting factors II, V, VII, and X, bleeding in patients on concomitant anticoagulant therapy, polycythemia, and aggravation of porphyria.[Ref]

Hypersensitivity

Hypersensitivity side effects have included urticaria, angioedema, and anaphylactoid/anaphylactic reactions.[Ref]

Respiratory

Respiratory side effects have included exacerbation of asthma.[Ref]

General

General side effects have included increase or decrease in weight, edema, arthralgias, and leg cramps.[Ref]

Metabolic

Metabolic side effects have included reduced carbohydrate tolerance, increased serum cholesterol, retention of sodium, chloride, water, potassium, calcium, and inorganic phosphates.[Ref]

Some side effects of Covaryx may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.