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Dienestrol

Last reviewed on RxList: 1/29/2005
Discontinued Warning IconPlease Note: This Brand Name drug is no longer available in the US.
(Generic versions may still be available.)

Drug Description

Ortho* Dienestrol Cream
PHYSICIAN INFORMATION

DESCRIPTION

1. ESTROGENS HAVE BEEN REPORTED TO INCREASE THE RISK OF ENDOMETRIAL CARCINOMA.

Three independent case control studies have shown an increased risk of endometrial cancer in postmenopausal women exposed to exogenous estrogens for prolonged periods. 1-3 This risk was independent of the other known risk factors for endometrial cancer. These studies are further supported by the finding that incidence rates of endometrial cancer have increased sharply since 1969 in eight different areas of the United States with population-based cancer reporting systems, an increase which may berelated to the rapidly expanding use ofestrogens during the last decade. 4

The three case control studies reported that the risk of endometrial cancer in estrogen users was about 4.5 to 13.9 times greater than in nonusers. The risk appears to depend on both duration of treatment 1 and on estrogen dose.3 In view of these findings, when estrogens are used for the treatment of menopausal symptoms, the lowest dose that will control symptoms should be utilized and medication should be discontinued as soon as possible. When prolonged treatment is medically indicated, the patient should be reassessed on at least a semiannual basis to determine the need for continued therapy. Although the evidence must be considered preliminary, one study suggests that cyclic administration of low doses of estrogen may carry less risk than continuous administration; 3 it therefore appears prudent to utilize such a regimen.

Close clinical surveillance of all women taking estrogens is important. In all cases of undiagnosed persistent or recur-ring abnormal vaginal bleeding, adequate diagnostic measures should be undertaken to rule out malignancy.

There is no evidence at present that "natural" estrogens are more or less hazardous than "synthetic" estrogens at equiestrogenic doses.

2. ESTROGENS SHOULD NOT BE USED DURING PREGNANCY.

The use of female sex hormones, both estrogens and progestogens, during early pregnancy mayseriously damage the offspring. It has been shown that females exposed in utero to diethylstilbestrol, a non-sterodial estrogen, have an increased risk of developing in later life a form of vaginal or cervical cancer that ordinarily is extremely rare. 5,6 This risk has been estimated as not greater than 4 per 1,000 exposures. 7 Furthermore, a high percentage of such exposed women (from 30 to 90 percent) have been found to have vaginal adenosis, 8,13 epithelial changes of the vagina and cervix. Although these changes are histologically benign, it is not known whether they are precursors of malignancy. Although similar data are not available with the use ofother estrogens, it cannot be presumed they would not induce similar changes.

Several reports suggest an association between intra-uterine exposure to female sex hormones and congenital anomalies, including congenital heart defects and limb reduction defects. 13-16 One case control study16 estimated a 4.7 fold increased risk of limb reduction defects in infants exposed in utero to sex hormones (oral contraceptives, hormone withdrawal tests for pregnancy, or attempted treatment for threatened abortion). Some ofthese exposures were very short and involved only a few days of treatment. The data suggest that the risk of limb reduction defects in exposed fetuses is somewhat less than 1 per 1,000.

In the past, female sex hormones have been used during pregnancy in an attempt to treat threatened or habitual abortion. There is considerable evidence that estrogens are ineffective for these indications, and there is no evidence from well controlled studies that progestogens are effective for these uses.

If ORTHO Dienestrol Cream is used during pregnancy, or if the patient becomes pregnant while using this drug, she should be apprised of the potential risks to the fetus, and the advisability of pregnancy continuation.


ORTHO Dienestrol Cream
Cream for intravaginal use only

Active Ingredient: Dienestrol 0.01 % Dienestrol is a synthetic, non-steroidal estrogen. It is compounded in a cream base suitable for intravaginal use only. The cream base is composed of glyceryl monostearate, peanut oil, glycerin, benzoic acid, glutamic acid, butylated hydroxyanisole, citric acid, sodium hydroxide and water. The pH is approximately 4.3.

diene

For Consumers

What are the precautions when taking dienestrol (Dienestrol)?

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Indications & Dosage

INDICATIONS

ORTHO Dienestrol Cream is indicated in the treatment of atrophic vaginitis and kraurosis vulvae.

ORTHO DIENESTROL CREAM HAS NOT BEEN SHOWN TO BE EFFECTIVE FOR ANY PURPOSE DURING PREGNANCY AND ITS USE MAY CAUSE SEVERE HARM TO THE FETUS (SEE DESCRIPTION: BOXED WARNING)

DOSAGE AND ADMINISTRATION

Given cyclically for short term use only:

For the treatment of atrophic vaginitis, or kraurosis vulvae associated with the menopause.

The lowest dose that will control symptoms should be chosen and medication should be discontinued as promptlyas possible.

Attempts to discontinue or taper medication should be made at 3 to 6 month intervals.

The usual dosage range is one or two applicatorsful per day for one or two weeks, then gradually reduced to one half initial dosage for a similar period. A maintenance dosage of one applicatorful, one to three times a week, may be used after restoration of the vaginal mucosa has been achieved.

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.

HOW SUPPLIED

Available in 2.75 oz. (78g) tubes with or without ORTHO* Measured Dose Applicator, 5g.

    With applicator: NDC 0062-5450-77
    Without applicator: NDC 0062-5450-00

Store at controlled room temperature.

Side Effects & Drug Interactions

SIDE EFFECTS

(See WARNINGS regarding induction of neoplasia, adverse effects on the fetus, increased incidence of gall bladder 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.

    Increase in size of uterine fibromyomata.
    Vaginal candidiasis.
    Breakthrough bleeding, spotting, change in menstrual flow.
    Dysmenorrhea. Premenstrual-like syndrome.
    Amenorrhea during and after treatment.
    Change in cervical eversion and in degree of cervical secretion.
    Cystitis-like syndrome.

2. Breasts.

    Tenderness, enlargement, secretion.

3. Gastrointestinal.

    Cholestatic jaundice.
    Nausea, vomiting.
    Abdominal cramps, bloating.

4. Skin.

5. Eyes.

    Steepening of corneal curvature.
    Intolerance to contact lenses.

6. CNS.

7. Miscellaneous.

DRUG INTERACTIONS

Drug/ Laboratory Test Interactions

Certain endocrine and liver function tests may be affected by estrogen-containing 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 thyroid-binding globulin (TBG) leading to in-creased 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.
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You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.

Warnings & Precautions

WARNINGS

1. Induction of malignant neoplasms. Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, cervix, vagina, and liver. There is now evidence that estrogens increase the risk of carcinoma of the endometrium in humans. (See DESCRIPTION: BOXED WARNING)

At the present time there is no satisfactory evidence that estrogens given to postmenopausal women increase the risk of cancer of the breast, 18 although a recent long- term followup of a single physician's practice has raised this possibility. 18a Because of the animal data, there is a need for caution in pre-scribing breast cancer or who have breast nodules, fibrocystic disease, estrogens for women with a strong family history of or abnormal mammograms.

2. Gall bladder disease. Arecent study has reported a 2 to 3- fold increase in the risk of surgically confirmed gall bladder disease in women receiving postmenopausal estrogens, 18 similar tothe 2-fold increase previously noted in users of oral contracep-tives. 19-24 In the case of oral contraceptives the increased risk appeared after two years of use. 24

3. Effects similar to those caused by estrogen- progestogen oral contraceptives. There are several serious adverse effects of oral contraceptives, most ofwhich have not, up to now, been documented as consequences of postmenopausal estrogen therapy. This may reflect the comparatively low doses of estrogen used in postmenopausal women. It would be expected that the larger doses of estrogen used to treat prostatic or breast cancer or postpartum breast engorgement are more likely to result in these adverse effects, and in fact, it has been shown that there is an increased risk of thrombosis in men receiving estrogens for prostatic cancer and women for postpartum breast engorgement. 20-23

a. Thromboembolic disease. It is now well established that users of oral contraceptives have an increased risk of various thromboembolic and thrombotic vascular diseases, such as thrombophlebitis, pulmonary embolism, stroke, and myo-cardial infarction 24-31 Cases of retinal thrombosis, mesenteric thrombosis, and optic neuritis have been reported in oral contraceptive users. There is evidence that the risk of several ofthese adverse reactions is related tothe dose ofthe drug. 32-33 An increased risk of postsurgery thromboembolic complica-tions has also been reported in users of oral contraceptives. 34, 35 If feasible, estrogen should be discontinued at least 4 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

While an increased rate of thromboembolic and thrombotic disease in postmenopausal users of estrogens has not been found, 18-36 this does not rule out the possibility that such an increase may be present or that subgroupsof women who have underlying risk factors or who are receiving large doses of estrogens may have increased risk. Therefore estrogens should not be used in persons with activethrombophlebitis orthrombo-embolic disorders, and they should not be used (except in treatment of malignancy) in persons with a history of such disorders in association with estrogen use. They should be used with caution in patients with cerebral vascular or coronary artery disease and only for those in whom estrogens are clearly needed.

Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risk of nonfatal myocardial infarction, pulmonary embolism and thrombophlebitis. When estrogen doses of this size are used, any of the thromboembolic and thrombotic adverse effects associated with oral contraceptive use should be considered a clear risk.

b. Hepatic adenoma. Benign hepatic adenomas appear to be associated with the use of oral contraceptives. 38-40 Although benign, and rare, these may rupture and may cause death through intra-abdominal hemorrhage. Such lesions have not yet been reported in association with other estrogen or progestogen preparations but should be considered in estrogen users having abdominal pain and tenderness, abdominal mass, or hypovolemic shock. Hepatocellular carcinoma has also been reported in women taking estrogen- containing oral contraceptives. 39 The relationship of this malignancy to these drugs is not known at this time.

c. Elevated blood pressure. Increased blood pressure is not uncommon in women using oral contraceptives. There is now a report that this may also occur with the use of estrogens during menopause. 41 Blood pressure should be monitored with estrogen use, especially if high doses are used.

d. Glucose tolerance. A worsening of glucose tolerance has been observed in a significant percentage of patients on estrogen-containing oral contraceptives. For this reason, diabetic patients should be carefully observed while receiving estrogen.

4. Hypercalcemia. Administration of estrogens may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If this occurs, the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

PRECAUTIONS

General

  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 refer-ence to blood pressure, breasts, abdomen, and pelvic organs, and should include a Papanicolaou smear. As a general rule, estrogen should not be prescribed for longer than one year without another physical examination being performed.
  2. Fluid retention - Because estrogens may cause somedegree of fluid retention, conditions which might be influenced by this factor such as epilepsy, migraine, and cardiac or renal dys-function, 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 appearto be associated with an increased incidence of mental depression. 24Although it is notclear whether this is due tothe estrogenic or progestogenic component ofthe 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 ofestrogens on epiphyseal closure, theyshould be used judiciously in young patients in whom bone growth is not complete.
  11. The lowest effective dose appropriate for the specific indication should be utilized. Studies of the addition of a progestin for seven or more days of a cycle of estrogen administration have reported a lowered incidence of endo-metrial hyperplasia. Morphological and biochemical studies of endometrium suggest that 10 to 13 days of progestin are needed to provide maximal maturation of the endometrium and to eliminate any hyperplastic changes. Whether this will provide protection from endometrial carcinoma has not been clearly established. There are possible additional risks which may be associated with the inclusion of progestin in estrogen replacement regimens. The potential risks include adverse effects on carbohydrateand lipid metabolism. The choice of progestin and dosage may be important in minimizing these adverse effects.

Information for Patients

See text of Patient Package Information which is reproduced in PATIENT INFORMATION.

Carcinogenesis, Mutagenesis, Impairment of Fertility

See WARNINGS section for information on carcinogenesis, mutagenesis and impairment of fertility.

Pregnancy

Teratogenic Effects: Pregnancy Category X. See CONTRAINDICATIONS section.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugsare excreted in human milk, caution should be exercised when estrogens are administered to a nursing woman.

Overdosage & Contraindications

OVERDOSE

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.

CONTRAINDICATIONS

Estrogens may cause fetal harm when administered to a pregnant woman (see BOXED WARNING). Estrogens are contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while using this drug, the patient should be apprised of the potential hazard to the fetus.

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

  1. Known or suspected cancer of the breast.
  2. Known or suspected estrogen-dependent neoplasia.
  3. Undiagnosed abnormal genital bleeding.
  4. Active thrombophlebitis or thromboembolic disorders.
  5. A past history of thrombophlebitis, thrombosis, or thrombo-embolic disorders associated with previous estrogen use.
Clinical Pharmacology

CLINICAL PHARMACOLOGY

Systemic absorption and mode of action of dienestrol are undetermined.

Medication Guide

PATIENT INFORMATION

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 synthetic 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, some of the risks involved in their use, and to help minimize these risks.

This leaflet includes 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

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

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 decrease the production of 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.
  5. To prevent painful swelling of the breasts after pregnancy in women who choose not to nurse their babies.

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 by an operation before natural menopause, 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 or 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 over-stimulation 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.

ESTROGENS TO PREVENT SWELLING OF THE BREASTS AFTER PREGNANCY

If you do not breast-feed your baby after delivery, your breasts may fill up with milk and become painful and engorged. This usually begins about three to four days after delivery and may last for a few days to up to a week or more. Sometimes the discomfort is severe, but usually it is not and can be controlled by pain-relieving drugs such as aspirin and by binding the breasts up tightly. Estrogens can be used to try to prevent the breasts from filling up. While this treatment is sometimes successful, in many cases the breasts fill up to some degree in spite of treatment. The dose of estrogens needed to prevent pain and swelling of the breasts is much larger than the dose needed to treat symptoms of the menopause and this may increase your chances of developing blood clots in the legs or lungs (see below). Therefore, it is important that you discuss the benefits and the risks of estrogen use with your doctor if you have decided not to breast-feed your baby.

SOME OF THE DANGERS OF ESTROGENS (See WARNINGS)

1. Cancer of the uterus. If estrogens are used in the post-menopausal period for more than a year, there is an increased risk of endometrial cancer (cancer of the uterus). Women taking estrogens have roughly five to ten 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 one chance in 1,000 each year of getting cancer of the uterus, a woman taking estrogens has five to ten 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.

If you have had your uterus completely removed (total hysterectomy), there is no danger of developing 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. At present there is no good evidence that women using estrogen in the menopause have an increased risk of such tumors, but there is no way yet to be sure they do not; and one study raises the possibility that use of estrogens in the menopause may increase the risk of breast cancer many years later. 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 w.s. to carry out more frequent examinations of your breasts.

3. Gall bladder disease. Women who use estrogens after menopause are more likely to develop gall bladder disease needing surgery than women who do not use estrogens. Birth control pills have a similar effect.

4. Abnormal blood clotting. Oral contraceptives, some of which contain estrogens, 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 a 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. Blood clots may result in the loss of a limb, paralysis or loss of sight, depending on where the blood clot is formed or lodges if it breaks loose.

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.

It is recommended that if you have had any blood clotting disorders including clotting in the legs or lungs, or a heart attack or stroke, you should not use estrogens.

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.

SOME OTHER EFFECTS OF ESTROGENS

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

  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.
  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 estrogens develop on rare occasions a tumor of the liver which can rupture and bleed into the abdomen. 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.
  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.

If any of the above occur, stop taking estrogens and call your doctor.

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 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, blood clotting disorders including clotting in the legs or lungs, or have had a stroke, heart attack or angina.

You must understand 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. You can help minimize the risk by being 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.
  7. Any other unusual condition or problem.

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.

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