Activella

Name: Activella

Uses of Activella

  • It is used to put off soft, brittle bones (osteoporosis) in women after change of life.
  • It is used to prevent or lower the signs of the change of life (menopause).
  • It may be given to you for other reasons. Talk with the doctor.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
  • Chest pain or pressure.
  • Shortness of breath.
  • Coughing up blood.
  • Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
  • Swelling, warmth, numbness, change of color, or pain in a leg or arm.
  • Very bad headache.
  • Very upset stomach or throwing up.
  • Very bad belly pain.
  • Very bad dizziness or passing out.
  • Change in eyesight.
  • Bulging eyes.
  • Change in how contact lenses feel in the eyes.
  • A lump in the breast, breast soreness, or nipple discharge.
  • Breast pain.
  • Vaginal itching or discharge.
  • Vaginal bleeding that is not normal.
  • Low mood (depression).
  • Memory problems or loss.
  • Swelling.

Contraindications

: Activella is contraindicated in women with any of the following conditions:

  • Undiagnosed abnormal genital bleeding
  • Known, suspected, or history of breast cancer
  • Known, past or suspected estrogen-dependent neoplasia
  • Active DVT, PE, or history of these conditions
  • Active arterial thromboembolic disease (for example stroke and MI), or a history of these conditions
  • Known anaphylactic reaction or angioedema or hypersensitivity to Activella
  • Known liver impairment or disease
  • Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disordersKnown protein C, protein S, or antithrombin deficiency, or other known thrombophilic disordersKnown protein C, protein S, or antithrombin deficiency, or other known thrombophilic disordersKnown protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders
  • Known or suspected pregnancy

Activella - Clinical Pharmacology

Mechanism of Action

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

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

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

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

Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, and central nervous system.

Pharmacodynamics

There are no pharmacodynamic data known for Activella tablets.

Pharmacokinetics

Absorption

Estradiol

Estradiol is absorbed through the gastrointestinal tract. Following oral administration of Activella tablets, peak plasma estradiol concentrations are reached within 5 to 8 hours. The oral bioavailability of estradiol following administration of Activella 1 mg/0.5 mg when compared to a combination oral solution is 53%. Administration of Activella 1 mg/0.5 mg with food did not modify the bioavailability of estradiol.

Norethindrone Acetate

After oral administration, norethindrone acetate is absorbed and transformed to norethindrone. Norethindrone reaches a peak plasma concentration within 0.5 to 1.5 hours after the administration of Activella tablets. The oral bioavailability of norethindrone following administration of Activella 1 mg/0.5 mg when compared to a combination oral solution is 100%. Administration of Activella 1 mg/0.5 mg with food increases norethindrone AUC 0-72 by 19% and decreases C max by 36%.

The pharmacokinetic parameters of estradiol (E 2), estrone (E 1), and norethindrone (NET) following oral administration of 1 Activella 1 mg/0.5 mg or 2 Activella 0.5 mg/0.1 mg tablet(s) to healthy postmenopausal women are summarized in Table 3.

TABLE 3 PHARMACOKINETIC PARAMETERS AFTER ADMINISTRATION OF 1 TABLET OF Activella 1 MG/0.5 MG OR 2 TABLETS OF Activella 0.5 MG/0.1 MG TO HEALTHY POSTMENOPAUSAL WOMEN

* geometric mean † geometric % coefficient of variation ‡ baseline unadjusted data § baseline unadjusted data  ¶ n=18 # n=16 Þ n=13 ß n=22 à n=21

1 x Activella

1 mg/0.5 mg

(n=24)

2 x Activella

0.5 mg/0.1 mg

(n=24)

Mean * (%CV) †

Mean * (%CV) †

Estradiol‡ (E 2)

AUC 0-t (pg/mL*h)

766.5 (48)

697.3 (53)

C max (pg/mL)

26.8 (36)

26.5 (37)

t max (h): median (range)

6.0 (0.5-16.0)

6.5 (0.5-16.0)

t 1/2 (h) §

14.0 ¶ (29)

14.5 # (27)

Estrone‡ (E 1)

AUC 0-t (pg/mL*h)

4469.1 (48)

4506.4 (44)

C max (pg/mL)

195.5 (37)

199.5 (30)

t max (h): median (range)

6.0 (1.0-9.0)

6.0 (2.0-9.0)

t 1/2 (h) § 

10.7 (44) Þ

11.8 (25) Þ

Norethindrone (NET)

AUC 0-t (pg/mL*h)

21043 (41)

8407.2 (43)

C max (pg/mL)

5249.5 (47)

2375.4 (41)

t max (h) : median (range)

0.7 (0.7-1.25)

0.8 (0.7-1.3)

t 1/2 (h)

9.8 (32) ß

11.4 (36) à

AUC = area under the curve, 0 – last quantifiable sample

C max = maximum plasma concentration,

t max = time at maximum plasma concentration,

t 1/2 = half-life

Following continuous dosing with once-daily administration of Activella 1 mg/0.5 mg, serum concentrations of estradiol, estrone, and norethindrone reached steady-state within two weeks with an accumulation of 33 to 47% above concentrations following single dose administration. Unadjusted circulating concentrations of E 2, E 1, and NET during Activella 1 mg/0.5 mg treatment at steady state (dosing at time 0) are provided in Figures 1a and 1b.

Figure 1a: Mean Baseline-Uncorrected Estradiol and Estrone Serum Concentration-Time Profiles Following Multiple Doses of Activella 1 mg/0.5 mg (N=24)

Distribution

Estradiol

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estradiol circulates in the blood bound to SHBG (37%) and to albumin (61%), while only approximately 1 to 2% is unbound.

Norethindrone Acetate

Norethindrone also binds to a similar extent to SHBG (36%) and to albumin (61%).

Metabolism

Estradiol

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

Norethindrone Acetate

The most important metabolites of norethindrone are isomers of 5α-dihydro-norethindrone and tetrahydro-norethindrone, which are excreted mainly in the urine as sulfate or glucuronide conjugates.

Excretion

Estradiol

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. The half-life of estradiol following single dose administration of Activella 1 mg/0.5 mg is 12 to 14 hours.

Norethindrone Acetate

The terminal half-life of norethindrone is about 8 to 11 hours.

Use in Specific Populations

No pharmacokinetic studies were conducted in specific populations, including women with renal or hepatic impairment.

Activella Drug Class

Activella is part of the drug class:

  • Progestogens and estrogens, fixed combinations

Side Effects of Activella

Serious side effects have been reported with Activella. See the “Activella Precautions” section.

Common side effects of Activella include:

  • headache
  • breast pain
  • irregular vaginal bleeding or spotting
  • stomach or abdominal cramps, bloating
  • nausea and vomiting
  • hair loss
  • fluid retention
  • vaginal yeast infection

This is not a complete list of Activella side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

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

Activella Precautions

Serious side effects have been reported with Activella including the following:

  • heart attack
  • stroke
  • blood clots
  • dementia
  • breast cancer
  • cancer of the lining of the uterus (womb)
  • cancer of the ovary
  • high blood pressure
  • high blood sugar
  • gallbladder disease
  • liver problems
  • changes in your thyroid hormone levels
  • enlargement of benign tumors (“fibroids”)

Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:

  • new breast lumps
  • unusual vaginal bleeding
  • changes in vision or speech
  • sudden new severe headaches
  • severe pains in your chest or legs with or without shortness of breath, weakness and fatigue

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

  • Talk with your healthcare provider regularly about whether you should continue taking Activella.
  • If you have a uterus, talk with your healthcare provider about whether the addition of a progestin is right for you.
  • The addition of a progestin is generally recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus (womb).
  • See your healthcare provider right away if you get vaginal bleeding while taking Activella.
  • Have a pelvic exam, 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 (breast x-ray), 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.

Do not take Activella if you:

  • are allergic to Activella or any of its components
  • have had your uterus (womb) removed (hysterectomy)
  • have unusual vaginal bleeding
  • currently have or have had certain cancers
  • had a stroke or heart attack
  • currently have or have had blood clots
  • currently have or have had liver problems
  • have been diagnosed with a bleeding disorder
  • think you may be pregnant

Activella and Lactation

Tell your doctor if you are breastfeeding or plan to breastfeed.

Activella should not be used while nursing. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogen and progestin have been identified in the breast milk of women receiving estrogen plus progestin therapy. Caution should be exercised when Activella is administered to a nursing woman.

Activella Dosage

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

  • the condition being treated
  • how you respond to this medication

The recommended doses of Activella are as follows:

  • to reduce moderate to severe hot flashes or to help reduce your chances of getting osteoporosis (thin weak bones): Activella 1 mg/0.5 mg or Activella 0.5 mg/0.1 mg tablet taken once daily
  • to treat moderate to severe menopausal changes in and around the vagina: Activella 1 mg/0.5 mg tablet taken once daily

Drug Interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking any of these medicines, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using medicines in this class with any of the following medicines is not recommended. Your doctor may decide not to treat you with a medication in this class or change some of the other medicines you take.

  • Boceprevir
  • Dasabuvir
  • Ombitasvir
  • Paritaprevir
  • Ritonavir
  • Tranexamic Acid

Using medicines in this class with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Anagrelide
  • Boceprevir
  • Bupropion
  • Carbamazepine
  • Ceritinib
  • Clozapine
  • Conivaptan
  • Dabrafenib
  • Darunavir
  • Dasabuvir
  • Donepezil
  • Eliglustat
  • Idelalisib
  • Isotretinoin
  • Lesinurad
  • Lixisenatide
  • Lumacaftor
  • Paclitaxel
  • Paclitaxel Protein-Bound
  • Piperaquine
  • Pirfenidone
  • Pitolisant
  • Pixantrone
  • Sugammadex
  • Theophylline
  • Tizanidine
  • Ulipristal

For Healthcare Professionals

Applies to conjugated estrogens / medroxyprogesterone: oral tablet

General

General side effects have included headache (28% to 36%), abdominal pain (16% to 23%), asthenia (6% to 10%), back pain (13% to 16%), and flu-like symptoms (10% to 13%), pelvic pain (4% to 5%), infection (14% to 18%), and generalized pain (11% to 13%).[Ref]

The manufacturer recommends close observation if conjugated estrogens must be used in patients who may be particularly sensitive to fluid retention because of underlying asthma, epilepsy, migraine, heart disease, and renal dysfunction.[Ref]

Metabolic

Metabolic side effects of estrogen have included increased serum triglyceride levels resulting in pancreatitis in patients with familial lipoprotein metabolic defects. However, metabolic effects in patients treated with conjugated estrogens include generally favorable alterations in plasma lipid profiles. Specifically, increased HDL and decreased cholesterol and LDL levels occur.

Metabolic side effects of medroxyprogesterone have included weight changes (increases and decreases), glucose intolerance, and changes in serum cholesterol concentrations.[Ref]

Weight gain is more frequently encountered than weight loss during medroxyprogesterone therapy. In women using intramuscular medroxyprogesterone for contraception, the mean weight gain after one year of therapy is 2.5 kg. After two, four, and six years, patients gain a mean of 3.7, 6.3, and 7.5 kg, respectively.

Data regarding the effect of medroxyprogesterone on lipid profiles have been conflicting. Some studies report possible negative effects on lipid profiles while others have documented a reduction in total and low density lipoprotein cholesterol and an increase in high density lipoprotein cholesterol levels.[Ref]

Cardiovascular

Cardiovascular side effects of estrogens have included increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism.

Cardiovascular side effects of medroxyprogesterone have included thromboembolic disorders such as thrombophlebitis, deep vein thrombosis, pulmonary embolism, cerebrovascular accidents, and retinal thrombosis. In addition, edema, hypertension, tachycardia, and syncope have been reported. Because medroxyprogesterone can cause edema, it should be used cautiously in patients with underlying disease (like migraine headaches, asthma, heart disease, renal dysfunction, or seizure disorders) which may be exacerbated by edema or fluid retention.[Ref]

Oncologic

A number of studies have suggested that the risk of endometrial carcinoma is removed (or delayed) by the administration of progestins in combination with estrogen therapy.

The risk of breast cancer due to use of conjugated estrogens is controversial. Meta analysis of epidemiological data supports a modest risk increase associated with long-term hormone replacement therapy (HRT).

A study of Swedish women has reported that a 10% increase in the relative risk of breast cancer may occur and that the risk is related to increasing duration of estrogen use had a 70% greater relative risk of breast cancer than controls. That study, however, examined use of a variety of estrogen preparations of which estradiol was the most frequently prescribed. In addition, women who took progestins did not demonstrate a decreased risk of breast cancer and may even have been at higher risk.

The Toronto Breast Cancer Study has reported that women who receive unopposed conjugated estrogens for less than 15 years are not at increased risk of breast cancer. In that study, an increase in the risk of breast cancer for women who used conjugated estrogens form more than 15 years was not ruled out.

The Case Control Surveillance Study reported "no evidence that the use of unopposed conjugated estrogens increases the risk of breast cancer, even after long duration of use or long latent intervals, but the possibility of a modest increase (less than doubling) could not be excluded."

Follow-up data to the Nurses' Health Study of 1992 concluded, however, that there is an increased risk of breast cancer in women taking estrogen replacement therapy and that the risk is not reduced by concurrent use of progestins. (In that study, greater risk was associated with advanced age and prolonged duration of hormonal therapy.)

A study of middle-aged women in the Puget Sound area concluded that "on the whole, the use of estrogen with progestin HRT [hormone replacement therapy] does not appear to be associated with an increased risk of breast cancer in middle-aged women."

A significant increase in the incidence of breast cancer in beagle dogs in addition to an apparent increase in the incidence of endometrial cancer in rhesus monkeys was noted in early animal carcinogenicity studies.

International long-term studies designed to assess the risk of medroxyprogesterone in humans, sponsored by the World Health organization, failed to find an increased risk of cancer in users of medroxyprogesterone. Overall, there was no significant increase in the risk of breast cancer, cervical cancer, or epithelial ovarian cancer. Data from these studies did, however, support a significant (8 fold) reduction in the incidence of endometrial cancer among medroxyprogesterone users.

A New Zealand study suggested that women taking depot medroxyprogesterone acetate may be at higher risk for breast cancer during the first 5 years, but therapy for more than 5 years confers no increased risk of breast cancer.

A prospective cohort study (11 years) of 37,105 women by Gapstur et al evaluated the histology of the breast cancer in women with ever HRT use. Little evidence of association was found between duration of ever HRT use and the incidence of ductal carcinoma in situ or invasive ductal/lobular carcinoma. The duration of ever HRT use was associated with risk of invasive carcinoma with a favorable prognosis [relative risk (RR) = 1.81, 95% confidence interval (CI), 1.07 to 3.07 for HRT use less than or equal to 5 years and RR = 2.65, CI, 1.32 to 5.23 for HRT use > 5 years, p = 0.005]. The relative risk of invasive carcinoma with a favorable prognosis for current users (adjusted for age and other risk factors) was 4.42, CI, 2.00 to 9.76 for less than or equal to 5 years and 2.63, CI 1.18 to 5.89 for > 5 years). Risk of invasive ductal or lobular carcinoma for current users less than or equal to 5 years was RR = 1.38, CI, 1.03 to 1.85.[Ref]

Oncologic side effects of unopposed estrogen therapy have included an increased risk of endometrial carcinoma and breast cancer.[Ref]

Gastrointestinal

Gastrointestinal side effects of conjugated estrogen therapy have included nausea and vomiting. Some studies have demonstrated a 2 to 4 fold increase in gallbladder disease in postmenopausal women taking estrogen therapy.

Gastrointestinal side effects of medroxyprogesterone have included nausea, abdominal pain, bloating, and anorexia in up to 5% of patients treated.

Postmarketing reports have included ischemic colitis.[Ref]

Cases of oral pigmentation and ischemic colitis have been reported rarely.[Ref]

Genitourinary

Withdrawal bleeding is a common complaint among postmenopausal women receiving sequential (10 to 14 days per cycle) medroxyprogesterone therapy. In postmenopausal women receiving continuous medroxyprogesterone and estrogen therapy, 75% or more are amenorrheic by one year of therapy.

In women receiving medroxyprogesterone for contraception, more than 50% are amenorrheic by one year of therapy.

In women on estrogen replacement therapy, the addition of medroxyprogesterone or other progestin for at least 10 to 14 days of each cycle significantly reduces the risk of endometrial hyperplasia and, thus, the risk of endometrial carcinoma. Low-dose continuous medroxyprogesterone therapy also reduces the risk of endometrial hyperplasia associated with the use of unopposed estrogen.

In patients in whom abnormal bleeding persists or is severe, the possibility of an organic pathology should be considered and ruled out.[Ref]

Genitourinary side effects of conjugated estrogens-medroxyprogesterone have included mastodynia (12% to 38%). Dysmenorrhea and pelvic pain have also been reported.

Conjugated estrogens may also cause abnormal uterine bleeding (which must be carefully distinguished from bleeding related to endometrial carcinoma). In addition, conjugated estrogens may increase the size of preexisting uterine leiomyomata. Several cases of pseudoincontinence (excessive vaginal discharge perceived by patients as urinary incontinence) have been reported in premenopausal women who have undergone hysterectomy oophorectomy and received postoperative conjugated estrogens.

Genitourinary side effects of medroxyprogesterone have included primarily menstrual changes such as amenorrhea, irregular bleeding, spotting, and heavy bleeding. Changes in libido and anorgasmia may also occur.[Ref]

Endocrine

Cushing's syndrome is uncommon and appears to be associated with a long duration of therapy and moderate to high doses of medroxyprogesterone. Doses used for hormonal replacement therapy and for long-term contraception are not associated with Cushing's syndrome.

Medroxyprogesterone has mild glucocorticoid activity. In cases of medroxyprogesterone induced Cushing's syndrome, low cortisol and adrenocorticotrophic hormone (ACTH) levels with a reduced pituitary-adrenal reserve have been documented. Acute adrenal insufficiency may ensure following withdrawal of medroxyprogesterone.[Ref]

Endocrine side effects of estrogen have included increased levels of thyroxin-binding globulin, leading to an increase in total thyroid serum levels and a decrease in resin uptake of T3. Free thyroid hormone levels remain unchanged. Other endocrine effects include decreased fasting plasma glucose.

Endocrine side effects of medroxyprogesterone have included breast tenderness, galactorrhea with or without hyperprolactinemia, prevention of lactation, hirsutism, and Cushing's syndrome.[Ref]

Dermatologic

Dermatologic side effects of conjugated estrogens have included pruritus and rash (5% to 10%).

Dermatologic side effects of medroxyprogesterone have included acne, reduced hair growth, alopecia, melasma, chloasma, rash, excessive sweating, dry skin, scleroderma, erythema multiforme, and erythema nodosum. Melasma may persist following discontinuation of therapy.[Ref]

Musculoskeletal

Conflicting data concerning the effects of medroxyprogesterone on bone mineral density have been reported.

In one study, women 25 to 51 years of age receiving medroxyprogesterone 150 mg intramuscularly every three months for five or more years for long-term contraception had a reduction in bone mineral density compared with premenopausal controls. However, bone mineral density in the treatment group was still significantly greater than that observed in postmenopausal controls.

A study of 200 women who received medroxyprogesterone 150 mg intramuscularly every three months for a median duration of 12 years (range 2 to 26 years) reported that bone density was significantly reduced in medroxyprogesterone users. However, bone mineral density in women starting depot medroxyprogesterone after the age of 20 years and using it for 15 or fewer years was greater than the remainder of the cohort.

A study to determine the potential for postmenopausal fracture due to residual effects of depot medroxyprogesterone in former users reported the risk to be small and unlikely to have substantial impact in postmenopausal women. No significant differences in bone density were found, however, women who had used depot medroxyprogesterone for greater than 2 years had a trend toward lower bone densities.

Bone density in 185 women receiving long-term depot medroxyprogesterone for a mean of 5 years (range of 1-16 years) was only minimally below the normal population despite decreased estrogen levels.[Ref]

Musculoskeletal side effects of medroxyprogesterone have included changes in bone mineral density. Such effect are thought to be due to medroxyprogesterone induced estrogen deficiency. Arthralgias and leg cramps have also been reported.[Ref]

Nervous system

Nervous system side effects have included headache, migraine, dizziness, mental depression, exacerbation of chorea, mood disturbances, anxiety, irritability, exacerbation of epilepsy, dementia, and growth potentiation of benign meningioma. A case of chorea has been reported in association with conjugated estrogen therapy.[Ref]

Hepatic

Hepatic side effects of estrogen therapy have included cases of focal nodular hyperplasia, liver cell adenomas, hepatic hemangiomas and well differentiated hepatocellular carcinomas.

Hepatic side effects associated with medroxyprogesterone therapy have included elevations in liver function tests, jaundice, cholestatic jaundice, and cholelithiasis.[Ref]

Many of the reports of hepatic tumors have occurred in women taking long-term oral contraceptives. However, some tumors have been reported in women taking isolated estrogen therapy.[Ref]

Hypersensitivity

Hypersensitivity side effects of conjugated estrogen have included anaphylaxis. Some of these reactions may have been associated with the dyes contained in some conjugated estrogen formulations.

Hypersensitivity side effects of medroxyprogesterone have included urticaria, angioneurotic edema, and anaphylaxis or anaphylactoid reactions[Ref]

Respiratory

Rare cases of exacerbations of pulmonary lymphangioleiomyomatosis have occurred. In addition, combinations of high-dose conjugated estrogens and progestin have been reported to increase the hypoxic ventilatory response.[Ref]

Respiratory side effects of conjugated estrogens-medroxyprogesterone have included pharyngitis (11% to 13%), rhinitis and sinusitis (5% to 8%).[Ref]

Other

Other side effects of estrogen therapy have included a possible increase the risk of "fibrocystic breast disease" by as much as twofold.[Ref]

Psychiatric

Psychiatric side effects of conjugated estrogens have included cases of rapid mood cycling in patients with severe depression.[Ref]

Hematologic

Hematologic side effects of conjugated estrogens have included hypercoagulability.

Hematologic side effects of medroxyprogesterone have included rare reports of hematologic dyscrasias. Hypercoagulability with or without thromboembolic activity has been reported.[Ref]

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

Usual Adult Dose for Atrophic Vaginitis

Regimen 1 (Cyclic Combined Estrogen-Progestin Therapy): Conjugated estrogens 0.625 mg orally once a day AND Medroxyprogesterone acetate 5 mg orally once a day for 14 days per month.

-or-

Regimen 2 (Continuous Combined Estrogen-Progestin Therapy): Conjugated estrogens 0.45 mg orally once a day AND Medroxyprogesterone acetate 1.5 mg orally once a day or conjugated estrogens 0.625 mg orally once a day AND Medroxyprogesterone acetate 2.5 mg or 5 mg orally once a day.

In general, the duration of hormone therapy for the treatment of postmenopausal symptoms like atrophic vaginitis, kraurosis vulvae, or atrophic urethritis should be limited. Treatment for one to five years is generally sufficient.

Precautions

Regimen 1 and Regimen 2 (the combined regimens) are contraindicated in patients with established hyperlipidemia or ischemic heart disease.

Combined hormone replacement therapy should not be initiated or continued in women for prevention of coronary heart disease because the health risks may exceed the benefits. The Women's Health Initiative (WHI) study was terminated early because a significantly higher risk of invasive breast cancer, stroke and myocardial infarction was associated with long-term use of conjugated estrogens/medroxyprogesterone. In addition, the results of the Heart and Estrogen/progestin Replacement Study Follow-up (HERS II) have indicated that long-term use increases the risk of thromboembolism, heart attacks, and biliary surgery.

Conjugated estrogens / medroxyprogesterone Pregnancy Warnings

Specific categories of malformations associated with conjugated estrogens use include cardiovascular defects, hypospadias, eye and ear malformations, and Down syndrome. In the Collaborative Perinatal Project involving 50,282 pregnancies, 866 first trimester exposures to progestational agents were documented. Of these, there were 130 exposures to medroxyprogesterone. The incidence of cardiovascular defects was significantly increased, with a standardized relative risk of 1.8. While not statistically significant, data also suggested an increased risk of hypospadias among offspring of women treated with progestational agents in the first trimester. In the Michigan Medicaid Birth Defects Study involving 229,101 pregnancies from 1985 to 1992, there were 327 first trimester exposures to medroxyprogesterone (written communication, Franz Rosa, MD, Food and Drug Administration, 1994). Overall, 15 cases of birth defects were observed (13 cases expected). Seven cases of cardiovascular defects occurred compared with 3 cases expected, representing a significant increase in the incidence of cardiovascular defects. Of interest, in all seven cases, the indication for maternal treatment with medroxyprogesterone was amenorrhea and not threatened spontaneous abortion. No cases of hypospadias occurred. Other studies have failed to find an association between first trimester use of progestational agents and congenital anomalies, including cardiovascular and genitourinary defects. In addition, follow-up studies have concluded that the use of medroxyprogesterone during pregnancy does not affect the long-term growth and development of children. There are data which suggest an increase in the frequency of low birth weight among infants of accidental pregnancies during contraception with intramuscular medroxyprogesterone.

Conjugated estrogens-medroxyprogesterone has not been formally assigned to a pregnancy category by the FDA. Conjugated estrogens and medroxyprogesterone have been assigned to pregnancy Risk Factor X by Briggs et al. Animal studies have not been reported. There are no controlled data in human pregnancy. Conjugated estrogens-medroxyprogesterone is considered contraindicated during pregnancy.

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